Affinity For Glucocorticoid Receptor Research Articles

PI3Kδ Inhibition Potentiates Glucocorticoids in B-lymphoblastic Leukemia by Decreasing Receptor Phosphorylation and Enhancing Gene Regulation.

Glucocorticoids are the cornerstone of B-lymphoblastic leukemia (B-ALL) therapy. Because response to glucocorticoids alone predicts overall outcomes for B-ALL, enhancing glucocorticoid potency should improve treatment. We previously showed that inhibition of the lymphoid-restricted PI3Kδ with idelalisib enhances glucocorticoid activity in B-ALL cells. Here, we show that idelalisib enhances glucocorticoid potency in 90% of primary B-ALL specimens and is most pronounced at sub-saturating doses of glucocorticoids near the EC50. Potentiation is associated with enhanced regulation of all glucocorticoid-regulated genes, including genes that drive B-ALL cell death. Idelalisib reduces phosphorylation of the glucocorticoid receptor (GR) at PI3Kδ/MAPK1 (ERK2) targets S203 and S226. Ablation of these phospho-acceptor sites enhances sensitivity to glucocorticoids with ablation of S226 in particular reducing synergy. We also show that phosphorylation of S226 reduces the affinity of GR for DNA in vitro. We propose that PI3Kδ inhibition improves glucocorticoid efficacy in B-ALL in part by decreasing GR phosphorylation, increasing DNA binding affinity, and enhancing downstream gene regulation. This mechanism and the response of patient specimens suggest that idelalisib will benefit most patients with B-ALL, but particularly patients with less responsive, including high-risk, disease. This combination is also promising for the development of less toxic glucocorticoid-sparing therapies.

SAT331 A Case Of Iatrogenic Cushing’s Syndrome Due To The Concomitant Use Of Cobicistat With An Inhaled Glucocorticoid Followed By Adrenal Insufficiency Upon Discontinuation Of Cobicistat

Abstract Disclosure: L. Noor: None. J. Mullally: None. R. Glassman: None. Cobicistat is an inhibitor of cytochrome P4503A (CYP3A) used to increase the systemic exposure of antiretroviral drugs for treatment of HIV, and because of it’s mechanism of action, can have significant drug interactions. A similar “pharmacologic booster” ritonavir has now been widely reported to cause cases of iatrogenic Cushing’s syndrome when used in combination with glucocorticoids, but the data on this risk with cobicistat is much more limited. This case describes a patient who developed florid Cushing’s syndrome while on cobicistat and inhaled glucocorticoids followed by secondary adrenal insufficiency upon discontinuation of cobicistat. A 60 year old male with past medical history of well-controlled HIV on elvitegravir, cobicistat, emtricitabine and tenofovir, asthma on chronic inhaled fluticasone/salmeterol, presented with several months of progressive abdominal distention, back pain, irritability, easy bruising, proximal muscle weakness and weight gain. On physical exam, he appeared Cushingoid with central obesity, supraclavicular fullness, dorsocervical fat pad, wide violaceous striae on his abdomen and multiple ecchymoses. Iatrogenic Cushing's syndrome was suspected and labs showed undetectable morning serum cortisol and 24 hour urine free cortisol as well as newly elevated A1C of 5.7%. DEXA scan showed osteopenia. CT abdomen pelvis showed small adrenal glands. His HIV medication was switched to a combination of bictegravir, emtricitabine and tenofovir and he subsequently developed significant fatigue, nausea, abdominal discomfort and headaches. He was started on replacement doses of prednisone and his symptoms improved significantly. The prednisone dose is being gradually tapered, with ongoing recovery of the hypothalamic-pituitary-adrenal(HPA) axis, with now low, but detectable cortisol and ACTH levels. We present a unique case of iatrogenic Cushing’s syndrome due to concomitant use of cobicistat with inhaled fluticasone and the subsequent development of secondary adrenal insufficiency upon discontinuation of cobicistat. Cobicistat is an inhibitor of CYP3A which can cause decreased metabolism of exogenous glucocorticoids resulting in HPA axis suppression and exogenous Cushing’s syndrome. Fluticasone causes more cortisol suppression than other inhaled steroids because of it’s long half-life, higher binding affinity for glucocorticoid receptors and high lipophilicity. Concomitant use of cobicistat and glucocorticoids, including inhaled fluticasone, should be avoided and clinicians should be aware of the potential for iatrogenic Cushing’s syndrome and consequent adrenal insufficiency upon discontinuation of cobicistat after use with concomitant glucocorticoids. Presentation: Saturday, June 17, 2023

The animal and cell models that uncovered FKBP51 as a regulator of glucocorticoid receptor function.

