WorldWideScience

Sample records for glucocorticoid protects rodent

  1. A rodent model of rapid-onset diabetes induced by glucocorticoids and high-fat feeding

    Directory of Open Access Journals (Sweden)

    Yaniv Shpilberg

    2012-09-01

    Glucocorticoids (GCs are potent pharmacological agents used to treat a number of immune conditions. GCs are also naturally occurring steroid hormones (e.g. cortisol, corticosterone produced in response to stressful conditions that are thought to increase the preference for calorie dense ‘comfort’ foods. If chronically elevated, GCs can contribute to the development of type 2 diabetes mellitus (T2DM, although the mechanisms for the diabetogenic effects are not entirely clear. The present study proposes a new rodent model to investigate the combined metabolic effects of elevated GCs and high-fat feeding on ectopic fat deposition and diabetes development. Male Sprague-Dawley rats (aged 7–8 weeks received exogenous corticosterone or wax (placebo pellets, implanted subcutaneously, and were fed either a standard chow diet (SD or a 60% high-fat diet (HFD for 16 days. Animals given corticosterone and a HFD (cort-HFD had lower body weight and smaller relative glycolytic muscle mass, but increased relative epididymal mass, compared with controls (placebo-SD. Cort-HFD rats exhibited severe hepatic steatosis and increased muscle lipid deposition compared with placebo-SD animals. Moreover, cort-HFD animals were found to exhibit severe fasting hyperglycemia (60% increase, hyperinsulinemia (80% increase, insulin resistance (60% increase and impaired β-cell response to oral glucose load (20% decrease compared with placebo-SD animals. Thus, a metabolic syndrome or T2DM phenotype can be rapidly induced in young Sprague-Dawley rats by using exogenous GCs if a HFD is consumed. This finding might be valuable in examining the physiological and molecular mechanisms of GC-induced metabolic disease.

  2. Involvement of glucocorticoid in induction of lingual T1R3 in rodents.

    Science.gov (United States)

    Ogawa, Nobuhumi; Kanki, Keita; Honda, Kotaro; Tomooka, Yasuhiro; Ryoke, Kazuo; Watanabe, Tatsuo

    2015-08-15

    We previously reported that in rats, chronic exposure to stress inhibits the induction of the common receptor (T1R3) for sweet and umami tastes. Here, we investigated whether endogenous glucocorticoids (GCs) might be responsible for this inhibition. In addition, we used mouse taste-bud cells (TB cells) expressing T1R3 to examine the effect of exogenous GC on T1R3 induction. Both adrenal glands were removed from rats [adrenalectomized (ADX) rats] and T1R3 mRNA expression in fungiform papillae was examined by real-time RT-PCR. T1R3 mRNA expression was significantly reduced in the ADX rats (versus sham-ADX rats). The reduced mRNA expression was restored to the level seen in the sham-ADX rats by administration of dexamethasone (DEX) at the smallest dose tested (0.1ng/kg, i.p.). However, with larger doses of DEX (10 and 1000ng/kg, i.p.) there was no such restoration (i.e., the expression level did not differ from that seen in ADX rats). Expression of the mRNA for the GC receptor-α was detected in mouse TB cells by RT-PCR. Significantly reduced T1R3 mRNA expression, as measured by real-time RT-PCR, was observed in TB cells at 24h after application of DEX (0.1, 1.0, or 10μM). These results suggest that in rodents: (a) a low concentration of endogenous GC is necessary and sufficient for induction of T1R3 expression, and that higher concentrations may actually inhibit such induction, and (b) this inhibitory effect may be due, at least in part, to a direct action of GC on taste cells. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Telomerase protects adult rodent olfactory ensheathing glia from early senescence.

