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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
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↗
PubMed2005

Predictors of endothelial dysfunction in young women with polycystic ovary syndrome.

CONTEXT: Women with polycystic ovary syndrome (PCOS) may be at increased risk for cardiovascular disease. Endothelial dysfunction is an early marker of atherosclerosis. OBJECTIVES: The objectives of this study were to 1) compare endothelial function in young women with PCOS and regularly menstruating control women, and 2) to identify the determinants of endothelial function and investigate its relationship with body mass index in women with PCOS. DESIGN: This was a cross-sectional study. SETTING: This study was conducted at a tertiary cardiovascular research center. PATIENTS: Sixty-two young women with PCOS (mean age, 22.7 yr) and 17 control women, matched as a group for age and body mass index, were studied. Twenty-three women with PCOS were lean, 21 were overweight, and 18 were obese. MAIN OUTCOME MEASURES: Endothelium-dependent and -independent vascular function was assessed by measuring flow-mediated dilation (FMD) and nitrate-mediated dilation in the brachial artery (diameter change during hand hyperemia and after sublingual glyceryl trinitrate administration, respectively). RESULTS: FMD and nitrate-mediated dilation were significantly lower in PCOS than in control women (reduced by approximately 50 and 25%, respectively; both P < 0.0005). Insulin resistance, total testosterone, and total cholesterol were independent predictors of FMD, accounting for 21, 10, and 9% of the variance, respectively (P < 0.005 for all). A trend of deterioration in FMD from lean to overweight and obese PCOS women was observed, but differences among groups were not statistically significant. CONCLUSIONS: Women with PCOS have significant endothelial dysfunction at an early age (i.e. early 20s), and largely independent of obesity. This suggests that women with PCOS are at increased risk for early onset cardiovascular disease and may gain particular benefit from measures to improve endothelial function.

Adult↗
PubMed2005

G protein beta interacts with the glucocorticoid receptor and suppresses its transcriptional activity in the nucleus.

Extracellular stimuli that activate cell surface receptors modulate glucocorticoid actions via as yet unclear mechanisms. Here, we report that the guanine nucleotide-binding protein (G protein)-coupled receptor-activated WD-repeat Gbeta interacts with the glucocorticoid receptor (GR), comigrates with it into the nucleus and suppresses GR-induced transactivation of the glucocorticoid-responsive genes. Association of Ggamma with Gbeta is necessary for this action of Gbeta. Both endogenous and enhanced green fluorescent protein (EGFP)-fused Gbeta2 and Ggamma2 proteins were detected in the nucleus at baseline, whereas a fraction of EGFP-Gbeta2 and DsRed2-GR comigrated to the nucleus or the plasma membrane, depending on the exposure of cells to dexamethasone or somatostatin, respectively. Gbeta2 was associated with GR/glucocorticoid response elements (GREs) in vivo and suppressed activation function-2-directed transcriptional activity of the GR. We conclude that the Gbetagamma complex interacts with the GR and suppresses its transcriptional activity by associating with the transcriptional complex formed on GR-responsive promoters.

Active Transport, Cell Nucleus↗
PubMed2005

Monoamine oxidase-A is a major target gene for glucocorticoids in human skeletal muscle cells.

Skeletal myopathy is a common complication of endogenous and exogenous glucocorticoid excess, yet its pathogenetic mechanisms remain unclear. There is accumulating evidence that mitochondrial dysfunction and oxidative stress are involved in this process. To explore the glucocorticoid-induced transcriptional adaptations that may affect mitochondrial function in skeletal muscle, we studied gene expression profiles in dexamethasone-treated primary human skeletal myocytes using a cDNA microarray, which contains 501 mitochondria-related genes. We found that monoamine oxidase A (MAO-A) was the most significantly up-regulated gene. MAO-A is the primary enzyme metabolizing catecholamines and dietary amines, and its role in skeletal muscle remains largely unexplored. Dexamethasone induced dose- and time-dependent increases of MAO-A gene and protein expression, while its effects on MAO-B were minimal. Both the glucocorticoid receptor (GR) and the Sp1 transcription factor were required for dexamethasone-induced MAO-A mRNA expression, as blockade of the GR with RU 486 or ablation of Sp1 binding with mithramycin abrogated MAO-A mRNA induction. The observed dexamethasone effect was biologically functional, as this steroid significantly increased MAO-mediated hydrogen peroxide production. We suggest that MAO-A-mediated oxidative stress can lead to cell damage, representing a novel pathogenetic mechanism for glucocorticoid-induced myopathy and a potential target for therapeutic intervention.

