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Glucocorticoids - Top 30 Publications

Critical illness-related corticosteroid insufficiency (CIRCI): a narrative review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM).

To provide a narrative review of the latest concepts and understanding of the pathophysiology of critical illness-related corticosteroid insufficiency (CIRCI).

Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017.

To update the 2008 consensus statements for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in adult and pediatric patients.

Thyroid emergencies : Thyroid storm and myxedema coma.

Thyroid emergencies are rare life-threatening endocrine conditions resulting from either decompensated thyrotoxicosis (thyroid storm) or severe thyroid hormone deficiency (myxedema coma). Both conditions develop out of a long-standing undiagnosed or untreated hyper- or hypothyroidism, respectively, precipitated by an acute stress-associated event, such as infection, trauma, or surgery. Cardinal features of thyroid storm are myasthenia, cardiovascular symptoms, in particular tachycardia, as well as hyperthermia and central nervous system dysfunction. The diagnosis is made based on clinical criteria only as thyroid hormone measurements do not differentiate between thyroid storm and uncomplicated hyperthyroidism. In addition to critical care measures therapy focusses on inhibition of thyroid hormone synthesis and secretion (antithyroid drugs, perchlorate, Lugol's solution, cholestyramine, thyroidectomy) as well as inhibition of thyroid hormone effects in the periphery (β-blocker, glucocorticoids).Cardinal symptoms of myxedema coma are hypothermia, decreased mental status, and hypoventilation with risk of pneumonia and hyponatremia. The diagnosis is also purely based on clinical criteria as measurements of thyroid hormone levels do not differ between uncomplicated severe hypothyroidism and myxedema coma. In addition to substitution of thyroid hormones and glucocorticoids, therapy focusses on critical care measures to treat hypoventilation and hypercapnia, correction of hyponatremia and hypothermia.Survival of both thyroid emergencies can only be optimized by early diagnosis based on clinical criteria and prompt initiation of multimodal therapy including supportive measures and treatment of the precipitating event.

Purity and Stability of the Membrane-Limited Glucocorticoid Receptor Agonist Dexamethasone-BSA.

Cellular effects of glucocorticoids can be separated into classical transcriptional regulation via activation of the canonical nuclear glucocorticoid receptor and rapid actions mediated by activation of one or more putative membrane-associated glucocorticoid receptors that regulate both transcriptional and non-transcriptional signaling. Dexamethasone-bovine serum albumin (Dex-BSA), is one of several membrane-limited steroid receptor agonists. Dex-BSA and other steroid conjugates such as corticosterone-, estradiol- and testosterone-BSA have been used to study rapid steroid effects initiated by a putative membrane receptor. The purity and stability of the steroid-BSA conjugate is crucial, therefore, since any steroid that is not bound to or that dissociates from the BSA conjugate could penetrate into the intracellular compartment and confound the experiment. We used fluorine NMR to determine if free Dex could be detected over time in a commercially available Dex-BSA dissolved in H2O. Non-covalently bound Dex was detected in the Dex-BSA solution, but the level of free Dex remained constant over time and over a range of temperatures, indicating that the free Dex was not a result of instability of the Dex-BSA conjugate. The free Dex was lost when the Dex-BSA was denatured and subjected to dialysis, which suggested that it was trapped in the Dex-BSA three-dimensional structure and not covalently bound to the BSA. The purified, renatured Dex-BSA retained its rapid activity, which confirmed that the observed effects of Dex-BSA are not caused by non-covalently-bound Dex. Therefore, the Dex contaminant found in the Dex-BSA solution is likely to be tightly, but non-covalently, bound to BSA, and the Dex-BSA activity remains membrane-limited. Our findings indicate that Dex-BSA remains a suitable membrane-restricted glucocorticoid receptor agonist, but suggest that denaturing purification is a useful control for the study of membrane-initiated steroid-BSA actions.

Selective glucocorticoid receptor antagonist CORT125281 activates brown adipose tissue and alters lipid distribution in male mice.

