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Introduction: Unlike white adipose tissue depots, bone marrow adipose tissue (BMAT) expands during caloric restriction (CR). Although mechanisms for BMAT expansion remain unclear, prior research suggested an intermediary role for increased circulating glucocorticoids. Methods: In this study, we utilized a recently described mouse model (BMAd-Cre) to exclusively target bone marrow adipocytes (BMAds) for elimination of the glucocorticoid receptor (GR) (i.e. Nr3c1) whilst maintaining GR expression in other adipose depots. Results: Mice lacking GR in BMAds (BMAd-Nr3c1-/-) and control mice (BMAd-Nr3c1+/+) were fed ad libitum or placed on a 30% CR diet for six weeks. On a normal chow diet, tibiae of female BMAd-Nr3c1-/- mice had slightly elevated proximal trabecular metaphyseal bone volume fraction and thickness. Both control and BMAd-Nr3c1-/- mice had increased circulating glucocorticoids and elevated numbers of BMAds in the proximal tibia following CR. However, no significant differences in trabecular and cortical bone were observed, and quantification with osmium tetroxide and mCT revealed no difference in BMAT accumulation between control or BMAd-Nr3c1-/- mice. Differences in BMAd size were not observed between BMAd-Nr3c1-/- and control mice. Interestingly, BMAd-Nr3c1-/- mice had decreased circulating white blood cell counts 4 h into the light cycle. Discussion: In conclusion, our data suggest that eliminating GR from BMAd has minor effects on bone and hematopoiesis, and does not impair BMAT accumulation during CR. [ABSTRACT FROM AUTHOR]

IntroductionUnlike white adipose tissue depots, bone marrow adipose tissue (BMAT) expands during caloric restriction (CR). Although mechanisms for BMAT expansion remain unclear, prior research suggested an intermediary role for increased circulating glucocorticoids. MethodsIn this study, we utilized a recently described mouse model (BMAd-Cre) to exclusively target bone marrow adipocytes (BMAds) for elimination of the glucocorticoid receptor (GR) (i.e. Nr3c1) whilst maintaining GR expression in other adipose depots. ResultsMice lacking GR in BMAds (BMAd-Nr3c1-/-) and control mice (BMAd-Nr3c1+/+) were fed ad libitum or placed on a 30% CR diet for six weeks. On a normal chow diet, tibiae of female BMAd-Nr3c1-/- mice had slightly elevated proximal trabecular metaphyseal bone volume fraction and thickness. Both control and BMAd-Nr3c1-/- mice had increased circulating glucocorticoids and elevated numbers of BMAds in the proximal tibia following CR. However, no significant differences in trabecular and cortical bone were observed, and quantification with osmium tetroxide and μCT revealed no difference in BMAT accumulation between control or BMAd-Nr3c1-/- mice. Differences in BMAd size were not observed between BMAd-Nr3c1-/- and control mice. Interestingly, BMAd-Nr3c1-/- mice had decreased circulating white blood cell counts 4 h into the light cycle.DiscussionIn conclusion, our data suggest that eliminating GR from BMAd has minor effects on bone and hematopoiesis, and does not impair BMAT accumulation during CR.

Objective • To investigate whether the efficacy of tacrolimus (TAC) monotherapy is non-inferior to TAC combined with glucocorticoids (TAC+GC) in the treatment of idiopathic membranous nephropathy (IMN), and evaluate its safety. Methods • This pilot study was conducted by the Department of Renal Rheumatology and Immunology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine from November 2017 to March 2021. High-risk patients with biopsy-proven IMN were recruited and randomly divided into two groups: TAC monotherapy group only received TAC treatment [an initial dose of 0.050-0.075 mg/(kg・d), maintaining trough blood concentration of 5-10 ng/mL]; TAC combined with GC group (TAC+GC group) received TAC (the same as TAC monotherapy group) combined with prednisone [an initial dose of 0.5 mg/(kg・d) for 8-12 weeks, then tapered until complete withdrawal]. The baseline data of the two groups of patients were collected, and the efficacy indicators and safety indicators of the patients were observed and recorded during the visit. The primary end points of the study were the total remission rate and complete remission rate of proteinuria at 24 weeks of treatment. The secondary end points included the efficacy indicators [24 h urinary protein quantification, serum albumin level and estimated glomerular filtration rate level at 24 weeks of treatment] and the incidence of adverse events (elevated blood glucose, thrombosis and infection). Non-inferiority test was used to compare the total remission rate of proteinuria in the two groups, and the non-inferiority margin was set as 一 10%. Fisher's precision probability test was used to compare the total remission rate, complete remission rate and adverse events rate of the two groups of patients. Non parametric tests were used to compare the differences of the percentage changes of the efficacy indicators from baseline values after treatment between the two groups. Results • A total of 36 IMN patients were enrolled, with 18 in TAC monotherapy group and 18 in TAC+GC group. There was no statistically significant difference between the baseline data of the two groups. During the treatment, 1 case was lost in TAC monotherapy group and 3 cases in TAC+GC group. Finally, 36 patients were included in the full analysis set (FAS), 32 patients were included in the per protocol set (PPS), and 36 patients were included in the safety set. The results of non-inferiority test showed that it was not observed that the efficacy of TAC monotherapy was not inferior to that of TAC combined with GC. The risk difference of total remission rate of proteinuria in the two groups was 0 (95%CI -31.9-31.9, P=0.269), and the lower limit was below the non-inferiority margin. In FAS and PPS, there was no significant difference in complete remission rate and total remission rate between the two groups at 24 weeks of treatment, and no significant difference in the percentage changes of the efficacy indicators from baseline values after treatment between the two groups. Ten patients (4 cases in TAC monotherapy group, and 6 cases in TAC+GC group) developed elevated blood glucose over the period of treatment, with no significant difference between the two groups; one patient (TAC+GC group) developed right upper extremity venous thrombosis. Conclusion* This pilot study finds that the total remission rate and complete remission rate of the two groups are similar at 24 weeks of treatment. The frequency of adverse events in TAC monotherapy group is relatively lower than that in TAC combined with GC group. However, the available data cannot prove that the efficacy of TAC monotherapy is non-inferior to that of TAC combined with GC in the treatment of IMN. [ABSTRACT FROM AUTHOR]