Adolescent↗
PubMed2005

Effects of dehydroepiandrosterone and alprazolam on hypothalamic-pituitary responses to exercise.

CONTEXT: The hypothalamic-pituitary-adrenal axis (HPA) is restrained by activation of gamma-amino-butyric acid receptors. Alprazolam (APZ) and dehydroepiandrosterone (DHEA) are purported to be gamma-amino-butyric acid agonists and antagonists, respectively. OBJECTIVE: Our objective was to examine the effects of APZ and DHEA alone and in combination on HPA axis activity. DESIGN: This was a double-blind, crossover, placebo-controlled study. SETTING: The study setting was the general community. PARTICIPANTS: Subjects consisted of 15 men (age, 20-45 yr) with a body mass index of 20-25 kg/m2. INTERVENTIONS: DHEA (100 mg/d) or placebo was given for 4 wk, followed by a 2-wk washout; participants ingested 0.5 mg APZ or placebo 10 and 2 h before high-intensity exercise. OUTCOME MEASURES: We measured basal and exercise-induced ACTH, arginine vasopressin (AVP), cortisol, DHEA, and GH responses. It was hypothesized that DHEA would enhance and APZ would blunt exercise-induced ACTH and cortisol release. RESULTS: DHEA significantly increased the AVP response to exercise (P < 0.01). APZ treatment significantly increased basal GH and blunted plasma cortisol, ACTH, AVP, and DHEA responses to exercise (P < 0.05). DHEA and APZ in combination significantly increased the GH response to exercise (P < 0.01). CONCLUSIONS: DHEA may alter a subset of receptors involved in AVP release. Together DHEA and APZ may up-regulate GH during exercise by blunting a suppressive (HPA axis) and potentiating an excitatory (glutamate receptor) system.

Adjuvants, Immunologic↗
PubMed2005

Cardiac implications of increased arterial entry and reversible 24-h central and peripheral norepinephrine levels in melancholia.

The mortality of chronic heart failure (CHF) doubles either when CHF patients are depressed or when their plasma norepinephrine (NE) level exceeds those of controls by approximately 40%. We hypothesized that patients with major depression had centrally driven, sustained, stress-related, and treatment-reversible increases in plasma NE capable of increasing mortality in CHF patients with depression. We studied 23 controls and 22 medication-free patients with melancholic depression. In severely depressed patients before and after electroconvulsive therapy (ECT), we measured cerebrospinal fluid (CSF) NE, plasma NE, plasma epinephrine (EPI), and plasma cortisol hourly for 30 h. In mildly-to-moderately depressed melancholic patients, we assessed basal and stress-mediated arterial NE appearance. Severely depressed patients had significant increases in mean around-the-clock levels of CSF NE (P < 0.02), plasma NE (P < 0.02), plasma EPI (P < 0.02), and plasma cortisol (P < 0.02). CSF NE, plasma NE, and cortisol all rose together throughout the night and peaked in the morning. Each fell to control values after ECT. Mildly-to-moderately melancholic patients also had increased basal (P < 0.05) and stress-related (P < 0.03) arterial NE-appearance rates. Severely melancholic depressed, medication-free patients had around-the-clock increases in plasma NE levels capable of increasing mortality in CHF. Twenty-four-hour indices of central noradrenergic, adrenomedullary, and adrenocortical secretion were also elevated. Concurrent diurnal rhythms of these secretions could potentiate their cardiotoxicity. Even mildly-to-moderately depressed melancholic patients had clinically relevant increases in the arterial NE-appearance rate. These findings will not apply to all clinical subtypes of major depression.