Many New World primates are glucocorticoid-resistant secondary to expression of low affinity glucocorticoid receptors. We identified the role of FKBP51 in hormone responsiveness by showing that multiple cell lines derived from New World primates share the same activities: (1) soluble cell extracts conferred low binding affinity to high affinity glucocorticoid receptors; (2) FK506 increased receptor binding in soluble cell extracts; and (3) cellular FKBP51 was elevated and FKBP52 was lower. Details of these cell lines and their availability are described. Subsequently, we showed that New World primate and human FKBP51 decreased glucocorticoid activity in heterologous COS-7 cell cultures. Future studies using the FKBP51 antagonist SAFit2 in New World primates are proposed.

A specialized Hsp90 co-chaperone network regulates steroid hormone receptor response to ligand.

SUMMARYHeat shock protein-90 (Hsp90) chaperone machinery is involved in the stability and activity of its client proteins. The chaperone function of Hsp90 is regulated by co-chaperones and post-translational modifications. Although structural evidence exists for Hsp90 interaction with clients, our understanding of the impact of Hsp90 chaperone function toward client activity in cells remains elusive. Here, we dissect the impact of recently identified higher eukaryotic co-chaperones, FNIP1/2 (FNIPs) and Tsc1, toward Hsp90 client activity. Our data show that Tsc1 and FNIP2 form mutually exclusive complexes with FNIP1, and that unlike Tsc1, FNIP1/2 interact with the catalytic residue of Hsp90. Functionally, these co-chaperone complexes increase the affinity of the steroid hormone receptors glucocorticoid receptor and estrogen receptor to their ligands in vivo. We provide a model for the responsiveness of the steroid hormone receptor activation upon ligand binding as a consequence of their association with specific Hsp90:co-chaperone subpopulations.

The expression level and binding affinity of glucocorticoid receptors in patients with Cushing’s syndrome

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

MAGI2-AS3 rs7783388 polymorphism contributes to colorectal cancer risk through altering the binding affinity of the transcription factor GR to the MAGI2-AS3 promoter.

BackgroundIt has been indicated that the single nuclear polymorphisms (SNPs) in the long noncoding RNA (lncRNA) have association with colorectal cancer (CRC) susceptibility.MethodsWe enrolled 1078 cases with CRC and 1175 age‐ and gender‐matched cancer‐free controls to explore whether the polymorphisms in MAGI2‐AS3 have associations with CRC risk. qRT‐PCR, expression quantitative trait loci (eQTL) analyses, dual‐luciferase reporter assay, chromatin immunoprecipitation (ChIP), flow cytometry, and transwell assays were performed to explore the specific mechanisms in which MAGI2‐AS3 rs7783388 variation influenced the tumorigenesis of CRC.ResultsSubjects carrying rs7783388 GG genotype presented a higher risk of CRC compared with the AG/AA genotypes. Mechanistically, we found that the functional genetic variant of rs7783388 A > G decreased binding affinity of transcription factor glucocorticoid receptor (GR) to the MAGI2‐AS3 promoter, resulting in decreased transcriptional activity that subsequently downregulated MAGI2‐AS3 expression. Furthermore, functional experiments elucidated that MAGI2‐AS3 overexpression suppressed CRC cell proliferation, migration, and invasion capacities, arrested cell cycle at G0/G1 phase, and promoted cell apoptosis.ConclusionTaken together, our study demonstrated that the potential function of MAGI2‐AS3 as a tumor suppressor for CRC, and the MAGI2‐AS3 rs7783388 polymorphism is associated with the increased susceptibility to CRC by altering the binding ability of GR to the MAGI2‐AS3 promoter.