• Osteoporosis, its causes, and medications reviewed thoroughly. • Glucocorticoids' role in osteoporosis and their mechanism discussed. • List of glucocorticoids and clinical applications provided. • Treatment options for glucocorticoid-induced osteoporosis analyzed. Glucocorticoids (GCs) are steroid hormones that are extensively used in the treatment of autoimmune diseases, inflammation, and cancer. The major ill effect of administering GCs is that it has a deleterious effect on bone, which leads to GC-induced osteoporosis. GC therapy induces bone loss and is associated with the risk of nonvertebral and vertebral fractures, as it works in combination by increasing bone reabsorption and suppressing bone formation during the initial phase of therapy. It is seen and established that GC in excess or in low dose for 3 months or more can be a risk factor for fracture, and the risk increases with an increase in dose and duration of usage. The most common cause of secondary osteoporosis is the administration of GC inside the body to treat various diseases. The degree of bone loss is directly proportional to the GC dose and the exposure duration. The first step is to evaluate the patients' risk factors for the development of glucocorticoids that induce osteoporosis, which include the dose, duration of use, patient age, sex, previous fractures, and other medical conditions. [ABSTRACT FROM AUTHOR]

Objective: The expression of glucocorticoid receptors within platelets from newly diagnosed Immune Thrombocytopenia (ITP) patients in the adult was investigated. Methods: GR expression in platelets from newly diagnosed ITP patients and healthy controls was measured using flow cytometry. Subsequently, platelets RNA and proteins were isolated and used for confirming the flow cytometry results by using RT-qPCR and ELISA. Results: Flow cytometry showed that the percentages of platelets expressing GRα and GRβ from ITP patients were significantly higher than those from healthy controls (P < 0.05). qPCR and ELISA confirmed that GRα and GRβ were increased at both RNA transcription and protein expression levels within platelets from ITP patients compared with healthy controls. Conclusion: We speculated that the up-regulation of glucocorticoid receptor within platelets may be an important biological feature of platelets in patients with ITP, and may also play an important role in the treatment of ITP, which is worthy of further study. [ABSTRACT FROM AUTHOR]

Corticosteroids are one of the most effective medications available for a wide variety of inflammatory diseases, including rheumatoid arthritis, inflammatory bowel disease, autoimmune diseases, and chronic lung diseases such as asthma; however, 5–10% of asthma patients respond poorly to corticosteroids and require high doses, secondary immunosuppressants, such as calcineurin inhibitors and methotrexate, or disease-modifying biologics that can be toxic and/or expensive. Though steroid-resistant asthma affects a small percentage of patients, it consumes significant health resources and contributes to substantial morbidity and mortality. In addition, the side effects caused by excessive use of steroids dramatically impact patients’ quality of life. Recognition of patients who respond poorly to steroid therapy is important due to the persistent and considerable problems they face in managing their conditions, which bears a significant socioeconomic burden. Along with the recognition of such patients, elucidation of the molecular mechanisms of steroid resistance is equally important, so that administration of a high dosage of steroids, and the consequent adverse effects, can be avoided. This review provides an update on the mechanisms of steroid function and the possible new therapeutic modalities to treat steroid-resistant asthma.

Abstract Background Acute lymphoblastic leukemia is the most prevalent neoplasia among children. Despite the tremendous achievements of state-of-the-art treatment strategies, drug resistance is still a major cause of chemotherapy failure leading to relapse in pediatric acute lymphoblastic leukemia. The underlying mechanisms of such phenomenon are not yet clear and subject to further exploration. Prior research has shown that microRNAs can act as post-transcriptional regulators of many genes related to drug resistance. However, details of microRNA regulation mechanisms in pediatric acute lymphoblastic leukemia are far from completely understood. Methods We utilized a computational approach based upon emerging biomedical and biological ontologies and semantic technologies to investigate the important roles of microRNA: mRNA regulation on glucocorticoid resistance in pediatric acute lymphoblastic leukemia. In particular, various filtering mechanisms were designed based on the user-provided MeSH term to narrow down the most promising microRNAs in an effective manner. Results During our manual search on background literature, we found a total of 18 candidate microRNAs that possibly regulate glucocorticoid resistance in pediatric acute lymphoblastic leukemia. After the first-round filtering using the Broader-Match option where both the user-provided MeSH term and its direct parent term were utilized, the number of targets for 18 microRNAs was reduced from 232 to 74. During the second-round filtering with the Exact-Match option where only the MeSH term itself was utilized, the number of targets was further reduced to 19. Finally, we conducted semantic searches in the OmniSearch software tool on the five likely regulating microRNAs and identified two most likely microRNAs. Conclusions We successfully identified two microRNAs, hsa-miR-142-3p and hsa-miR-17-5p, which are computationally predicted to closely relate to glucocorticoid resistance, thus potentially serving as novel biomarkers and therapeutic targets in pediatric acute lymphoblastic leukemia.