Glucocorticoids influence a wide range of metabolic processes in the human body and excessive glucocorticoid exposure is known to contribute to the development of metabolic disease. We evaluated the utility of the novel glucocorticoid receptor (GR) antagonist CORT125281 for its potential to overcome adiposity, glucose intolerance and dyslipidaemia, and compared this head-to-head with classic GR antagonist RU486 (mifepristone). We show that, while RU486 displays cross-reactivity to the progesterone and androgen receptor, CORT125281 selectively inhibits GR transcriptional activity. In a mouse model for diet-induced obesity, rhythmicity of circulating corticosterone levels was disturbed. CORT125281 restored this disturbed rhythmicity, in contrast to RU486 that further inhibited endogenous corticosterone levels and suppressed adrenal weight. Both CORT125281 and RU486 reduced body weight gain and fat mass. In addition CORT125281, but not RU486, lowered plasma levels of triglycerides, cholesterol and free fatty acids, and strongly stimulated triglyceride-derived fatty acid uptake by brown adipose tissue depots. In combination with reduced lipid content in brown adipocytes, this indicates that CORT125281 enhances metabolic activity of brown adipose tissue depots. CORT125281 was also found to increase liver lipid accumulation. Taken together, CORT125281 displayed a wide range of beneficial metabolic activities, that are in part distinct from RU486, but clinical utility may be limited due to liver lipid accumulation. This warrants further evaluation of GR antagonists or selective modulators that are not accompanied by liver lipid accumulation, while preserving their beneficial metabolic activities.

Pioneer Factors FOXA1 and FOXA2 Assist Selective Glucocorticoid Receptor Signaling In Human Endometrial Cells.

Successful pregnancy relies on dynamic control of cell signaling in order to achieve uterine receptivity and the necessary biological changes required for endometrial decidualization, embryo implantation, and fetal development. Glucocorticoids are master regulators of intracellular signaling and can directly regulate embryo implantation and endometrial remodeling during murine pregnancy. In immortalized human uterine cells, we have shown that glucocorticoids and estradiol co-regulate thousands of genes. Recently, glucocorticoids and estradiol were shown to co-regulate the expression of Left-right determination factor 1 (LEFTY1), previously implicated in the regulation of decidualization. To elucidate the molecular mechanism by which glucocorticoids and estradiol regulate the expression of LEFTY1, immortalized and primary human endometrial cells were evaluated for gene expression and receptor recruitment to regulatory regions of the LEFTY1 gene. Glucocorticoid administration induced expression of LEFTY1 mRNA and protein and recruitment of the glucocorticoid receptor (GR) and activated polymerase II to the promoter of LEFTY1. Glucocorticoid-mediated recruitment of GR was dependent on pioneer factors FOXA1 and FOXA2. Estradiol was found to antagonize glucocorticoid-mediated induction of LEFTY1 by reducing recruitment of GR, FOXA1, FOXA2, and activated polymerase II to the LEFTY1 promoter. Gene expression analysis identified several genes whose glucocorticoid-dependent induction required FOXA1 and FOXA2 in endometrial cells. These results suggest a novel mechanism by which estradiol antagonizes GR-dependent induction of specific genes by preventing the recruitment of the pioneer factors FOXA1 and FOXA2 in a physiologically relevant model.

Critical Illness-Related Corticosteroid Insufficiency (CIRCI): A Narrative Review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM).

To provide a narrative review of the latest concepts and understanding of the pathophysiology of critical illness-related corticosteroid insufficiency (CIRCI).

Type III Interferons in Systemic Lupus Erythematosus: Association Between Interferon λ3, Disease Activity, and Anti-Ro/SSA Antibodies.

The aim of this study was to assess associations between serum type III (λ) interferons (IFN-λ) and disease activity in systemic lupus erythematosus (SLE).

Type III Interferons in Systemic Lupus Erythematosus: Association Between Interferon λ3, Disease Activity, and Anti-Ro/SSA Antibodies.

The aim of this study was to assess associations between serum type III (λ) interferons (IFN-λ) and disease activity in systemic lupus erythematosus (SLE).