    Science.gov (United States)

    Llamusí, María-Beatriz; Rubio, Mari-Paz; Ramón-Cueto, Almudena

    2011-05-01

    Adult olfactory bulb ensheathing glia (OB-OEG) promote the repair of acute, subacute, and chronic spinal cord injuries and autologous transplantation is a feasible approach. There are interspecies differences between adult rodent and primate OB-OEG related to their longevity in culture. Whereas primate OB-OEG exhibit a relatively long life span, under the same culture conditions rodent OB-OEG divide just three to four times, are sensitive to oxidative stress and become senescent after the third week in vitro. Telomerase is a "physiological key regulator" of the life span of normal somatic cells and also has extratelomeric functions such as increased resistance to oxidative stress. To elucidate whether telomerase has a role in the senescence of rodent OB-OEG, we have introduced the catalytic subunit of telomerase mTERT into cultures of these cells by retroviral infection. Native and modified adult rat OB-OEG behaved as telomerase-competent cells as they divided while expressing mTERT but entered senescence once the gene switched off. After ectopic expression of mTERT, OB-OEG resumed division at a nonsenescent rate, expressed p75 and other OEG markers, and exhibited the morphology of nonsenescent OB-OEG. The nonsenescent period of mTERT-OEG lasted 9weeks and then ectopic mTERT switched off and cells entered senescence again. Our results suggest a role of telomerase in early senescence of adult rodent OB-OEG cultures and a protection from oxidative damage. This article is part of a Special Issue entitled: Understanding olfactory ensheathing glia and their prospect for nervous system repair. Copyright © 2010 Elsevier Inc. All rights reserved.

  4. Protection of Stored Plant Products Using Chlorophacinone Against Rodent Pests

    Directory of Open Access Journals (Sweden)

    Marina Vukša

    2010-01-01

    Full Text Available Apart from some preventive measures advisably taken during construction of storage facilities or at the time of product storage, treatments with chemical rodenticides are the most widely practiced method of controlling commensal rodents. Their control in storage facilities is normally carried out after animal presence has been observed, and treatments from early autumn onwards throughout the season provide the best effect. The aim of this paper is to present the effects of rodent control using baits with less content am chlorofacinon than recommended, to the protection of stored plant products. The experiments were set up using the relevant OEPP/EPPO method. A ready for use (RB paste bait formulation was used with different contents (0.005% and 0.0075% of the active ingredient chlorophacinone.Baits were laid in boxes along rodent routes, underneath pallets with sacs and in places where major damage had been observed. Baits for house mouse were placed at a rate of 10-20 g per 1-3 m, while 30-50 g of bait for brown rats were laid at specific points. Daily bait intake was monitored over a period of ten days and the portions were replaced with new ones as needed. Placebo baits were laid in identical boxes for four days before the experiment began. The abundance of house mouse was estimated based on the highest and lowest daily intake of bait divided by the species’ daily requirement. Mice presence was monitored over the next 20 days. Rodenticide efficacy was calculated using Abbott’s formula. The data in this experiment show that chorophacinone contents of 0.005% and 0.0075% in RB baits had no effect on the palatability and bait efficacy in controlling house mouse and brown rat indoors. The average efficacy of chorophacinone was 87-93% against house mouse and 90-100% against brown rat.

  5. Protective effect of chlorpromazine on endotoxin toxicity and TNF production in glucocorticoid-sensitive and glucocorticoid-resistant models of endotoxic shock

    OpenAIRE

    1991-01-01

    The present study was designed to define the potential of chlorpromazine (CPZ) as a protective agent against lipopolysaccharide (LPS) toxicity in comparison with glucocorticoids, and to obtain initial correlations with its effects on the levels of tumor necrosis factor (TNF), a pivotal mediator of endotoxic shock. It was found that CPZ protects mice, normal or adrenalectomized, and guinea pigs against lethality of LPS, and inhibited TNF serum levels, like dexamethasone (DEX), a well-known inh...