Brown fat is a potential target in the treatment of metabolic disorders as recruitment and activation of this thermogenic organ increases energy expenditure and promotes satiation. A large variety of G-protein coupled receptors, known as classical drug targets in pharmacotherapy, is expressed in brown adipocytes. In the present study, we analyzed transcriptome data for the expression of these receptors to identify potential pathways for the recruitment and activation of thermogenic capacity in brown fat. Our analysis revealed 12 Gs-coupled receptors abundantly expressed in murine brown fat. We screened ligands for these receptors in brown adipocytes for their ability to stimulate UCP1-mediated respiration and Ucp1 gene expression. Adrenocorticotropic hormone (ACTH), a ligand for the melanocortin 2 receptor (MC2R), turned out to be the most potent activator of UCP1 whereas its capability to stimulate Ucp1 gene expression was comparably low. Adrenocorticotropic hormone is the glandotropic hormone of the endocrine hypothalamus–pituitary–adrenal-axis stimulating the release of glucocorticoids in response to stress. In primary brown adipocytes ACTH acutely increased the cellular respiration rate similar to isoproterenol, a β-adrenergic receptor agonist. The effect of ACTH on brown adipocyte respiration was mediated via the MC2R as confirmed by using an antagonist. Inhibitor-based studies revealed that ACTH-induced respiration was dependent on protein kinase A and lipolysis, compatible with a rise of intracellular cAMP in response to ACTH. Furthermore, it is dependent on UCP1, as cells from UCP1-knockout mice did not respond. Taken together, ACTH is a non-adrenergic activator of murine brown adipocytes, initiating the canonical adenylyl cyclase–cAMP–protein kinase A-lipolysis-UCP1 pathway, and thus a potential target for the recruitment and activation of thermogenic capacity. Based on these findings in primary cell culture, the physiological significance might be that cold-induced ACTH in concert with norepinephrine released from sympathetic nerves contributes to BAT thermogenesis. Notably, dexamethasone attenuated isoproterenol-induced respiration. This effect increased gradually with the duration of pretreatment. In vivo, glucocorticoid release triggered by ACTH might oppose beta-adrenergic stimulation of metabolic fuel combustion in BAT and limit stress-induced hyperthermia.

Brown fat is a potential target in the treatment of metabolic disorders as recruitment and activation of this thermogenic organ increases energy expenditure and promotes satiation. A large variety of G-protein coupled receptors, known as classical drug targets in pharmacotherapy, is expressed in brown adipocytes. In the present study, we analyzed transcriptome data for the expression of these receptors to identify potential pathways for the recruitment and activation of thermogenic capacity in brown fat. Our analysis revealed 12 Gs-coupled receptors abundantly expressed in murine brown fat. We screened ligands for these receptors in brown adipocytes for their ability to stimulate UCP1-mediated respiration and Ucp1 gene expression. Adrenocorticotropic hormone (ACTH), a ligand for the melanocortin 2 receptor (MC2R), turned out to be the most potent activator of UCP1 whereas its capability to stimulate Ucp1 gene expression was comparably low. Adrenocorticotropic hormone is the glandotropic hormone of the endocrine hypothalamus–pituitary–adrenal-axis stimulating the release of glucocorticoids in response to stress. In primary brown adipocytes ACTH acutely increased the cellular respiration rate similar to isoproterenol, a β-adrenergic receptor agonist. The effect of ACTH on brown adipocyte respiration was mediated via the MC2R as confirmed by using an antagonist. Inhibitor-based studies revealed that ACTH-induced respiration was dependent on protein kinase A and lipolysis, compatible with a rise of intracellular cAMP in response to ACTH. Furthermore, it is dependent on UCP1, as cells from UCP1-knockout mice did not respond. Taken together, ACTH is a non-adrenergic activator of murine brown adipocytes, initiating the canonical adenylyl cyclase–cAMP–protein kinase A-lipolysis-UCP1 pathway, and thus a potential target for the recruitment and activation of thermogenic capacity. Based on these findings in primary cell culture, the physiological significance might be that cold-induced ACTH in concert with norepinephrine released from sympathetic nerves contributes to BAT thermogenesis. Notably, dexamethasone attenuated isoproterenol-induced respiration. This effect increased gradually with the duration of pretreatment. In vivo , glucocorticoid release triggered by ACTH might oppose beta-adrenergic stimulation of metabolic fuel combustion in BAT and limit stress-induced hyperthermia. [ABSTRACT FROM AUTHOR]