Interference of stress with the somatotropic axis in pigs - lights on new biomarkers.

The acceptance of animal products is increasingly associated with standardized animal welfare, which relates to appropriate animal husbandry from birth to slaughter. In particular, shipment to the slaughterhouse is considered as a critical process exposing the animals to a number of, in part severe, stressors. New biomarkers may be useful for the assessment of animal welfare. The IGF-system has been assessed in a commercial pig transport in conjunction with established markers of stress response. Furthermore, the effect of repeated restraint as an experimental model for repeated acute stress was investigated. During shipment from farm to slaughterhouse, plasma concentrations of IGFBP-3 and IGFBP-2 were significantly reduced (p < 0.01). After shipment, the plasma concentrations of IGFBP-5, glucocorticoids and IL-2 increased but decreased after lairage (p < 0.05) whereas IGF-1 decreased after shipment (p < 0.01). Repeated acute stress increased concentrations of IGFBP-3 and IGF-1 in exsanguination blood (p < 0.05). Differential IGF- signatures can indicate altered endocrine or metabolic control and thus contain complex animal-related information. The somatotropic axis may be of particular interest when established biomarkers such as cortisol, glucose, or lactate cannot be used for the assessment of animal stress or welfare.

Higher growth rate and gene expression in male zebra finch embryos are independent of manipulation of maternal steroids in the eggs.

Sexual dimorphism in prenatal development is widespread among vertebrates, including birds. Its mechanism remains unclear, although it has been attributed to the effect of maternal steroid hormones. The aim of this study was to investigate how increased levels of steroid hormones in the eggs influence early embryonic development of male and female offspring. We also asked whether maternal hormones take part in the control of sex-specific expression of the genes involved in prenatal development. We experimentally manipulated hormones' concentrations in the egg yolk by injecting zebra finch females prior to ovulation with testosterone or corticosterone. We assessed growth rate and expression levels of CDK7, FBP1 and GHR genes in 37 h-old embryos. We found faster growth and higher expression of two studied genes in male compared to female embryos. Hormonal treatment, despite clearly differentiating egg steroid levels, had no effect on the sex-specific pattern of the embryonic gene expression, even though we confirmed expression of receptors of androgens and glucocorticoids at such an early stage of development. Thus, our study shows high stability of the early sex differences in the embryonic development before the onset of sexual differentiation and indicates their independence of maternal hormones in the egg.

Pharmacotranscriptomic biomarkers in glucocorticoid treatment of pediatric inflammatory bowel disease.

Pharmacotranscriptomics aims to reach more accurate drug dosing based on interindividual transcriptome variations. Here, we provide an overview of RNA biomarkers that could predict the response to glucocorticoids (GCs), considered the standard for treatment of inflammatory bowel diseases (IBD), both in adult and pediatric patients. Although new biological agents are very effective in the IBD treatment, GCs are still widely used for induction of remission in IBD patients with moderate to severe disease. It is important to identify patients that are poor responders to GCs therapy, because suboptimal response is frequent and associated with various side effects. A number of genetic variants related to GC mechanism of action has been studied. However, the majority of reported associations are not consistent. In this regard, pharmacogenomic research is now exploring the world of RNAs. An appropriate regulation of the transcriptome, which mainly comprises mRNAs and non-coding RNAs that control gene expression, has a strong impact in the modulation of GCs activity. The aim of this review is to present the current knowledge of the role of the transcriptome in modulating GC response in pediatric IBD. We will discuss the available literature, concerning the development of pharmacotranscriptomic biomarkers, focusing particularly on non-coding RNAs, and present the results in this field that elucidate a concrete benefit of translating the knowledge gained in the "omics" studies into clinical practice.

Glucocorticoid Sparing of Benralizumab in Asthma.

The Role and Regulation of the 11 Beta-Hydroxysteroid Dehydrogenase Enzyme System in Patients with Inflammatory Bowel Disease.