  6. Melatonin protects chondrocytes from impairment induced by glucocorticoids via NAD+-dependent SIRT1.

    Science.gov (United States)

    Yang, Wei; Kang, Xiaomin; Qin, Na; Li, Feng; Jin, Xinxin; Ma, Zhengmin; Qian, Zhuang; Wu, Shufang

    2017-10-01

    Intra-articular injection of glucocorticoids is used to relieve pain and inflammation in osteoarthritis patients, which is occasionally accompanied with the serious side effects of glucocorticoids in collagen-producing tissue. Melatonin is the major hormone released from the pineal gland and its beneficial effects on cartilage has been suggested. In the present study, we investigated the protective role of melatonin on matrix degeneration in chondrocytes induced by dexamethasone (Dex). The chondrocytes isolated from mice knee joint were treated with Dex, melatonin, EX527 and siRNA targeted for SIRT6, respectively. Dex treatment induced the loss of the extracellular matrix, NAD + /NADH ratio and NADPH concentration in chondrocytes. Melatonin alone have no effect on the quantity of proteoglycans and collagen type IIa1, however, the pretreatment of melatonin reversed the negative effects induced by Dex. Meanwhile, the significant decrease in NAD + /NADH ratio and NADPH concentration in Dex group were up-regulated by pretreatment of melatonin. Furthermore, it was revealed that inhibition of SIRT1 blocked the protective effects of melatonin. The enhancement of NAD + -dependent SIRT1 activity contributes to the chondroprotecfive effects of melatonin, which has a great benefit to prevent dexamethasone-induced chondrocytes impairment. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Protective effect of chlorpromazine on endotoxin toxicity and TNF production in glucocorticoid-sensitive and glucocorticoid-resistant models of endotoxic shock

    Science.gov (United States)

    1991-01-01

    The present study was designed to define the potential of chlorpromazine (CPZ) as a protective agent against lipopolysaccharide (LPS) toxicity in comparison with glucocorticoids, and to obtain initial correlations with its effects on the levels of tumor necrosis factor (TNF), a pivotal mediator of endotoxic shock. It was found that CPZ protects mice, normal or adrenalectomized, and guinea pigs against lethality of LPS, and inhibited TNF serum levels, like dexamethasone (DEX), a well-known inhibitor of TNF synthesis. CPZ protected against LPS lethality when administered 30 minutes (min) before, simultaneously, or up to 10 min after LPS and was ineffective when given 30 min after LPS, paralleling the inhibitory effect on TNF production. In another experimental model, where mice were sensitized to LPS toxicity by actinomycin D, CPZ significantly inhibited LPS lethality and hepatotoxicity, whereas under these conditions DEX was inactive. These experiments indicate that CPZ has a protective action in both glucocorticoid-sensitive and -resistant models of endotoxic shock. PMID:2033366

  8. Rodent malaria: BCG-induced protection and immunosuppression

    International Nuclear Information System (INIS)

    Smrkovski, L.L.; Strickland, G.T.

    1978-01-01

    One dose of 10 7 viable units of Mycobacterium bovis, strain BCG, protected a significant number of Swiss mice from a primary challenge with 10 4 thoracic sporozoites of Plasmodium berghei. Immunization with irradiated sporozoites induced greater protection than that observed in BCG-treated animals. Mice treated with BCG and surviving a primary sporozoite challenge were not protected from rechallenge, whereas mice immunized with irradiated sporozoites and surviving initial challenge of sporozoites were solidly immune to further challenge. Immunizing mice with BCG and irradiated sporozoites simulataneously resulted in a synergistic effect of increased protection against a primary challenge of sporozoites only if the two immunogens were administered on the same day and if the mice were challenged 1 to 3 days later. Mice given BCG and irradiated sporozoites and surviving a primary challenge of sporozoites were unable to survive rechallenge. BCG given to mice previously immunized with irradiated sporozoites suppressed their protective immunity against sporozoite challenge

  9. BCL-2 protects human and mouse Th17 cells from glucocorticoid-induced apoptosis

    Science.gov (United States)

    Banuelos, J.; Shin, S.; Cao, Y.; Bochner, B. S.; Morales-Nebreda, L.; Budinger, G. R. S.; Zhou, L.; Li, S.; Xin, J.; Lingen, M. W.; Dong, C.; Schleimer, R. P.; Lu, N. Z.