SUN-031 Megestrol Acetate for Bodybuilding Resulting in Abrupt Hypothalamic-Pituitary Dysfunction

Introduction: Megestrol acetate (MA) is a synthetic progestin often used for appetite stimulation and weight gain in patients with cachexia related to AIDS, cancer or terminal illness. MA is frequently implicated in development of both glucocorticoid excess and adrenal insufficiency (AI) in a somewhat unpredictable manner. Less commonly reported adverse effects of MA include dysfunction of the hypothalamic pituitary axis. Few cases in literature exist regarding the use of MA in young, healthy patients and the potential clinical severity of pituitary dysfunction in this population. Case: A 24-year-old male was previously healthy but frustrated by an inability to gain muscle mass. Evaluation one-year prior was unrevealing and included a total testosterone of 1100ng/dL (264-916ng/dL). In the interim, he was prescribed MA 625/5mg for 2 months with rapid development of abdominal adiposity, depressed mood, low libido and erectile dysfunction. Repeat evaluation revealed a precipitous drop in total testosterone to 66 ng/dL at which point he self-discontinued MA. He then began to experience palpitations, sweats, poor concentration, and undesirable weight loss along with worsening symptoms of sexual and erectile dysfunction.Three months after MA discontinuation, he appeared well with physical examination and vital signs within normal limits. Surprisingly, repeat studies revealed total testosterone <3, free testosterone <0.2 (9.3 -26.5 pg/mL), LH 1.3 (1.7-8.6 mIU/mL), FSH 2.2 (1.5-12.3 mIU/mL), Prolactin 33.4 (4.0-15.2 ng/mL) as well as 8AM cortisol 2.2 ug/dL and ACTH 22.7 pg/mL. A basic metabolic panel, thyroid function studies and pituitary MRI were unremarkable. The patient was empirically placed on prednisone 5mg daily pending ACTH stimulation testing for HPA axis reassessment. Topical testosterone replacement therapy was initiated due to intolerance of hypogonadal symptoms. Discussion: MA, by virtue of affinity for glucocorticoid receptors, has the potential to cause hyperglycemia and Cushing’s syndrome. Secondary AI often results from withdrawal of MA however central AI can also occur with active administration by unclear mechanisms. Hypogonadism and hyperprolactinemia are additional under-reported adverse effects of MA with symptoms often masked by AI or elements of chronic illness. In study of men age 60-85 year on MA, a mean percentage change of ACTH -89.5%, LH -49%, TSH -14.7% and Prolactin +150% were seen from baseline after 12 weeks of therapy as was decreased cortisol. Limited data exists in young patients such as ours given limited indications for the agent’s use. Importantly, MA should be prescribed with understanding that weight gain is predominantly adipose rather than muscle mass and that its safety is limited by potential HP axis dysfunction, namely adrenal and gonadal deficiencies.

Mifepristone Treatment in Pregnant Murine Model Induced Mammary Gland Dysplasia and Postpartum Hypogalactia.

Mammary gland dysplasia and postpartum hypogalactia often occur in humans and in the livestock breeding industry. However, their underlying mechanisms are not clear yet. Mifepristone, which has a high affinity for progesterone (P4) and glucocorticoid receptors, was exploited here to induce the disorders of mammary gland development and lactation. Four strategies were devised for treating pregnant mice with mifepristone. In the first strategy, mice were administered 1.20 mg mifepristone/kg body weight (BW) on pregnancy day 4 (Pd4). In the second strategy, mifepristone was administered to mice twice, with 1.20 mg/kg BW on Pd4 and 0.40 mg/kg BW on Pd8. In the third strategy, mice were treated with a single dose of 0.40 mg mifepristone/kg BW on Pd8. In the fourth strategy, mice were administered 0.40 mg mifepristone/kg BW on Pd8 and 0.20 mg mifepristone/kg BW on Pd12. The results suggested that mifepristone administration at the dose of 1.20 mg/kg BW on Pd4 caused significant reduction in milk production on lactation day 1 (Ld1), Ld2, and Ld3, as assessed using a weigh-suckle-weigh assay. Mammary β-casein expression, milk yields, litter growth rates, gland structure, and serum concentrations of 17-β estrogen (E2), P4, prolactin (PRL), growth hormone (GH), corticosterone (CORT) and oxytocin (OT) as well as the receptors of these hormones were determined during pregnancy or lactation after performing the first (Pd4) strategy. The results demonstrated that mifepristone administration during early pregnancy decreased β-casein expression, milk yields and litter growth rates, induced fewer alveoli, enlarged alveolar lumina, and altered the levels of E2, P4, PRL, GH, CORT, and OT as well as the mRNA expression of these hormonal receptors during pregnancy or early lactation. The present study on pregnant mice treated with mifepristone offers an innovative murine model to study the mechanism underlying mammary gland dysplasia and postpartum hypogalactia.