Glucocorticoids are known to modulate a number of immunological responses including counteracting inflammation. Within tissues expressing the glucocorticoid and mineralocorticoid receptors including the colon, glucocorticoid metabolism is regulated by the isoenzymes of 11ß-hydroxysteroid dehydrogenase (11β-HSD). 11β-HSD1 acts as an oxidoreductase converting inactive cortisone into active cortisol, while 11β-HSD2 acts as a dehydrogenase converting active cortisol to inactive cortisone. Hexose-6 phosphate dehydrogenase (H6PDH) is a key regulator of 11β-HSD1 activity via its generation of NADPH. Variations in the 11β-HSD enzyme system in relation to levels of expression and regulation may have a role in IBD. The aim of this study was to investigate possible abnormalities of 11β-HSD enzyme system in the colon of patients with IBD.

Treatment of pretibial myxedema with intralesional immunomodulating therapy.

Local immune regulation therapy has been one of the therapeutic methods used for the treatment of autoimmune thyroid disease in patients with pretibial myxedema (PTM). However, the poor response rate and high recurrence rate are still major problems. Whether a premixed corticosteroid, compound betamethasone, could enhance remission rate and decrease recurrence rate in patients with PTM was investigated in the present study.

The influence of stress hormones and aggression on cooperative behaviour in subordinate meerkats.

In cooperative breeders, aggression from dominant breeders directed at subordinates may raise subordinate stress hormone (glucocorticoid) concentrations. This may benefit dominants by suppressing subordinate reproduction but it is uncertain whether aggression from dominants can elevate subordinate cooperative behaviour, or how resulting changes in subordinate glucocorticoid concentrations affect their cooperative behaviour. We show here that the effects of manipulating glucocorticoid concentrations in wild meerkats (Suricata suricatta) on cooperative behaviour varied between cooperative activities as well as between the sexes. Subordinates of both sexes treated with a glucocorticoid receptor antagonist (mifepristone) exhibited significantly more pup protection behaviour (babysitting) compared to those treated with glucocorticoids (cortisol) or controls. Females treated with mifepristone had a higher probability of exhibiting pup food provisioning (pup-feeding) compared to those treated with cortisol. In males, there were no treatment effects on the probability of pup-feeding, but those treated with cortisol gave a higher proportion of the food they found to pups than those treated with mifepristone. Using 19 years of behavioural data, we also show that dominant females did not increase the frequency with which they directed aggression at subordinates at times when the need for assistance was highest. Our results suggest that it is unlikely that dominant females manipulate the cooperative behaviour of subordinates through the effects of aggression on their glucocorticoid levels and that the function of aggression directed at subordinates is probably to reduce the probability they will breed.

Glucocorticoid Sparing of Benralizumab in Asthma.

Glucocorticoid Sparing of Benralizumab in Asthma.

Adenosine Receptor Stimulation Improves Glucocorticoid-Induced Osteoporosis in a Rat Model.

Glucocorticoid-induced osteoporosis (GIO) is a secondary cause of bone loss. Bisphosphonates approved for GIO, might induce jaw osteonecrosis; thus additional therapeutics are required. Adenosine receptor agonists are positive regulators of bone remodeling, thus the efficacy of adenosine receptor stimulation for treating GIO was tested. In a preventive study GIO was induced in Sprague-Dawley rats by methylprednisolone (MP) for 60 days. Animals were randomly assigned to receive polydeoxyribonucleotide (PDRN), an adenosine A2 receptor agonist, or PDRN and DMPX (3,7-dimethyl-1-propargylxanthine, an A2 antagonist), or vehicle (0.9% NaCl). Another set of animals was used for a treatment study, following the 60 days of MP-induction rats were randomized to receive (for additional 60 days) PDRN, or PDRN and DMPX (an adenosine A2 receptor antagonist), or zoledronate (as control for gold standard treatment), or vehicle. Control animals were administered with vehicle for either 60 or 120 days. Femurs were analyzed after treatments for histology, imaging, and breaking strength analysis. MP treatment induced severe bone loss, the concomitant use of PDRN prevented the developing of osteoporosis. In rats treated for 120 days, PDRN restored bone architecture and bone strength; increased b-ALP, osteocalcin, osteoprotegerin and stimulated the Wnt canonical and non-canonical pathway. Zoledronate reduced bone resorption and ameliorated the histological features, without significant effects on bone formation. Our results suggest that adenosine receptor stimulation might be useful for preventing and treating GIO.