Adult↗
PubMed2005

Sex-related differences in stimulated hypothalamic-pituitary-adrenal axis during induced gonadal suppression.

CONTEXT: Sex-related differences in the stress response are well described in the animal literature but in humans are inconsistent and appear to reflect both the method used to stimulate the hypothalamic-pituitary-adrenal (HPA) axis and the age of the subjects. Sex-related differences in reproductive steroid levels further confound efforts to define the specific role of the sex of the individual in stress axis responsivity. OBJECTIVE: The aim of this study was to address this role independent of differences in reproductive steroid levels. We compared HPA axis response to pharmacological (CRH) and physiological (exercise) stressors in two groups of young to middle-aged (18-45 yr) men (n = 10 and 8) and women (n = 12 and 13) undergoing gonadal suppression with leuprolide acetate (monthly im injection of 7.5 mg in men and 3.75 mg in women). DESIGN: Exercise and CRH stimulation tests were performed during induced hypogonadal conditions. SETTING: The study was conducted at a National Institutes of Health Clinical Center Outpatient Clinic. PATIENT OR OTHER PARTICIPANTS: Male and female normal volunteers participated in the study. MAIN OUTCOME MEASURES: The main outcome measures were stimulated ACTH and cortisol levels. RESULTS: Both CRH (1 microg/kg) stimulation and graded treadmill exercise stimulation occurred in the month after the second leuprolide injection to ensure gonadal suppression. Despite the absence of sex differences in estradiol or testosterone at the time of testing, men showed increased stimulated ACTH (repeated-measures ANOVA for CRH, P < 0.005) and cortisol (repeated-measures ANOVA for exercise, P < 0.05) compared with women. Among the summary measures, area under the curve (AUC) for cortisol was significantly greater in men than women after exercise. Although the AUC for ACTH was not significantly different across sexes, the initial AUC (0-30 min) was significantly greater in men for both procedures. No significant sex differences were found in a measure of adrenal responsivity, the cortisol to ACTH ratio, for either procedure. Cortisol-binding globulin levels did not differ between men and women and were not correlated with stimulated HPA axis measures. These data confirm earlier reports of sex differences in stimulated HPA axis activity and demonstrate that these differences exist even under induced hypogonadal conditions (i.e. in the absence of characteristic differences in reproductive steroids).

Adolescent↗
PubMed2005

A novel point mutation in the ligand-binding domain (LBD) of the human glucocorticoid receptor (hGR) causing generalized glucocorticoid resistance: the importance of the C terminus of hGR LBD in conferring transactivational activity.

Glucocorticoid resistance is a rare, familial or sporadic condition characterized by partial end-organ insensitivity to glucocorticoids. The clinical spectrum of the condition is broad, ranging from completely asymptomatic to severe hyperandrogenism and/or mineralocorticoid excess. The molecular basis of glucocorticoid resistance has been ascribed to mutations in the human glucocorticoid receptor-alpha (hGRalpha) gene, which impair one or more of the molecular mechanisms of GR action, thus altering tissue sensitivity to glucocorticoids. We identified a new case of generalized glucocorticoid resistance in a young woman who presented with a long-standing history of fatigue, anxiety, hyperandrogenism, and hypertension. The disease was caused by a novel, heterozygous mutation (T-->C) at nucleotide position 2318 (exon 9) of the hGRalpha gene, which resulted in substitution of leucine by proline at amino acid position 773 in the ligand-binding domain of the receptor. We systematically investigated the molecular mechanisms through which the natural hGRalphaL773P mutant impaired glucocorticoid signal transduction. Compared with the wild-type hGRalpha, hGRalphaL773P demonstrated a 2-fold reduction in the ability to transactivate the glucocorticoid-inducible mouse mammary tumor virus promoter, exerted a dominant negative effect on the wild-type receptor, had a 2.6-fold reduction in the affinity for ligand, showed delayed nuclear translocation (30 vs. 12 min), and, although it preserved its ability to bind to DNA, displayed an abnormal interaction with the GR-interacting protein 1 coactivator in vitro. We conclude that the carboxyl terminus of the ligand-binding domain of hGRalpha is extremely important in conferring transactivational activity by altering multiple functions of this composite transcription factor.