682 Characterization of a novel selective non-steroidal glucocorticoid receptor agonist with low systemic exposure and reduced potential for skin atrophy

Topical glucocorticoids (GCs) are widely used drugs in dermatology but are associated with both local and systemic adverse effects. With the aim to provide an effective but safer topical treatment, we here describe LEO 134310, a novel non-steroidal glucocorticoid receptor (GR) agonist with low systemic exposure and reduced potential for induction of skin atrophy. LEO 134310 is a full GR agonist with high affinity for GR and nanomolar potency in human PBMCs. Furthermore, selectivity for GR was demonstrated within a panel of nuclear hormone receptors, including the mineralocorticoid receptor, which has been associated with induction of skin atrophy. Topical treatment with LEO 134310 in human skin explants resulted in full agonism, measured by GR target engagement, with maximal effects comparable to BMV and CP, although at higher dosage strength. The lower potency of LEO 134310 in human skin explants could be explained by a combination of lower skin penetration, metabolism in the skin and in vitro potency. LEO 134310 was rapidly deactivated in the blood and other compartments by enzymatic hydrolysis, leading to low systemic exposure of active parent compound. Consequently, a 10-fold higher therapeutic index was achieved with LEO 134310 compared to BMV and CP in the TPA-induced skin inflammation mouse model. Induction of skin atrophy after topical treatment with LEO 134310 in minipigs was minimal in contrast to significant epidermal thinning induced by treatment with CP and BMV. In conclusion, LEO 134310 may potentially offer an improved topical treatment solution for patients with inflammatory skin diseases.

Anti-inflammatory duration of action of fluticasone furoate/vilanterol trifenatate in asthma: a cross-over randomised controlled trial

BackgroundFluticasone furoate/Vilanterol trifenatate (FF/VI) is an inhaled corticosteroid/long-acting beta-agonist combination with a prolonged bronchodilator duration of action. We characterised the time-course of onset and offset of airway anti-inflammatory action of FF/VI, as assessed by fraction of exhaled nitric oxide (FeNO), and compared this to the bronchodilator duration of action.MethodsA single-centre, randomised, double-blind, placebo-controlled, two-period, crossover study was undertaken in 28 steroid-naïve adults with asthma. Participants with an FEV1 ≥ 60% predicted, reversible airway disease, and FeNO > 40 ppb received FF/VI 100/25 mcg or placebo once daily for 14 days. FeNO and peak expiratory flow were measured twice-daily during treatment and during a 21-day washout period. FEV1 was measured for five days from treatment cessation. The primary outcome measure was FeNO change from baseline ratio for 21 days following treatment cessation.ResultsIn the 27 subjects who completed the study, median (range) baseline FeNO was 87 ppb (42–212). FF/VI 100/25 mcg reduced FeNO by day 3, ratio FF/VI versus placebo 0.72 (95% confidence interval 0.61–0.86) with the maximum reduction occurring at day 14, 0.32 (0.27–0.37). Following cessation of treatment FeNO remained suppressed for 18 days, ratio on day 18 0.77 (0.59–1.00), whereas improvements in FEV1 and peak flow were maintained for 3 to 4 days post-treatment.ConclusionsThe anti-inflammatory duration of action of FF/VI is consistent with the high glucocorticoid receptor affinity and long lung retention of fluticasone furoate. The anti-inflammatory effect of FF/VI was of greater duration than its bronchodilator effect in adults with mild asthma.Funding GlaxoSmithKline (201499).Trial registrationProspectively registered on ClinicalTrials.gov registry number NCT02712047.