A Survey of Glucocorticoid Adverse Effects and Benefits in Rheumatic Diseases: The Patient Perspective.

The aim of this study was to explore, from the patient's perspective, the beneficial and adverse effects (AEs) of glucocorticoids (GCs) in patients with rheumatic diseases, to be used in the development of a patient-reported outcome measure.

Neural Basis of Major Depression: Beyond Monoamine Hypothesis.

Monoamine hypothesis has been accepted as the most common hypothesis of major depression for a long period because of its simplicity and understandability. Actually, most of currently used antidepressants have been considered to act based on monoamine hypothesis. However, it has been pointed out as an important problem of monoamine hypothesis that it is unable to explain the latency of response to antidepressants. In addition, a large number of patients with major depression has been refractory to currently used antidepressants yet. Therefore, monoamine-alternate hypotheses are required to explain the latency of response to antidepressants. Such hypotheses were expected to contribute to identifying new hopeful therapeutic targets for major depression. A number of past studies have revealed that the volume of the hippocampus is decreased in patients with major depression likely caused by the failure of hypothalamic-pituitary-adrenal axis and following elevation of glucocorticoids. Two hypotheses have been proposed to explain the volume of the hippocampus: neuroplasticity hypothesis and neurogenesis hypothesis. Neuroplasticity hypothesis explains the hippocampal volume is decreased by the morphological changes of hippocampal neurons such as the shortening length of dendrites and the decreased number and density of spines. Neurogenesis hypothesis explains the hippocampal volume is decreased by the decrease of neurogenesis in the hippocampal dentate gyrus. These hypotheses are able to explain the latency of response to antidepressants. In this review, we first overview how neuroplasticity and neurogenesis hypotheses have been developed. Following it, we describe the details of these hypotheses.

The impact of long-term systemic glucocorticoid use in severe asthma: A UK retrospective cohort analysis.

Systemic glucocorticoids (SGCs) are a treatment option for severe asthma but are associated with the development of adverse events (AEs). Evidence on the extent of SGC use and the relationship between SGC dose and AE risk in severe asthma is limited.

Prenatal Glucocorticoid Exposure Modifies Endocrine Function and Behaviour for 3 Generations Following Maternal and Paternal Transmission.

Fetal exposure to high levels of glucocorticoids programs long-term changes in the physiologic stress response and behaviours. However, it is not known whether effects manifest in subsequent generations of offspring following maternal (MT) or paternal (PT) transmission. We treated pregnant guinea pigs with three courses of saline or synthetic glucocorticoid (sGC) at a clinically relevant dose. Altered cortisol response to stress and behaviours transmitted to juvenile female and male F2 and F3 offspring from both parental lines. Behavioural effects of sGC in F1-F3 PT females associated with altered expression of genes in the prefrontal cortex and hypothalamic paraventricular nucleus (PVN). Exposure to sGC programmed large transgenerational changes in PVN gene expression, including type II diabetes, thermoregulation, and collagen formation gene networks. We demonstrate transgenerational programming to F3 following antenatal sGC. Transmission is sex- and generation-dependent, occurring through both parental lines. Paternal transmission to F3 females strongly implicates epigenetic mechanisms of transmission.

Associations between Voriconazole Therapeutic Drug Monitoring, Toxicity and outcome in Liver Transplant Patients; an Observational Study.