Adult↗
PubMed2005

Children experience cognitive decline despite reversal of brain atrophy one year after resolution of Cushing syndrome.

Adults with Cushing syndrome frequently develop brain atrophy, memory impairment, and depression, with partial to complete resolution after cure. The effect of excess glucocorticoid exposure on the brain of children has not been systematically studied. Eleven children (six girls, five boys; ages, 8-16 yr) with endogenous Cushing syndrome seen at the National Institutes of Health Clinical Center from 1999-2000 and 10 healthy age- and sex-matched control subjects were studied. Cognitive and psychological evaluations and magnetic resonance imaging of the brain were done before and 1 yr after cure for patients with Cushing syndrome and once for controls. The estimated duration of Cushing syndrome was 4.4 +/- 1.2 yr. When compared with control subjects, children with Cushing syndrome had significantly smaller cerebral volumes (P < 0.001), larger ventricles (P = 0.02), and smaller amygdala (P = 0.004). At baseline, there were no significant differences in IQ between the two groups, and no psychopathology was identified. Despite reversal of cerebral atrophy 1 yr after surgical cure (total cerebral volume, 947 +/- 94 vs.1050 +/- 74 ml, P < 0.001; ventricular volume, 21.4 +/- 12.5 vs. 14.5 +/- 11.6 ml, P < 0.001), children with Cushing syndrome experienced a significant (P < 0.05) decline in Wechsler IQ scores (Full Scale, 112 +/- 19 vs. 98 +/- 14) and a decline in school performance, without any associated psychopathology. The effect of glucocorticoid excess on the brain of children appears to be different from adults. Despite rapid reversibility of cerebral atrophy, children experience a significant decline in cognitive function 1 yr after correction of hypercortisolism.

Adolescent↗
PubMed2005

Peripheral injection of sauvagine prevents repeated colorectal distension-induced visceral pain in female rats.

We investigated the effects of peripheral injection of sauvagine, a CRF2>CRF1 receptor (corticotropin-releasing factor) agonist compared with CRF, on two sets of tonic colorectal distension (CRDs 30, 40, 50 mmHg, 3-min on/off)-induced visceromotor response (VMR) measured as area under the curve (AUC) of abdominal muscle contraction in conscious female rats. Sauvagine (10 or 20 microg/kg, s.c.) abolished the 226.7+/-64.3% and 90.4+/-38.1% increase in AUC to the 2nd CRD compared with the 1st CRD (performed 30 min before) in female Fisher and Sprague-Dawley (SD) rats, respectively. CRF had no effect while the CRF1 antagonist, antalarmin (20 mg/kg, s.c.), alone or with sauvagine, blocked the enhanced response to the 2nd CRD, performed 60 min after the 1st CRD, and reduced further the AUC by 33.5+/-23.3% and 63.5+/-7.2%, respectively in Fisher rats. These data suggest that peripheral CRF2 receptor activation exerts antinociceptive effects on CRD-induced visceral pain, whereas CRF1 contributes to visceral sensitization.

Abdominal Pain↗
PubMed2005

Major depression is associated with significant diurnal elevations in plasma interleukin-6 levels, a shift of its circadian rhythm, and loss of physiological complexity in its secretion: clinical implications.