In rat Leydig cells, glucocorticoids (GCs) inhibit testosterone production through the interaction with the glucocorticoid receptor (GR). However, the sensitivity of those cells to GCs is regulated by the enzyme 11β‐hydroxysteroid dehydrogenase Type 1 (11β‐HSD1). In the testes of the toad Rhinella arenarum, the presence of an 11β‐HSD similar to type 2 and a cytosolic GR has also been described. However, there is a lack of information regarding the effects of GCs on amphibian testicular steroidogenesis. In this study, the effects of corticosterone on androgen production, and the activity of two steroidogenic enzymes in toad testes were reported. Corticosterone inhibits androgen production via the GR because the GR antagonist RU486 prevents corticosterone‐induced inhibition of testosterone. Corticosterone also reduced the activity of the cytochrome P450 17‐hydroxylase, C17,20‐lyase (Cyp450 c17) without affecting the 3β‐hydroxysteroid dehydrogenase/isomerase activity. This effect on Cyp450 c17 was likewise inhibited by RU486. On the other hand, corticosterone had no effect on the amount of steroidogenic acute regulator protein. These results suggest that GCs inhibit steroidogenesis in toad testes by reducing of Cyp450 c17 activity via a GR‐mediated mechanism. In rat Leydig cells, glucocorticoids (GCs) inhibit testosterone production through the interaction with the glucocorticoid receptor (GR). However, the sensitivity of those cells to GCs is regulated by the enzyme 11β‐hydroxysteroid dehydrogenase Type 1 (11β‐HSD1). In the testes of the toad Rhinella arenarum, the presence of an 11β‐HSD similar to Type 2 and a cytosolic GR has also been described HIGHLIGHTS: GCs inhibit steroidogenesis in toad testes by the suppression of Cyp450c17 via GR‐mediated mechanism.Corticosterone reduced the activity of the Cyp450c17 without affecting 3β‐HD/I.Corticosterone has no effect on the amount of StAR protein. [ABSTRACT FROM AUTHOR]

Milestones of brain development in mammals are completed before birth, which provide the prerequisite for cognitive and intellectual performances of the offspring. Prenatal challenges, such as maternal stress experience or infections, have been linked to impaired cognitive development, poor intellectual performances as well as neurodevelopmental and psychiatric disorders in the offspring later in life. Fetal microglial cells may be the target of such challenges and could be functionally modified by maternal markers. Maternal markers can cross the placenta and reach the fetus, a phenomenon commonly referred to as "vertical transfer." These maternal markers include hormones, such as glucocorticoids, and also maternal immune cells and cytokines, all of which can be altered in response to prenatal challenges. Whilst it is difficult to discriminate between the maternal or fetal origin of glucocorticoids and cytokines in the offspring, immune cells of maternal origin—although low in frequency—can be clearly set apart from offspring's cells in the fetal and adult brain. To date, insights into the functional role of these cells are limited, but it is emergingly recognized that these maternal microchimeric cells may affect fetal brain development, as well as post-natal cognitive performances and behavior. Moreover, the inheritance of vertically transferred cells across generations has been proposed, yielding to the presence of a microchiome in individuals. Hence, it will be one of the scientific challenges in the field of neuroimmunology to identify the functional role of maternal microchimeric cells as well as the brain microchiome. Maternal microchimeric cells, along with hormones and cytokines, may induce epigenetic changes in the fetal brain. Recent data underpin that brain development in response to prenatal stress challenges can be altered across several generations, independent of a genetic predisposition, supporting an epigenetic inheritance. We here discuss how fetal brain development and offspring's cognitive functions later in life is modulated in the turnstile of prenatal challenges by introducing novel and recently emerging pathway, involving maternal hormones and immune markers. [ABSTRACT FROM AUTHOR]

Increased proinflammatory cytokines, such as interleukin (IL)-1β, may play an important role in the etiology of depression because they cause the hypothalamic–pituitary–adrenal axis to release glucocorticoids (GC) and induce dysfunction of serotonin and norepinephrine neurotransmission. Sustained increase in GC may activate microglia to induce neuroinflammation, and suppress astrocytes to produce neurotrophins, which lead to neuronal apoptosis. Here, we tested the hypothesis that glucocorticoid receptor (GR) antagonist mifepristone (RU486) may attenuate IL-1β-induced depression-like behavior by regulating the neuroinflammation and neurotrophin functions of microglia and astrocytes. Rats received intracerebroventricular injections of IL-1β (10 ng) and/or subcutaneous injections of RU486 for 14 days. Then animal depression-like behaviors, serum corticosterone concentration, the levels of pro-inflammatory cytokines (TNF-α, IL-6), mRNA and protein expressions of CD11b, GFAP and neurotrophins (pro-BDNF, BDNF, GDNF and their receptors TrkB, p75, GFRα-1 and GFRα-2) in the amygdala were studied. Compared to controls, significantly decreased rearing score and increased defecation in the open field test, decreases in ratio of open/closed time in the elevated plus maze and in sucrose preference, while increased level of corticosterone in the serum were found in the rats administrated with IL-1β. IL-1β administration also reduced the expressions of GFAP, BDNF, GDNF and its receptor GFR-α1, but increased the expressions of CD11b, pro-BDNF, p75 and pro-inflammatory cytokines (TNF-α, IL-6) concentrations. RU486 treatment markedly attenuated these changes induced by IL-1β, except for the expressions of GFR-α1. In conclusion, RU486 may improve depression-like changes by suppressing microglia and inflammation and promoting astrocytes to restore neurotrophin function. [ABSTRACT FROM AUTHOR]

Objective: This study examined whether a novel indicator of overall childhood adversity, incorporating number of adversities, severity, and chronicity, predicted central obesity beyond contributions of “modifiable” risk factors including psychosocial characteristics and health behaviors in a diverse sample of midlife adults. The study also examined whether the overall adversity score (number of adversities×severity×chronicity) better predicted obesity compared to cumulative adversity (number of adversities), a more traditional assessment of childhood adversity. Materials/Methods: 210 Black/African Americans and White/European Americans, mean age=45.8; ±3.3years, were studied cross-sectionally. Regression analysis examined overall childhood adversity as a direct, non-modifiable risk factor for central obesity (waist–hip ratio) and body mass index (BMI), with and without adjustment for established adult psychosocial risk factors (education, employment, social functioning) and heath behavior risk factors (smoking, drinking, diet, exercise). Results: Overall childhood adversity was an independent significant predictor of central obesity, and the relations between psychosocial and health risk factors and central obesity were not significant when overall adversity was in the model. Overall adversity was not a statistically significant predictor of BMI. Conclusions: Overall childhood adversity, incorporating severity and chronicity and cumulative scores, predicts central obesity beyond more contemporaneous risk factors often considered modifiable. This is consistent with early dysregulation of metabolic functioning. Findings can inform practitioners interested in the impact of childhood adversity and personalizing treatment approaches of obesity within high-risk populations. Prevention/intervention research is necessary to discover and address the underlying causes and impact of childhood adversity on metabolic functioning. [ABSTRACT FROM AUTHOR]