    2016-01-01

    Background Glucocorticoid resistance has been associated with Th17-driven inflammation, the mechanisms of which are not clear. We determined whether human and mouse Th17 cells are resistant to glucocorticoid-induced apoptosis. Methods Freshly isolated human blood Th17 cells and in vitro differentiated Th17 cells from IL-17F red fluorescent protein reporter mice were treated with dexamethasone, a potent glucocorticoid. Apoptosis was measured using annexin V and DAPI staining. Screening of apoptosis genes was performed using the apoptosis PCR array. Levels of molecules involved in apoptosis were measured using quantitative RT-PCR, flow cytometry, and Western blotting. Knockdown of BCL-2 in murine Th17 cells was performed via retroviral transduction. Cytokines were measured using ELISA. A murine Th17-driven severe asthma model was examined for Th17 glucocorticoid sensitivity in vivo. Results Human and mouse Th17 cells and mouse Th2 cells were resistant to glucocorticoid-induced apoptosis. Th17 cells had glucocorticoid receptors levels comparable to those in other T effectors cells. Th17 cells had high levels of BCL-2, knockdown of which sensitized Th17 cells to dexamethasone-induced apoptosis. Production of IL-22, but not IL-17A and IL-17F, was suppressed by glucocorticoids. STAT3 phosphorylation in Th17 cells was insensitive to glucocorticoid inhibition. Lung Th17 cells in the murine severe asthma model were enhanced, rather than suppressed, by glucocorticoids. Conclusion Th17 cells are resistant to glucocorticoid-induced apoptosis and cytokine suppression, at least in part due to high levels of BCL-2. These findings support a role of Th17 cells in glucocorticoid-resistant inflammatory conditions such as certain endotypes of asthma. PMID:26752231

  10. Glucocorticoids Suppress the Protective Effect of Cyclooxygenase-2-Related Signaling on Hippocampal Neurogenesis Under Acute Immune Stress.

    Science.gov (United States)

    Ma, Yanbo; Matsuwaki, Takashi; Yamanouchi, Keitaro; Nishihara, Masugi

    2017-04-01

    Stress and glucocorticoids suppress adult neurogenesis in the hippocampus. However, the molecular mechanisms underlying stress-induced impairment of adult neurogenesis are poorly understood. We previously suggested that cyclooxygenase (COX)-2 is a common mediator of stresses in the brain. Here, using a lipopolysaccharide (LPS)-induced acute infectious stress model, we evaluated the roles of COX-2 and its major downstream product prostaglandin E2 (PGE2) in adult neurogenesis and the influence of glucocorticoids on COX-2-related signaling. Treatment of rats with LPS significantly decreased neurogenesis in the dentate gyrus (DG) of the hippocampus, and this inhibitory effect of LPS on neurogenesis was reversed by the glucocorticoid receptor antagonist RU486. Moreover, RU486 significantly enhanced the increase in messenger RNA (mRNA) levels of COX-2 and microsomal prostaglandin E synthase (mPGES)-1 in the hippocampus following LPS stimulation. Administration of AH6809, a selective antagonist of the PGE2 EP2 receptor, as well as NS398, a COX-2 selective inhibitor, exacerbated the suppression of proliferation of neural progenitor cells (NPCs) in the DG. Gene expression of EP1, EP2, and EP3, but not EP4, receptors was also increased following LPS stimulation. Immunohistochemical studies indicated that NPCs expressed EP2 receptor, whereas the majority of cells expressing COX-2 and mPGES-1 were mature neurons in the DG. These results suggest that acute infectious stress upregulates COX-2-related signaling in neurons in the DG, which plays a protective role in neurogenesis through EP2 receptor at least partially. In addition, LPS-induced glucocorticoids suppress this COX-2-related signaling, resulting in decreased neurogenesis.

  11. Activation of glucocorticoid receptors in Müller glia is protective to retinal neurons and suppresses microglial reactivity.