The aim of this study was to investigate the variability of voriconazole plasma level and its relationship with clinical outcomes and adverse events, among liver transplant recipients to optimize the efficacy and safety of their treatment. Liver transplant recipients treated with voriconazole were included and voriconazole trough levels were quantified by the validated high-performance liquid chromatography method. Cytochrome P450 genotypes of CYP2C19 were evaluated in allograft liver tissues. A total of 832 voriconazole trough levels from 104 patients were measured. Proven, probable and possible invasive fungal infections were reported in (8/104, 7.7%), (42/104, 40.4%), and (54/104, 51.9%) patients, respectively. ROC curve analysis indicated that trough concentration ≥1.3 μg/ml minimized the incidence of treatment failure (95% CI 0.68-0.91; P < 0.001), and < 5.3 μg/ml minimized the incidence of any adverse events (95% CI 0.83-0.97; P < 0.001). Voriconazole trough levels were significantly higher in heterozygous extensive metabolizers, poor metabolizers and co-administration with proton pump inhibitors. In ultra-rapid metabolizers, oral administration of voriconazole and concomitant use of glucocorticoids, voriconazole blood concentrations were significantly reduced. Furthermore, there was no statistically significant association of patients' age, weight, gender, co-administration of tacrolimus and cyclosporine with voriconazole trough level. In conclusion, the results of our analysis indicated large inter and intra-individual variabilities of voriconazole concentrations in liver transplant recipients. Voriconazole trough concentrations between ≥1.3 μg/ml and < 5.3 μg/ml are optimal for treatment and minimize adverse events. Optimizing drug efficacy and safety need rational doses for voriconazole therapy.

SELECTIVE GLUCOCORTICOID RECEPTOR MODULATION INHIBITS CYTOKINE RESPONSES IN A CANINE MODEL OF MILD ENDOTOXEMIA.

Selective glucocorticoid receptor modulators (GRMs) promise to reduce adverse events of glucocorticoids while maintaining anti-inflammatory potency. The present study tested the anti-inflammatory activity of two novel non-steroidal GRMs (GRM1: BI 607812 BS, GRM2: BI 653048 BS*H3PO4) in comparison to prednisolone in a canine model of low dose endotoxemia. This study compared the anti-inflammatory and pharmacokinetic profile of escalating daily oral doses of GRM1 (1, 2.5, 5 and 10mg/kg) and GRM2 (0.1, 0.25 and 1mg/kg) with prednisolone (0.25 and 0.5mg/kg) and placebo after intravenous infusion of endotoxin (0.1μg/kg) to Beagle dogs. This was followed by a 14-day evaluation study of safety and pharmacokinetics. Endotoxin challenge increased TNF-α ∼2000-fold and interleukin-6 (IL-6) 100-fold. Prednisolone and both GRMs suppressed peak TNF-α and IL-6 by 71-82% as compared with placebo. The highest doses of GRM1 and GRM2 reduced the mean body temperature increase by ∼30%. The endotoxin-induced rise in plasma cortisol was strongly suppressed in all treatment groups. Pharmacokinetics of both GRMs were non-linear. Adverse effects of endotoxemia such as vomiting were mitigated by GRM2 and prednisolone, indicating an antiemetic effect. During the 14-day treatment period, the adverse event profile of both GRMs appeared to be similar to prednisolone. Both GRMs had anti-inflammatory effects comparable to prednisolone and showed good safety profiles. Compounds targeting the glucocorticoid receptor selectively may provide an alternative to traditional glucocorticoids in the treatment of inflammatory disease.

Up-regulation of Rho-associated kinase 1/2 by glucocorticoids promotes migration, invasion and metastasis of melanoma.