BACKGROUND: Major depressive disorder (MDD) is associated with increased risk for premature coronary heart disease and bone loss. Single time measurements of plasma IL-6, a good predictor of future risk for both cardiovascular disease and osteoporosis, revealed significant elevations in depressed patients. The objective of this study was to rigorously compare plasma IL-6 levels, measured over 24 h, in MDD patients and healthy controls. Given the activating role of IL-6 on the hypothalamic-pituitary-adrenal (HPA) axis, and the relevance of its dysregulation in MDD, we also analyzed the relations between IL-6 and cortisol levels. METHODS: We studied nine patients and nine controls, individually matched by gender, age (+/-5 yr), body mass index (+/-2 kg/m2), and menstrual cycle phase. Diagnosis of MDD was confirmed by structured clinical interview based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I diagnostic criteria. Self-reported mood ratings were assessed by multiple visual analog scales. The rhythmicity and complexity of IL-6 and cortisol secretion were tested by cosinor analyses, approximate entropy (ApEn) and cross-ApEn algorithms. RESULTS: MDD patients had significant mean IL-6 elevations from 1000-1200 h and at 1500 h (P ranging from <0.05 to <0.01) vs. controls. In addition, in MDD, the circadian rhythm of IL-6 was shifted by 12 h, and its physiological complexity was reduced, with no difference in the cross-ApEn of IL-6 and cortisol between the two groups, and significant time-lagged correlations only in the controls. IL-6 levels correlated significantly with mood ratings. CONCLUSIONS: We report profound morning elevations of plasma IL-6 and a reversal of its circadian rhythm in MDD patients, in the absence of hypercortisolism. These findings may be relevant to the increased risk for coronary heart disease and bone loss in MDD.

Adult↗
PubMed2005

Increased prevalence of chronic autoimmune (Hashimoto's) thyroiditis in children and adolescents with vitiligo.

BACKGROUND: An increased prevalence of autoimmune (Hashimoto's) thyroiditis in adult patients with vitiligo has been described. This association has scarcely been studied in children. OBJECTIVE: We sought to assess children and adolescents with vitiligo for autoimmune thyroid disorder and to identify any predisposing factors of this association. METHODS: In all, 54 children and adolescents (23 boys, 31 girls; mean age 11.4 years) with known vitiligo were studied by physical examination and laboratory studies. RESULTS: Four patients with vitiligo were already known to have Hashimoto's thyroiditis. In 9 of the remaining 50 patients, autoimmune thyroiditis was revealed at the time of the investigation. Of the 54 patients with vitiligo, 13 (24.1%) had autoimmune thyroiditis as compared with 9.6% of school-aged children from an iodine-replete area of Greece ( P = .002). There was no association between thyroiditis and clinical type of vitiligo, age at onset, mean duration of vitiligo, or sex. CONCLUSIONS: Hashimoto's thyroiditis is 2.5 times more frequent among children and adolescents with vitiligo than in a healthy age- and sex-matched population. It usually follows the onset of vitiligo. We propose that children and adolescents with vitiligo should be screened annually for thyroid dysfunction, particularly autoimmune thyroiditis.

Adolescent↗
PubMed2005

Increased plasma adiponectin concentrations in poorly controlled patients with phenylketonuria normalize with a strict diet: evidence for catecholamine-mediated adiponectin regulation and a complex effect of phenylketonuria diet on atherogenesis risk factors.