A Functional Mutation in KIAA1462 Promoter Decreases Glucocorticoid Receptor Affinity and Affects Egg-Laying Performance in Yangzhou Geese

The identification of genetic markers is valuable for improving the egg-laying performance in goose production. The single-nucleotide polymorphism (SNP) rs1714766362 in an intron of the goose KIAA1462 gene was found to be relevant to laying performance in our previous study. However, its function remains unclear. In this study, the full-length coding sequence of KIAA1462 gene was firstly characterized in Yangzhou geese. Q-PCR (Quantitative Real Time Polymerase Chain Reaction) results showed that KIAA1462 was highly expressed in the liver, ovary, and mature F1 follicles. For SNP rs1714766362, geese with the AA genotype showed better laying performance than the TT ones and exhibited a higher KIAA1462 expression level in the ovary. Gain- and loss-of function experiments in granulosa cells revealed that KIAA1462 affected the expression of the apoptosis marker gene caspase-3. Considering that rs1714766362 locates in an intron area, we compared the KIAA1462 promoter regions of AA and TT individuals and identified the SNP c.-413C>G (Genbank ss2137504176), which was completely linked to SNP rs1714766362. According to the transcription factor prediction results, the glucocorticoid receptor (GR) would bind to the SNP site containing the C but not the G allele. In this study, we proved this hypothesis by an electrophoretic mobility shift assay (EMSA). In summary, we identified a novel mutation in the promoter of KIAA1462 gene which can modulate GR binding affinity and affect the laying performance of geese.

Relationship Between Homodimeric Glucocorticoid Receptor and Transcriptional Regulation Assessed via an In Vitro Fluorescence Correlation Spectroscopy-Microwell System

Glucocorticoid receptor (GR) is a hormone-activated transcription regulatory protein involved in metabolism as well as adrenocortical responses to psychosocial stress. Ligand-activated GR localizes to the nucleus, where GR homodimers regulate gene transcription via direct binding to glucocorticoid response elements (GREs). The role of GR homodimers in transcriptional activation has not yet been elucidated. In this study, we determined the concentration of GR homodimer, and its dissociation constant (Kd), at the single-cell level, by using fluorescence correlation spectroscopy (FCS) combined with a microwell system. Results from dissociation constant analysis and diffusion analysis suggested that GR forms complexes with other proteins as well as homodimers. We determined the relationship between the concentration of GR homodimer and transcriptional activity using a triple-color FCS-microwell system-based fluorescent reporter assay. The binding affinity of GR to GREs was analyzed via fluorescence cross-correlation spectroscopy (FCCS). Our findings indicate that the GR homodimer is essential for activating target gene transcription.

430 Preclinical evaluation of a novel non-steroidal glucocorticoid receptor agonist with low systemic exposure and reduced potential for skin atrophy

Topical corticosteroids are widely used efficacious drugs but are associated with both local and systemic adverse effects. With the aim to provide an effective but safer topical treatment, we here describe a novel non-steroidal glucocorticoid receptor (GR) agonist with low systemic exposure and reduced potential for skin atrophy induction. LEO 134310 was shown to be a full GR agonist with high affinity for GR and low nanomolar potency in an inflammatory functional assay in human PBMCs. GR was the only nuclear hormone receptor affected by LEO 134310 in a panel of nuclear receptors, including the mineralocorticoid receptor, a receptor which has been associated with induction of skin atrophy. In blood and liver LEO 134310 is rapidly inactivated at a labile site, leading to high systemic clearance. In accordance with this profile, topical treatment with LEO 134310 in a TPA-induced dermatitis mouse model resulted in comparable efficacy to betamethasone valerate (BMV), with no systemic adverse effects at maximally effective doses. In contrast, BMV and clobetasol propionate (CP) markedly reduced body weight at maximally effective doses after topical treatment. Furthermore, skin atrophy after 4-week application to minipigs was minimal after treatment with LEO 134310 compared with significant skin atrophy induced by treatment with CP and BMV. LEO 134310 showed similar levels of target engagement as BMV, measured by FKBP5 mRNA, but lower than CP. Finally, topical treatment with LEO 134310 in a human skin explant model resulted in full agonism, measured by GR target engagement, albeit at higher dosage strength than required for BMV and CP. In conclusion, LEO 134310A shows an improved therapeutic index in preclinical studies compared to traditional corticosteroids and may potentially offer an improved topical treatment solution for patients with atopic dermatitis and psoriasis.