Although glucocorticoids (GCs) regulate proliferation, differentiation and apoptosis of tumor cells, their influence on metastasis of tumor cells is poorly understood. Melanoma is a type of skin cancers with high metastasis. We investigated the effect of GCs on metastasis of melanoma cells and its mechanism. We found that GCs significantly promoted the adhesion, migration, invasion of melanoma cells in vitro and lung metastasis in experimental melanoma metastasis mice. Dexamethasone (Dex), a synthetic GC, did not change the RhoA, RhoB and RhoC signalings, but significantly increased the expression and activity of Rho-associated kinase 1/2 (ROCK1/2). The effect of Dex was to increase ROCK1/2 stability mediated by glucocorticoid receptor. Inhibiting ROCK1/2 activity with Y-27632, a ROCK1/2 inhibitor abrogated the pro-migration and pro-metastasis effects of GCs in vitro and in vivo, indicating that ROCK1/2 mediated the pro-metastasis effects of GCs. Activation of PI3K/AKT also contributed to the pro-migration and pro-invasion effects of Dex partially through up-regulating ROCK1/2 expression. Additionally, Dex also down-regulated the expression of tissue inhibitors of matrix metalloproteinase-2. Taken together, our findings provide new data to understand the possible promoting roles and mechanisms of GCs in melanoma metastasis.

SIRT1 is a transcriptional enhancer of the glucocorticoid receptor acting independently to its deacetylase activity.

Glucocorticoids have strong effects on diverse human activities through the glucocorticoid receptor (GR). Sirtuin 1 (SIRT1) is a NAD(+)-dependent histone deacetylase and promotes longevity by influencing intermediary metabolism and other regulatory activities including mitochondrial function. In this study, we examined the effects of SIRT1 on GR-mediated transcriptional activity. We found that SIRT1 enhanced GR-induced transcriptional activity on exogenous and endogenous glucocorticoid-responsive genes, whereas knockdown of SIRT1 attenuated it. This effect of SIRT1 was independent to its deacetylase activity, as the SIRT1 mutant defective in this activity (H363Y) enhanced GR transcriptional activity, and the compounds inhibiting or activating the SIRT1 deacetylase activity did not influence it. RNA-seq analysis revealed that SIRT1 knockdown influenced ∼30% of the glucocorticoid-responsive transcriptome for most of which it acted as an enhancer for positive/negative effects of this hormone. SIRT1 physically interacted with GR, and was attracted to GR-bound glucocorticoid response elements in a glucocorticoid-dependent fashion. SIRT1 cooperatively activated GR transcriptional activity with the PPARγ coactivator-1α also in its deacetylase activity-independent fashion. Thus, SIRT1 is a novel transcriptional enhancer of GR-induced transcriptional activity possibly by functioning as a scaffold for the transcriptional complex formed on GR.

Drugs and hyperglycemia: A practical guide.

Drug-induced diabetes is one of the factors contributing to the increasing incidence of diabetes worldwide. This review considers the frequency, pathogenesis and treatment of drug-induced diabetes. Drugs that induce diabetes include hormonal therapy, especially glucocorticoids and androgen blockers, cardiovascular drugs, especially statins, beta-blockers and diuretics, antipsychotics, especially clozapine, olanzapine and quetiapine, antiretrovirals (protease inhibitors and non-reverse transcriptase inhibitors - NRTIs) and other drugs (mechanistic target of rapamycin inhibitors -mTORs, post organ transplantation drugs, tyrosine kinase inhibitors and interferon-alpha). Abnormalities of the distal gluco-regulatory pathways of hyperglycemia involve decreased insulin secretion and frequent insulin resistance, whereas the proximal defects are unknown, thus limiting targeted treatment. Drug-induced diabetes is potentially reversible and the risk is underestimated. There is little information on its long-term effects on microvascular complications as clinical trials have not been long enough and neither have they focused on these factors. Overall management includes awareness of a drug's diabetogenic potential, underlying diabetes risk, benefits and risks of continuing vs discontinuing the drug, plus a consideration of drug duration and dose. While diabetes and its severity can be identified and controlled, the likelihood of future diabetes complications frequently cannot. This, balanced against the predicted benefit of the drug, results in clinical uncertainty. Empirical approaches to drug-related hyperglycemia include decreasing the dose or selecting an alternative treatment, if possible. In the absence of drug-specific evidence, treatment of drug-induced hyperglycemia and diabetes is similar to comprehensive standard diabetes care, including lifestyle modifications, oral/injectable antidiabetic agents and insulin. Important clinical considerations include surveillance of glucose before and during treatment and, in some cases, institution of diabetes preventive measures like lifestyle modification and early treatment. Future research is needed to elucidate pathophysiology and optimal targeted treatment for drug-induced diabetes and its long-term complications.