    Science.gov (United States)

    Gallina, Donika; Zelinka, Christopher Paul; Cebulla, Colleen M; Fischer, Andy J

    2015-11-01

    Reactive microglia and macrophages are prevalent in damaged retinas. Glucocorticoid signaling is known to suppress inflammation and the reactivity of microglia and macrophages. In the vertebrate retina, the glucocorticoid receptor (GCR) is known to be activated and localized to the nuclei of Müller glia (Gallina et al., 2014). Accordingly, we investigated how signaling through GCR influences the survival of neurons using the chick retina in vivo as a model system. We applied intraocular injections of GCR agonist or antagonist, assessed microglial reactivity, and the survival of retinal neurons following different damage paradigms. Microglial reactivity was increased in retinas from eyes that were injected with vehicle, and this reactivity was decreased by GCR-agonist dexamethasone (Dex) and increased by GCR-antagonist RU486. We found that activation of GCR suppresses the reactivity of microglia and inhibited the loss of retinal neurons resulting from excitotoxicity. We provide evidence that the protection-promoting effects of Dex were maintained when the microglia were selectively ablated. Similarly, intraocular injections of Dex protected ganglion cells from colchicine-treatment and protected photoreceptors from damage caused by retinal detachment. We conclude that activation of GCR promotes the survival of ganglion cells in colchicine-damaged retinas, promotes the survival of amacrine and bipolar cells in excitotoxin-damaged retinas, and promotes the survival of photoreceptors in detached retinas. We propose that suppression of microglial reactivity is secondary to activation of GCR in Müller glia, and this mode of signaling is an effective means to lessen the damage and vision loss resulting from different types of retinal damage. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Administration of erythropoietin exerts protective effects against glucocorticoid-induced osteonecrosis of the femoral head in rats.

    Science.gov (United States)

    Chen, Sen; Li, Jianping; Peng, Hao; Zhou, Jianlin; Fang, Hongsong

    2014-04-01

    Accumulating evidence has indicated that erythropoietin (EPO) plays a role in anti-apoptosis and tissue protection in a number of human diseases. The present study was implemented to evaluate these anti-apoptotic and tissue-protective effects in glucocorticoid-induced osteonecrosis in rats. Osteonecrosis was induced by low-dose lipopolysaccharide and subsequent high-dose methylprednisolone pulse. Rats in the preventive group were treated with 500 U/kg/day recombinant human EPO (rhuEPO) for 1 week. Hematological and histomorphometric methods were then used to determine the effects of the administration of rhuEPO. An analysis of trabecular bone architecture was performed to evaluate bone mass change in the osteonecrosis zone. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay was performed to determine the apoptotic index of osteoblasts and osteocytes. Immunoblot analysis was performed to assess the expression of caspase-3 and vascular endothelial growth factor (VEGF) in the femoral head. Treatment with rhuEPO greatly improved the histological performance. Additionally, the incidence of osteonecrosis markedly decreased in the rats in the rhuEPO-treated group (22.2%) compared with the control group (66.7%). Furthermore, the expression of caspase-3 markedly decreased in the rhuEPO-treated group. Consistently, the apoptosis of osteoblasts and osteocytes, as determined by TUNEL assays, was inhibited following the administration of rhuEPO. By contrast, the expression of VEGF increased in the osteonecrosis zone in the rats treated with rhuEPO. The results from the present study demonstrate that EPO exerts prominent protective effects against glucocorticoid-induced osteonecrosis of the femoral head in rats by inhibiting the apoptosis of osteoblasts and osteocytes and increasing the expression of VEGF.

  13. Loss of the endothelial glucocorticoid receptor prevents the therapeutic protection afforded by dexamethasone after LPS.