Glucocorticoid receptor number and affinity differ between peripheral blood mononuclear cells and granulocytes in domestic pigs

The aim of the present study was to characterize the number and affinity of glucocorticoid receptors (GR) in peripheral blood mononuclear cells (PBMC) and granulocytes of domestic pigs because glucocorticoid signaling is considered important for animal health and welfare. To investigate GR binding characteristics in intact porcine immune cells, blood samples of 6 castrated male pigs were collected via indwelling vein catheters. Porcine PBMC and granulocytes were isolated using two-layer density gradients, followed by radioligand binding assays to determine the number of GR sites per cell and the dissociation constant Kd as a measure for GR binding affinity. The present study revealed a greater number of GR sites per cell (P = 0.039) in PBMC (mean ± SEM: 1,953 ± 207 sites/cell) compared to granulocytes (1,561 ± 159 sites/cell) in domestic pigs. Furthermore, porcine PBMC had a higher GR binding affinity than porcine granulocytes (P = 0.003) as the dissociation constant Kd of PBMC (1.8 ± 0.2 nM) was lower than that of granulocytes (3.5 ± 0.4 nM). Our results point to differences in underlying mechanisms of glucocorticoid signaling in different porcine leukocyte populations.

Stress and Depression: a Crucial Role of the Mineralocorticoid Receptor.

Cortisol and corticosterone act on the appraisal process, which comprises the selection of an appropriate coping style and the encoding of the experience for storage in the memory. This action exerted by the stress hormones is mediated by mineralocorticoid receptors (MRs), which are expressed abundantly in the limbic circuitry, particularly in the hippocampus. Limbic MR is down-regulated by chronic stress and during depression but induced by antidepressants. Increased MR activity inhibits hypothalamic-pituitary-adrenal axis activity, promotes slow wave sleep, reduces anxiety and switches circuit connectivity to support coping. Cortisol and emotion-cognition are affected by MR gene haplotypes based on rs5522 and rs2070951. Haplotype 1 (GA) moderates the effects of (early) life stressors, reproductive cycle and oral contraceptives. MR haplotype 2 (CA) is a gain of function variant that protects females against depression by association with an optimistic, resilient phenotype. Activation of MR therefore may offer a target for alleviating depression and cognitive dysfunction. Accordingly, the MR agonist fludrocortisone was found to enhance the efficacy of antidepressants and to improve memory and executive functions in young depressed patients. In conclusion, CORT coordinates via MR the networks underlying how an individual copes with stress, and this action is complemented by the widely distributed lower affinity glucocorticoid receptor (GR) involved in the subsequent management of stress adaptation. In this MR:GR regulation, the MR is an important target for promoting resilience.

Corticosterone and dopamine D2/D3 receptors mediate the motivation for voluntary wheel running in C57BL/6J mice

Physical exercise can improve cognition but whether this is related to motivation levels is unknown. Voluntary wheel running is a rewarding activity proposed as a model of motivation to exercise. To question the potential effects of exercise motivation on subsequent behaviour, we used a pharmacological approach targeting some reward mechanisms. The stress hormone corticosterone has rewarding effects mediated by activation of low affinity glucocorticoid receptors (GR). To investigate whether corticosterone synthesis motivates exercise via activation of GRs and subsequently, impacts on behaviour, we treated C57BL/6J mice acutely with the inhibitor of corticosterone synthesis metyrapone (35mg/kg) or repeatedly with the GR antagonist mifepristone (30mg/kg) prior to 1-h running wheel sessions. To investigate whether reducing motivation to exercise impacts on behaviour, we antagonised running-induced dopamine D2/D3 receptors activation with sulpiride (25 or 50mg/kg) and assessed locomotor, anxiety-related and memory performance after 20 running sessions over 4 weeks. We found that corticosterone synthesis contributes to running levels, but the maintenance of running behaviour was not mediated by activation of GRs. Intermittent exercise was not associated with changes in behavioural or cognitive performance. The persistent reduction in exercise levels triggered by sulpiride also had limited impact on behavioural performance, although the level of performance for some behaviours was related to the level of exercise. Altogether, these findings indicate that corticosterone and dopamine D2/D3 receptor activation contribute to the motivation for wheel running, but suggest that motivation for exercise is not a sufficient factor to alter behaviour in healthy mice.