Adiponectin (Adpn), an adipose tissue-derived hormone, prevents endothelial inflammation and early atherogenesis. Classic phenylketonuria (PKU), an inborn error of phenylalanine (Phe) metabolism, results in a reduction of catecholamine biosynthesis and requires treatment with lifelong low-Phe diet to prevent mental dysfunction and allow proper intellectual development. In this study, we evaluated the effect of the quality of PKU diet on plasma Adpn concentrations and related biochemical indices of endothelial dysfunction and atherogenesis. Patients with PKU were divided into groups A (n = 18), who were on a strict diet, and B (n = 18), who were on a loose diet, after evaluation of their 30-day dietetic diaries and measurement of Phe blood concentrations. Twenty healthy children of similar ages and body mass indexes served as controls (group C). Group A patients had normal circulating catecholamines and Adpn and decreased tumor necrosis factor alpha concentrations and low-density lipoprotein cholesterol/apolipoprotein B ratio compared with groups B and C. Despite these favorable parameters, however, homocysteine concentration was twice as high in group A compared with groups B and C. Interestingly, group B patients under loose dietary control had significantly elevated Adpn concentrations compared with groups A and C and increased tumor necrosis factor alpha and an unfavorable lipid profile, but normal levels of homocysteine. These data support the hypothesis that catecholamines inhibit Adpn secretion and that the elevated Adpn of the poorly controlled patients might moderate their risk for endothelial dysfunction and atherogenesis. Homocysteine production appears to be unfavorably affected by a strict PKU diet, diverging from the rest of the atherogenesis risk factors, which were improved in the well-controlled patients.

Adiponectin↗
PubMed2005

Sleep apnea is a manifestation of the metabolic syndrome.

Obstructive sleep apnea (OSA) is a prevalent disorder particularly among middle-aged, obese men, although its existence in women as well as in lean individuals is increasingly recognized. Despite the early recognition of the strong association between OSA and obesity, and OSA and cardiovascular problems, sleep apnea has been treated as a 'local abnormality' of the respiratory track rather than as a 'systemic illness.' In 1997, we first reported that the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNFalpha) were elevated in patients with disorders of excessive daytime sleepiness (EDS) and proposed that these cytokines were mediators of daytime sleepiness. Also, we reported a positive correlation between IL-6 or TNFalpha plasma levels and the body-mass-index (BMI). In subsequent studies, we showed that IL-6, TNFalpha, and insulin levels were elevated in sleep apnea independently of obesity and that visceral fat, was the primary parameter linked with sleep apnea. Furthermore, our findings that women with the polycystic ovary syndrome (PCOS) (a condition associated with hyperandrogenism and insulin resistance) were much more likely than controls to have sleep disordered breathing (SDB) and daytime sleepiness, suggests a pathogenetic role of insulin resistance in OSA. Other findings that support the view that sleep apnea and sleepiness in obese patients may be manifestations of the Metabolic Syndrome, include: obesity without sleep apnea is associated with daytime sleepiness; PCOS and diabetes type 2 are independently associated with EDS after controlling for SDB, obesity, and age; increased prevalence of sleep apnea in post-menopausal women, with hormonal replacement therapy associated with a significantly reduced risk for OSA; lack of effect of continuous positive airway pressure (CPAP) in obese patients with apnea on hypercytokinemia and insulin resistance indices; and that the prevalence of the metabolic syndrome in the US population from the Third National Health and Nutrition Examination Survey (1988-1994) parallels the prevalence of symptomatic sleep apnea in general random samples. Finally, the beneficial effect of a cytokine antagonist on EDS in obese, male apneics and that of exercise on SDB in a general random sample, supports the hypothesis that cytokines and insulin resistance are mediators of EDS and sleep apnea in humans. In conclusion, accumulating evidence provides support to our model of the bi-directional, feed forward, pernicious association between sleep apnea, sleepiness, inflammation, and insulin resistance, all promoting atherosclerosis and cardiovascular disease.

Comorbidity↗
PubMed2005

Vpr protein of human immunodeficiency virus type 1 binds to 14-3-3 proteins and facilitates complex formation with Cdc25C: implications for cell cycle arrest.