Abstract: Cardiac cachexia (CC) affects a large proportion of patients with chronic heart failure, a major public health issue in western countries. The pathophysiology of CC is complex and multifactorial, resulting from several factors interacting in a complex system with metabolic, immune and neurohormonal consequences, triggered to protect the heart and the circulation from damage. Despite the adverse clinical effects, CC diagnosis is not straightforward and has not specifically been targeted, with therapeutic strategies only comprising interventions with appetite stimulants, and anti-inflammatory substances. Here we review the molecular pathways underlying CC-related muscle wasting aiming to provide clues for the definition of CC-specific biomarkers and for the development of drugs that prevent and/or counteract muscle impairment, which will certainly impact the management of cardiovascular disorders. [Copyright &y& Elsevier]

Abstract: Background: Role of multidrug resistance-1 (MDR-1) gene polymorphisms has not been clarified in nephrotic syndrome (NS). Additionally, researchers studied several genetic polymorphisms to explain their influence on different patients' responses to steroid; however the data were inconsistent. Therefore, we aimed to investigate the association of MDR-1 gene polymorphisms [C1236T, G2677T/A, C3435T] and haplotypes with susceptibility to childhood nephrotic syndrome, and whether they influence steroid response. Methods: We detected MDR-1 gene polymorphisms using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) in 138 NS patients and 140 age and sex matched healthy children. Results: The frequencies of MDR1 G2677T/A GT, GA, TT+AA genotypes or T allele, MDR1 C3435T TT genotype, and T allele genotype frequencies were significantly increased in NS group. While no significant differences were observed in distributions of C1236T genotypes or allele between NS patients and healthy children. Moreover, steroid non-responder NS patients had significantly higher frequencies of MDR1 G2677T/A GT, GA, and TT+AA genotypes than steroid responsive NS patients. We observed also that NS patients with age less than 6years old had increased frequencies of MDR1 G2677T/A GT, GA, TT+AA genotypes or T allele MDR1 C3435T CT, TT genotypes and T allele. Interestingly the frequency of the TGC haplotype of MDR1 was lower in the initial steroid responders than in non-responders NS patients. On the contrary, there were no any association between the MDR1 haplotypes with NS susceptibility and they did not influence renal pathological findings. Conclusion: Our data suggested that MDR1 C3435T or G2677T/A gene polymorphisms are risk factors of increased susceptibility, earlier onset of NS, and steroid resistance. [Copyright &y& Elsevier]

Abstract: Mammalian skin incorporates a local equivalent of the hypothalamic–pituitary–adrenal (HPA) axis that is critical in coordinating homeostatic responses against external noxious stimuli. Ultraviolet radiation B (UVB) is a skin-specific stressor that can activate this cutaneous HPA axis. Since C57BL/6 (B6) and DBA/2J (D2) strains of mice have different predispositions to sensorineural pathway activation, we quantified expression of HPA axis components at the gene and protein levels in skin incubated ex vivo after UVB or sham irradiation. Urocortin mRNA was up-regulated after all doses of UVB with a maximum level at 50mJ/cm2 after 12h for D2 and at 200mJ/cm2 after 24h for B6. Proopiomelanocortin mRNA was enhanced after 6h with the peak after 12h and at 200mJ/cm2 for both genotypes of mice. ACTH levels in tissue and media increased after 24h in B6 but not in D2. UVB stimulated β-endorphin expression was higher in D2 than in B6. Melanocortin receptor 2 mRNA was stimulated by UVB in a dose-dependent manner, with a peak at 200mJ/cm2 after 12h for both strains. The expression of Cyp11a1 mRNA — a key mitochondrial P450 enzyme in steroidogenesis, was stimulated at all doses of UVB irradiation, with the most pronounced effect after 12–24h. UVB radiation caused, independently of genotype, a dose-dependent increase in corticosterone production in the skin, mainly after 24h of histoculture. Thus, basal and UVB stimulated expression of the cutaneous HPA axis differs as a function of genotype: D2 responds to UVB earlier and with higher amplitude than B6, while B6 shows prolonged (up to 48h) stress response to a noxious stimulus such as UVB. [Copyright &y& Elsevier]