    Directory of Open Access Journals (Sweden)

    Julie E Goodwin

    Full Text Available Glucocorticoids are normally regarded as anti-inflammatory therapy for a wide variety of conditions and have been used with some success in treating sepsis and sepsis-like syndromes. We previously demonstrated that mice lacking the glucocorticoid receptor in the endothelium (GR EC KO mice are extremely sensitive to low-dose LPS and demonstrate prolonged activation and up regulation of NF-κB. In this study we pre-treated these GR EC KO mice with dexamethasone and assessed their response to an identical dose of LPS. Surprisingly, the GR EC KO mice fared even worse than when given LPS alone demonstrating increased mortality, increased levels of the inflammatory cytokines TNF-α and IL-6 and increased nitric oxide release after the dexamethasone pre-treatment. As expected, control animals pre-treated with dexamethasone showed improvement in all parameters assayed. Mechanistically we demonstrate that GR EC KO mice show increased iNOS production and NF-κB activation despite treatment with dexamethasone.

  14. Rupatadine protects against pulmonary fibrosis by attenuating PAF-mediated senescence in rodents.

    Science.gov (United States)

    Lv, Xiao-xi; Wang, Xiao-xing; Li, Ke; Wang, Zi-yan; Li, Zhe; Lv, Qi; Fu, Xiao-ming; Hu, Zhuo-wei

    2013-01-01

    A similar immune response is implicated in the pathogenesis of pulmonary fibrosis and allergic disorders. We investigated the potential therapeutic efficacy and mechanism of rupatadine, a dual antagonist of histamine and platelet-activation factor (PAF), in bleomycin- (BLM-) and silica-induced pulmonary fibrosis. The indicated dosages of rupatadine were administered in rodents with bleomycin or silica-induced pulmonary fibrosis. The tissue injury, fibrosis, inflammatory cells and cytokines, and lung function were examined to evaluate the therapeutic efficacy of rupatadine. The anti-fibrosis effect of rupatadine was compared with an H1 or PAF receptor antagonist, and efforts were made to reveal rupatadine's anti-fibrotic mechanism. Rupatadine promoted the resolution of pulmonary inflammation and fibrosis in a dose-dependent manner, as indicated by the reductions in inflammation score, collagen deposition and epithelial-mesenchymal transformation, and infiltration or expression of inflammatory cells or cytokines in the fibrotic lung tissue. Thus, rupatadine treatment improved the declined lung function and significantly decreased animal death. Moreover, rupatadine was able not only to attenuate silica-induced silicosis but also to produce a superior therapeutic efficacy compared to pirfenidone, histamine H1 antagonist loratadine, or PAF antagonist CV-3988. The anti-fibrotic action of rupatadine might relate to its attenuation of BLM- or PAF-induced premature senescence because rupatadine treatment protected against the in vivo and in vitro activation of the p53/p21-dependent senescence pathway. Our studies indicate that rupatadine promotes the resolution of pulmonary inflammation and fibrosis by attenuating the PAF-mediated senescence response. Rupatadine holds promise as a novel drug to treat the devastating disease of pulmonary fibrosis.

  15. Memantine protects against amphetamine derivatives-induced neurotoxic damage in rodents.

    Science.gov (United States)

    Chipana, C; Torres, I; Camarasa, J; Pubill, D; Escubedo, E

    2008-06-01

    We hypothesize that 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine (METH) interact with alpha-7 nicotinic receptors (nAChR). Here we examine whether memantine (MEM), an antagonist of NMDAR and alpha-7 nAChR, prevents MDMA and METH neurotoxicity. MEM prevented both serotonergic injury induced by MDMA in rat and dopaminergic lesion by METH in mice. MEM has a better protective effect in front of MDMA- and METH-induced neurotoxicity than methyllycaconitine (MLA), a specific alpha-7 nAChR antagonist. The double antagonism that MEM exerts on NMDA receptor and on alpha-7 nAChR, probably contributes to its effectiveness. MEM inhibited reactive oxygen species production induced by MDMA or METH in synaptosomes. This effect was not modified by NMDA receptor antagonists, but reversed by alpha-7 nAChR agonist (PNU 282987), demonstrating a preventive effect of MEM as a result of it blocking alpha-7 nAChR. In synaptosomes, MDMA decreased 5-HT uptake by about 40%. This decrease was prevented by MEM and by MLA but enhanced by PNU 282987. A similar pattern was observed when we measured the dopamine transport inhibited by METH. The inhibition of both transporters by amphetamine derivatives seems to be regulated by the calcium incorporation after activation of alpha-7 nAChR. MDMA competitively displaces [(3)H]MLA from rat brain membranes. MEM and METH also displace [(3)H]MLA with non-competitive displacement profiles that fit a two-site model. We conclude that MEM prevents MDMA and METH effects in rodents. MEM may offer neuroprotection against neurotoxicity induced by MDMA and METH by preventing the deleterious effects of these amphetamine derivatives on their respective transporters.