New evidences on the use of aldosterone receptor antagonists in left ventricular dysfunction: from myocardial infarction to heart failure

Heart failure and myocardial infarction result in considerable consumption of healthcare resources. Therefore, there is interest in the availability of drug therapies that can favorably modify their prognosis in the post-acute phase, reducing mortality and rehospitalization rates. Aldosterone antagonists represent a class of drugs which offer advantages in these settings, in addition to those obtained with beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, even though attention should be drawn to their potential adverse effects. In particular, eplerenone exhibits a better safety profile than spironolactone. Since it has very little affinity for glucocorticoid, androgen and progesterone receptors, eplerenone has less antiandrogenic and progestagenic effects, resulting in a lower incidence of gynecomastia. The EPHESUS study showed that eplerenone can reduce mortality in the short and long term and the rate of new hospitalizations after a myocardial infarction complicated by heart failure. In addition, in the EMPHASIS-HF study eplerenone reduced cardiovascular mortality and hospitalizations after mild heart failure (NYHA class IIa). Despite these important results, which confirmed those obtained with spironolactone in severe heart failure in the RALES study, aldosterone antagonists are still underutilized. In particular, eplerenone is not yet available in Italy, although it is recommended by the latest European Society of Cardiology guidelines.

Nocturnal Asthma: A Special Type of Asthma

Nocturnal asthma is defined by a drop in forced expiratory volume in 1 second (FEV1) of at least 15% between bedtime and awakening in patients with clinical and physiologic evidence of asthma. Nocturnal asthma is associated with a circadian pattern in lung function, distal airway inflammation, glucocorticoid receptor affinity, pulmonary capillary blood volume, and beta-2 adrenergic receptor function may also contribute. Knowledge of these characteristics, along with an understanding of the specific therapies directed at the circadian nature of this disease, can result in significant improvements in lung function, sleep quality, and asthma related quality of life.

Somatostatin Reduces the Acute Lung Injury of Mice via Increasing the Affinity of Glucocorticoid Receptor

Background/Aims: Although it has been reported that somatostatin (SOM) upregulated the level of 90-kD heat shock protein (Hsp90), which participates in the inflammatory regulation by its client proteins, such as glucocorticoid receptor (GR), it remains unclear if it has a protective role against acute lung injury (ALI). Methods: ALI model was established by the injection of oleic acid (OA) into the tail vein of mice. Lung injury was assessed by histological analysis, lung water content and arterial blood gases. The levels of Hsp90 and GR, the binding capacity and the affinity of GR were examined. Results: It was showed that pretreatment with SOM significantly increased Hsp90 levels and alleviated lung injuries in OA-injected mice. Furthermore, SOM increased the GR expression and improved the affinity of the GR in animals with lung injury. However, little alteration was found in the maximum binding capacity of the GR in mice with or without SOM. Conclusion: The data indicate SOM exerts a protective effect by increasing Hsp90 abundant and further enhancing the affinity of the GR. The beneficial effects of SOM treatment provide a new strategy for modulation of GR efficiency and alleviation of acute lung injury.

A Mixed Glucocorticoid/Mineralocorticoid Selective Modulator With Dominant Antagonism in the Male Rat Brain.

Adrenal glucocorticoid hormones are potent modulators of brain function in the context of acute and chronic stress. Both mineralocorticoid (MRs) and glucocorticoid receptors (GRs) can mediate these effects. We studied the brain effects of a novel ligand, C118335, with high affinity for GRs and modest affinity for MRs. In vitro profiling of receptor-coregulator interactions suggested that the compound is a "selective modulator" type compound for GRs that can have both agonistic and antagonistic effects. Its molecular profile for MRs was highly similar to those of the full antagonists spironolactone and eplerenone. C118335 showed predominantly antagonistic effects on hippocampal mRNA regulation of known glucocorticoid target genes. Likewise, systemic administration of C118335 blocked the GR-mediated posttraining corticosterone-induced enhancement of memory consolidation in an inhibitory avoidance task. Posttraining administration of C118335, however, gave a strong and dose-dependent impairment of memory consolidation that, surprisingly, reflected involvement of MRs and not GRs. Finally, C118335 treatment acutely suppressed the hypothalamus-pituitary-adrenal axis as measured by plasma corticosterone levels. Mixed GR/MR ligands, such as C118335, can be used to unravel the mechanisms of glucocorticoid signaling. The compound is also a prototype of mixed GR/MR ligands that might alleviate the harmful effects of chronic overexposure to endogenous glucocorticoids.