Abstract: Many pathological states characterized by muscle atrophy (e.g., sepsis, cachexia, starvation, metabolic acidosis and severe insulinopenia) are associated with an increase in circulating glucocorticoids (GC) levels, suggesting that GC could trigger the muscle atrophy observed in these conditions. GC-induced muscle atrophy is characterized by fast-twitch, glycolytic muscles atrophy illustrated by decreased fiber cross-sectional area and reduced myofibrillar protein content. GC-induced muscle atrophy results from increased protein breakdown and decreased protein synthesis. Increased muscle proteolysis, in particular through the activation of the ubiquitin proteasome and the lysosomal systems, is considered to play a major role in the catabolic action of GC. The stimulation by GC of these two proteolytic systems is mediated through the increased expression of several Atrogenes (“genes involved in atrophy”), such as FOXO, Atrogin-1, and MuRF-1. The inhibitory effect of GC on muscle protein synthesis is thought to result mainly from the inhibition of the mTOR/S6 kinase 1 pathway. These changes in muscle protein turnover could be explained by changes in the muscle production of two growth factors, namely Insulin-like Growth Factor (IGF)-I, a muscle anabolic growth factor and Myostatin, a muscle catabolic growth factor. This review will discuss the recent progress made in the understanding of the mechanisms involved in GC-induced muscle atrophy and consider the implications of these advancements in the development of new therapeutic approaches for treating GC-induced myopathy. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. [Copyright &y& Elsevier]

Highlights: [•] EE reduced the anxiety-like behaviours in the elevated zero-maze. [•] EE group had a better performance in the 4-RAWM in the first sessions. [•] EE reduced the COx activity in brain regions related to anxiety in the spatial task. [•] Hippocampus had a different pattern of COx activity along its septo-temporal axis. [Copyright &y& Elsevier]

Abstract: Steroid hormones are indispensable for control of vital processes, development, reproduction and modulation of behavior. Lack or complete dysfunction of glucocorticoid (GC) signaling, in particular, have lethal consequences. Even a minor change in the level of circulating cortisol can be of physiological and clinical significance. Analysis of the action mechanisms of GC is therefore of major importance, especially since natural and synthetic GC are widely used in the therapy of GC-responsive diseases. According to the classical genomic concept of steroid hormone action, the effects of GC are mediated by specific nuclear receptors (GR). Recent findings provide evidence for the existence of additional, plasma membrane (PM) located steroid receptors, which are thought to be responsible for rapid, non-genomic responses. We present evidence for a PM-residing protein, termed “steroid hormone recognition and effector complex” (SHREC), which plays a pivotal role in the complex network of PM-related non-genomic responses leading to GR-mediated genomic effects. This conclusion was drawn from studies using different in vitro and in vivo models of a GC-target: (1) highly purified fractions of osmotically active PM-vesicles isolated from rat and human hepatocytes, (2) a computational model of SHREC generated by the “automated receptor modeling” (ARM) method, (3) rat liver cell lines transfected with a GC-responsive reporter gene construct and (4) young women orally administered with selected steroids. We conclude that SHREC and the GR participate in the same signaling chain, SHREC↔steroid interaction is the initial step and an interdependent part of the complete GC signal propagation, thus called “membrane initiated steroid signaling” (MISS). [Copyright &y& Elsevier]

Abstract: Glucocorticoids (GC) are frequently used for therapy of various inflammatory lung diseases by either systemic or inhalative application. Because the oral application often has various side effects and because the inhalative application is not as potent, new formulations of GCs are required. We evaluated the effect of a liposomal (Lip) formulation of methylprednisolone (MP) on the expression of lipopolysaccharide (LPS)-induced proinflammatory tumor necrosis factor (TNF) and antiinflammatory interleukin-10 (IL-10) in human alveolar macrophages (AM). AM were obtained from bronchoalveolar lavage fluids of patients with various inflammatory lung diseases and precultured 20 h±MP, either liposomal or free, and then stimulated with LPS. Cells were harvested for analysis of mRNA levels by real-time reverse transcriptase polymerase chain reaction (RT-PCR); supernatants were used to measure protein concentrations by ELISA. We confirm the suppression of LPS-induced TNF production by an average of factor 7 at the mRNA level and factor 3 at the protein level. On the other hand, we detected a strong increase of the IL-10 production by MP. At the mRNA level, liposomal MP alone led to an 18-fold increase, and the LPS-induced IL-10 mRNA was enhanced by factor 2. At the protein level, MP alone had no effect, but LPS-induced IL-10 was increased by factor 2.5. Our data show that liposomal MP can consistently induce IL-10 and reduce TNF when macrophages are exposed for a prolonged period of time. In all respects, liposomal MP had similar activities as free MP, but liposomes were selectively taken up by monocytes and macrophages and not by lymphocytes in blood and in the lung. This suggests that liposomal glucocorticoids when applied locally in the lung may act efficiently but with less side effects. [Copyright &y& Elsevier]

The purpose of this investigation was to assess the ability of the hippocampus to withstand a metabolic challenge following chronic stress. An N-methyl-d-aspartate receptor excitotoxin (ibotenic acid, IBO) was infused into the CA3 region of the hippocampus following a period of restraint for 6 h/day/21 days. Following the end of restraint when CA3 dendritic retraction persists (3 to 4 days), rats were infused with IBO (or vehicle) into the CA3 region of the hippocampus. Stressed male rats showed significantly more CA3 damage after IBO infusion relative to controls and the saline-infused side. Moreover, IBO-exacerbation of damage in males was not observed in the CA3 region 3 to 4 days after acute stress (6 h restraint), nor in the CA1 region after chronic stress. Females were also examined and chronic stress did not exacerbate IBO damage in the CA3 region. Overall, these results demonstrate that chronic stress compromises the ability of the hippocampus to withstand a metabolic challenge days after the chronic stress regimen has subsided in male rats. Whether the conditions surrounding CA3 dendritic retraction in females represents vulnerability is less clear and warrants further investigation. [Copyright &y& Elsevier]