Combination Therapy of Intravenous Steroids and Orbital Irradiation is More Effective Than Intravenous Steroids Alone in Patients with Graves' Orbitopathy.

The aim of this study was to evaluate and compare the efficacy of intravenous (iv) glucocorticoids (GCs) with and without orbital radiotherapy (ORT) in a retrospective analysis of patients with active, moderate-to-severe Graves' orbitopathy (GO). Since diplopia has the strongest impact on quality of life, a careful work up of motility and binocular single vision (BSV) has been performed. The Essen-EUGOGO-Center database (n=3655) was screened for patients with untreated moderate-to-severe, active GO, onset ≤12 months. The inclusion criteria were met by 148 patients (n=76 ivGC, n=72 ivGC + ORT). We analyzed CAS (inactivation: ≤2), NOSPECS, lid-width, proptosis, motility, and field of BSV. To score the overall ophthalmic outcome, a severity-weighted-score (SOS) was compared with an established EUGOGO inflammation-weighted-score (IOS). Cumulative ivGCs dosages and duration of GO did not differ between the groups. Patients with combination therapy had a significantly more severe GO at baseline. Therefore, a subgroup with matched severity was additionally compared. In the IOS, both groups reached similar improvement rates (55.2 vs. 63.9%; p=0.31). However, in the SOS, the rates differed significantly (46.1 vs. 61.1%; p=0.03- unmatched and p=0.03 matched), despite similar rates of inactivation (65.8 vs. 63.8%). Impaired motility improved significantly more often after combination therapy (p=0.01 matched, p=0.004 unmatched). Treatment responders showed only partial improvement (proptosis: 2.5±0.5 mm; motility: 11.3±10.9°). In our retrospective analysis, combination therapy (ivGCs + ORT) was significantly more effective in reduction of severity and should therefore always be considered in moderate-to-severe GO stages, especially in the presence of motility disorders. However, the limited improvement in clinical parameters, despite the promising effect on inactivation of inflammation, has to be outlined to the patients.

Combination Therapy with Pirfenidone plus Prednisolone Ameliorates Paraquat-Induced Pulmonary Fibrosis.

Pirfenidone is known to slow the decline in vital capacity and increase survival in idiopathic pulmonary fibrosis (IPF). Besides, administration of glucocorticoids, e.g., prednisolone has been the conventional strategy to the treatment of patients with this disease, although their efficacy is under debate. Since multiple coactivated pathways are involved in the pathogenesis of IPF, combination therapy is a foundation strategy to cover many more synergetic mechanisms and increase response. The aim of the present study was to compare the therapeutic efficacy of prednisolone plus pirfenidone with pirfenidone alone in PQ-induced lung fibrosis. After development of PQ-induced lung fibrosis, pirfenidone, prednisolone, and their combination were administered for 14 consecutive days. Lung pathological lesions, along with increased hydroxyproline were determined in the paraquat group. Paraquat also caused oxidative stress and increasing the proinflammatory and profibrotic gene expression. Pirfenidone attenuated the PQ-induced pulmonary fibrosis from the analysis of antioxidant enzymes but prednisolone had no such effect. Co-treatment with pirfenidone and prednisolone suppressed lung hydroxyproline content, TGF-β1, and TNF-α; however, prednisolone alone could not suppress pulmonary fibrosis which was significantly suppressed only by pirfenidone. Pirfenidone also suppressed the increase in MMP-2 and TIMP-1 induced by PQ. All of these effects were exaggerated when pirfenidone coadministered with prednisolone. These findings suggest that pirfenidone exerts its antifibrotic effect through regulation of hydroxyproline content, oxidative stress and proinflammatory and profibrotic gene expression during the development of PQ-induced pulmonary fibrosis in rats and combination therapy with prednisolone can represent more potent therapeutic effects.