Vpr and selected mutants were used in a Saccharomyces cerevisiae two-hybrid screen to identify cellular interactors. We found Vpr interacted with 14-3-3 proteins, a family regulating a multitude of proteins in the cell. Vpr mutant R80A, which is inactive in cell cycle arrest, did not interact with 14-3-3. 14-3-3 proteins regulate the G(2)/M transition by inactivating Cdc25C phosphatase via binding to the phosphorylated serine residue at position 216 of Cdc25C. 14-3-3 overexpression in human cells synergized with Vpr in the arrest of cell cycle. Vpr did not arrest efficiently cells not expressing 14-3-3sigma. This indicated that a full complement of 14-3-3 proteins is necessary for optimal Vpr function on the cell cycle. Mutational analysis showed that the C-terminal portion of Vpr, known to harbor its cell cycle-arresting activity, bound directly to the C-terminal part of 14-3-3, outside of its phosphopeptide-binding pocket. Vpr expression shifted localization of the mutant Cdc25C S216A to the cytoplasm, indicating that Vpr promotes the association of 14-3-3 and Cdc25C, independently of the presence of serine 216. Immunoprecipitations of cell extracts indicated the presence of triple complexes (Vpr/14-3-3/Cdc25C). These results indicate that Vpr promotes cell cycle arrest at the G(2)/M phase by facilitating association of 14-3-3 and Cdc25C independently of the latter's phosphorylation status.

14-3-3 Proteins↗
PubMed2005

Glucocorticoid-induced osteoporosis: from basic mechanisms to clinical aspects.

Glucocorticoid (GC)-induced osteoporosis (GCOP) is the most common cause of osteoporosis in adults aged 20-45 years as well as the most common cause of iatrogenic osteoporosis. GC excess, either endogenous or exogenous, induces bone loss in 30-50% of cases. Indeed, bone loss leading to fractures is perhaps the most incapacitating, sometimes partially irreversible, complication of GC therapy. Nevertheless, GCOP is often underdiagnosed and left untreated. The following article provides an update on the cellular and molecular mechanisms implicated in the pathophysiology of GC-induced bone loss, as well as some guidelines on diagnostic, preventive and therapeutic strategies for this medical condition, in an effort to promote a better knowledge and greater awareness of GCOP by both the patient and the physician.

Animals↗
PubMed2005

Cytokine dysregulation, inflammation and well-being.

Cytokines mediate and control immune and inflammatory responses. Complex interactions exist between cytokines, inflammation and the adaptive responses in maintaining homeostasis, health, and well-being. Like the stress response, the inflammatory reaction is crucial for survival and is meant to be tailored to the stimulus and time. A full-fledged systemic inflammatory reaction results in stimulation of four major programs: the acute-phase reaction, the sickness syndrome, the pain program, and the stress response, mediated by the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Common human diseases such as atopy/allergy, autoimmunity, chronic infections and sepsis are characterized by a dysregulation of the pro- versus anti-inflammatory and T helper (Th)1 versus Th2 cytokine balance. Recent evidence also indicates the involvement of pro-inflammatory cytokines in the pathogenesis of atherosclerosis and major depression, and conditions such as visceral-type obesity, metabolic syndrome and sleep disturbances. During inflammation, the activation of the stress system, through induction of a Th2 shift, protects the organism from systemic 'overshooting' with Th1/pro-inflammatory cytokines. Under certain conditions, however, stress hormones may actually facilitate inflammation through induction of interleukin (IL)-1, IL-6, IL-8, IL-18, tumor necrosis factor-alpha and C-reactive protein production and through activation of the corticotropin-releasing hormone/substance P-histamine axis. Thus, a dysfunctional neuroendocrine-immune interface associated with abnormalities of the 'systemic anti-inflammatory feedback' and/or 'hyperactivity' of the local pro-inflammatory factors may play a role in the pathogenesis of atopic/allergic and autoimmune diseases, obesity, depression, and atherosclerosis. These abnormalities and the failure of the adaptive systems to resolve inflammation affect the well-being of the individual, including behavioral parameters, quality of life and sleep, as well as indices of metabolic and cardiovascular health. These hypotheses require further investigation, but the answers should provide critical insights into mechanisms underlying a variety of common human immune-related diseases.

Animals↗