: BackgroundGlucocorticoids during cardiopulmonary bypass benefit pediatric patients undergoing repair of congenital heart defects and are routine therapy, but underlying mechanisms have not been fully examined. The hypothesis was that glucocorticoids could improve cardiopulmonary recovery after cardiopulmonary bypass and deep hypothermic circulatory arrest.: MethodsCrossbred piglets (5 to 7 kg) were cooled with cardiopulmonary bypass, followed by 120-min deep hypothermic circulatory arrest. Animals were then warmed to 38°C, removed from bypass, and maintained for 120 min. Methylprednisolone (60 mg/kg) was administered in the cardiopulmonary bypass pump prime (intraoperative glucocorticoids) or 6 hours before bypass (30 mg/kg) in addition to the intraoperative dose (30 mg/kg; preoperative and intraoperative glucocorticoids). Controls (no glucocorticoids) received saline.: ResultsPulmonary vascular resistance in controls increased from a baseline of 152 ± 40 to 364 ± 29 dynes · s/cm5 at 2 hours of recovery (p < 0.001). Intraoperative glucocorticoids did not alleviate the increase in pulmonary vascular resistance (301 ± 55 dynes · s/cm5 at 2 hours of recovery, p < 0.001). However, animals receiving pre and intraoperative glucocorticoids had no increase in pulmonary vascular resistance (155 ± 54 dynes · s/cm5). Plasma endothelin-1 in controls increased from 1.3 ± 0.2 at baseline to 9.9 ± 2.0 pg/mL at 2 hours recovery (p < 0.01), whereas glucocorticoid-treated animals had lower endothelin-1 levels (4.5 ± 2.1 pg/ml, preoperative and intraoperative glucocorticoids; 4.9 ± 1.7 pg/mL, intraoperative glucocorticoids) at the end of recovery (p < 0.05). Intracellular adhesion molecule-1 in lung tissue was lower in animals receiving pre and intraoperative glucocorticoids (p < 0.05). Myeloperoxidase activity was elevated in control lungs at 2 hours of recovery compared with glucocorticoid-treated groups (p < 0.05). Inhibitor κBα, the inhibitor of nuclear factor-κB, was higher in lungs of animals receiving glucocorticoids compared with controls (p < 0.05).: ConclusionsGlucocorticoids prevented pulmonary hypertension after cardiopulmonary bypass and deep hypothermic circulatory arrest, which was associated with reduced plasma endothelin-1. Glucocorticoids also reduced pulmonary intercellular adhesion molecule-1 and myeloperoxidase activity. Inhibition of nuclear factor-κB, along with reduced neutrophil activation, contributed to glucocorticoid alleviation of pulmonary hypertension after cardiopulmonary bypass and deep hypothermic circulatory arrest. [Copyright &y& Elsevier]

The Na, K-ATPase plays an essential role in active alveolar epithelial fluid resorption. In fetal and adult alveolar epithelial cells, glucocorticoids (GC) increase Na, K-ATPase activity, mRNA levels, and transcription rate of the β1 subunit. In this study, we describe a glucocorticoid responsive element (GRE) in the coding region of the rat Na, K-ATPase β1 gene in a rat lung epithelial cell line. Transient transfection experiments with the β1 subunit coding region with or without the 5′ and 3′ untranslated regions demonstrated responsiveness to dexamethasone induction and also identified a GRE at +434 in exon IV. The +434 GRE conferred dexamethasone responsiveness in a heterologous thymidine kinase promoter irrespective of its orientation to the β1 promoter. Transcriptional upregulation by dexamethasone was abolished in +434 mutants. Electrophoretic mobility shift assays (EMSA) demonstrated specific binding of nuclear proteins to the +434 GRE and the presence of the GC receptor. This specific binding was inhibited by a GRE previously described in the rat Na, K-ATPase β1 gene at −631. In conclusion, we identified a GRE at +434 in the exon IV of the rat Na, K-ATPase β1 gene. [Copyright &y& Elsevier]

Here we show that stress exerts a differential effect on T-cell-dependent antibody production. IgG production is augmented after acute stress and impaired in a chronic situation. We found catecholamines and corticosterone levels were increased in acute situations although they were not modified after prolonged stress conditions. However, lymphocyte sensitivity to corticosterone and catecholamines was altered under stress conditions. These results point out the role of the adrenal''s hormones as mediators of the differential effects of stress on the immune response providing the basis for a functional significance of stress hormone receptors on lymphocytes. [Copyright &y& Elsevier]

Glucocorticoids (GC) such as hydrocortisone and dexamethasone (DEX) protect steroidogenic granulosa cells against apoptosis induced by serum deprivation, cAMP, tumor necrosis factor α stimulation or p53 activation. The protective effects were evident both in primary rat and human granulosa cells, which comprise the main population of the ovarian follicular cells, as well as in steroidogenic granulosa cell lines established in our laboratory. A correlation between the expression of Bcl-2 protein and protection against apoptosis induced by DEX was found in granulosa cell lines expressing various levels of Bcl-2. Incubation with DEX leads to development of a rigid network of actin cytoskeleton and increased incidence of adherence and gap junctions. Higher content of connexin 43 and total cadherins were found in GC stimulated cells compared to non-stimulated, suggesting that cell contact and intracellular communication contribute to the DEX induced resistance to apoptotic signals. Activation by DEX of MAPK and Akt/PKB but not p38 supported the view of a pleiotropic action of GC against apoptotic signals. Granzyme B, a protease characteristic for induction of apoptosis by T-cytotoxic lymphocytes and natural killer cells, was expressed and augmented during stimulation of apoptosis in the granulosa cells, and its synthesis and activation was blocked by DEX. It is concluded that GC exerted their anti-apoptotic effects in granulosa cells by multiple characteristic pathways. Moreover, the presence of endogenous granzyme B in granulosa cells suggest a novel intrinsic alternative apoptotic pathway that was earlier reported to be mediated uniquely by T-cytotoxic lymphocytes and natural killer cells. The anti-apoptotic effect of GC may play an important role in the healing process of the ovulatory follicle subsequent to follicular rupture and its rapid conversion to an active corpus luteum. [Copyright &y& Elsevier]

Glucocorticoids are among the most widely used agents for the treatment of inflammatory diseases. The primary mechanism of glucocorticoid action is via the glucocorticoid receptor (GR), which blocks the expression of proinflammatory cytokines and adhesion molecules. Repression of many pro-inflammatory genes occurs by inhibition of transcription factors including nuclear factor κB (NFκB) and activator protein-1 (AP-1). In this article, we discuss the physiological and molecular interaction that occurs between GR and proinflammatory cytokines signaling pathways. IUBMB Life, 55: 497-504, 2003 [ABSTRACT FROM AUTHOR]

Hyperactivity of the hypothalamic–pituitary–adrenal axis is a characteristic feature of depressive illness. The centrally located corticosteroid receptors, the glucocorticoid and mineralocorticoid receptors, are thought to be important modulators of this axis and changes in the levels of these receptors, particularly in the hippocampus, may underlie the hyperactivity observed. Various antidepressant drugs increase hippocampal mineralocorticoid and glucocorticoid receptor levels in vivo. These effects are thought to be mediated via alterations in monoaminergic neurotransmission. We examined whether serotonin (5HT) and noradrenaline (NA) have direct effects on glucocorticoid receptor and mineralocorticoid receptor expression in primary hippocampal neurones, and whether antidepressants also exert direct effects on target neurones. Exposure of hippocampal cells to 5HT for 4 days increased both glucocorticoid and mineralocorticoid receptor mRNA and protein expression. The induction of mineralocorticoid receptor mRNA was completely blocked by the 5HT7 receptor antagonist SB 269970. In contrast glucocorticoid receptor induction was insensitive to the 5HT7 receptor, whilst studies with the 5HT1A receptor agonist 8-hydroxy-2-(di-n-proplamino) tetralin hydrochloride and the 5HT1A receptor antagonist N-[2-[4-2-[O-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane carboxamide trihydrochloride (WAY 100635) suggest a partial role for 5HT1A receptors in hippocampal glucocorticoid receptor regulation. Treatment with NA for 4 days also increased glucocorticoid receptor expression but had no effect on mineralocorticoid receptor expression. This was blocked by propanolol suggesting action via β-adrenergic receptors. Similarly to NA, fluoxetine and amitriptyline also selectively increased glucocorticoid receptor mRNA and protein levels over this time course. However, glucocorticoid receptor induction by fluoxetine or amitriptyline was not blocked by WAY 100635 or propanolol.These results show that 5HT, NA and antidepressants act directly but via distinct mechanisms on hippocampal neurones to regulate mineralocorticoid and glucocorticoid receptor expression. Thusly manipulation of neurotransmitter or antidepressant levels in the brain may aid in reversing hypothalamic–pituitary–adrenal axis hyperactivity by restoring hippocampal corticosteroid receptor balance. [Copyright &y& Elsevier]

A recent article by Kwan and colleagues could elegantly demonstrate the necessary interaction between neuronal serotonin (5-HT) systems and the hypothalamic-pituitary-adrenal (HPA) axis through glucocorticoid receptors (GR), producing an adequate stress response, in this case, responding to hypoxia with an increase in hematopoietic stem and progenitor cells (HSPC). There is an intricate system connecting brain, body and mind and this exchange is only possible when all these systems-nervous, endocrine, and immune-have receptors on critical cells to receive information (via messenger molecules) from each of the other systems. There is evidence that the expression and function of GR in the hippocampus, mainly MR, is regulated by the stimulation of 5-HT receptors. Stressful stimuli increase 5-HT release and turnover in the hippocampus, and it seems reasonable to suggest that some of the changes in mineralocorticoid and GR expression may be mediated, in part at least, by the increase in 5-HT. Also serotonin and HPA axis dysfunctions have already been implicated in a variety of psychiatric disorders, especially depression. Early life stress (ELS) can have profound impact on these systems and can predispose subjects to a variety of adult metabolic and psychiatric conditions. It is important to analyze the mechanisms of this complex interaction and its subsequent programming effects on the stress systems, so that we can find new ways and targets for treatment of psychiatric disorders. Different areas of research on basic biological sciences are now being integrated and this approach will hopefully provide several new insights, new pharmacological targets and improve our global understanding of these highly debilitating chronic conditions, that we now call mental disorders., Competing Interests: Conflicts of Interest: MF Juruena has within the last year received honoraria for speaking from GSK, Lundbeck and Pfizer and is a Consultant Psychiatrist at University of Sao Paulo and SLaM (NHS UK); AH Young and AJ Cleare are supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. AJ Cleare has within the last 3 years received honoraria for lectures or consulting from Astra Zeneca, Lundbeck, Livanova & Allergan, and a research grant from Lundbeck. AH Young received honoraria for lectures and advisory boards for all major pharmaceutical companies with drugs used in affective and related disorders. Investigator-initiated studies from AZ, Eli Lilly and Lundbeck. B Agustini has no conflicts of interest to declare.