  16. Rupatadine protects against pulmonary fibrosis by attenuating PAF-mediated senescence in rodents.

    Directory of Open Access Journals (Sweden)

    Xiao-xi Lv

    Full Text Available A similar immune response is implicated in the pathogenesis of pulmonary fibrosis and allergic disorders. We investigated the potential therapeutic efficacy and mechanism of rupatadine, a dual antagonist of histamine and platelet-activation factor (PAF, in bleomycin- (BLM- and silica-induced pulmonary fibrosis. The indicated dosages of rupatadine were administered in rodents with bleomycin or silica-induced pulmonary fibrosis. The tissue injury, fibrosis, inflammatory cells and cytokines, and lung function were examined to evaluate the therapeutic efficacy of rupatadine. The anti-fibrosis effect of rupatadine was compared with an H1 or PAF receptor antagonist, and efforts were made to reveal rupatadine's anti-fibrotic mechanism. Rupatadine promoted the resolution of pulmonary inflammation and fibrosis in a dose-dependent manner, as indicated by the reductions in inflammation score, collagen deposition and epithelial-mesenchymal transformation, and infiltration or expression of inflammatory cells or cytokines in the fibrotic lung tissue. Thus, rupatadine treatment improved the declined lung function and significantly decreased animal death. Moreover, rupatadine was able not only to attenuate silica-induced silicosis but also to produce a superior therapeutic efficacy compared to pirfenidone, histamine H1 antagonist loratadine, or PAF antagonist CV-3988. The anti-fibrotic action of rupatadine might relate to its attenuation of BLM- or PAF-induced premature senescence because rupatadine treatment protected against the in vivo and in vitro activation of the p53/p21-dependent senescence pathway. Our studies indicate that rupatadine promotes the resolution of pulmonary inflammation and fibrosis by attenuating the PAF-mediated senescence response. Rupatadine holds promise as a novel drug to treat the devastating disease of pulmonary fibrosis.

  17. Serum glucocorticoid inducible kinase (SGK)-1 protects endothelial cells against oxidative stress and apoptosis induced by hyperglycaemia.

    Science.gov (United States)

    Ferrelli, Francesca; Pastore, Donatella; Capuani, Barbara; Lombardo, Marco F; Blot-Chabaud, Marcel; Coppola, Andrea; Basello, Katia; Galli, Angelica; Donadel, Giulia; Romano, Maria; Caratelli, Sara; Pacifici, Francesca; Arriga, Roberto; Di Daniele, Nicola; Sbraccia, Paolo; Sconocchia, Giuseppe; Bellia, Alfonso; Tesauro, Manfredi; Federici, Massimo; Della-Morte, David; Lauro, Davide

    2015-02-01

    Diabetic hyperglycaemia causes endothelial dysfunction mainly by impairing endothelial nitric oxide (NO) production. Moreover, hyperglycaemia activates several noxious cellular pathways including apoptosis, increase in reactive oxygen species (ROS) levels and diminishing Na(+)-K(+) ATPase activity which exacerbate vascular damage. Serum glucocorticoid kinase (SGK)-1, a member of the serine/threonine kinases, plays a pivotal role in regulating NO production through inducible NO synthase activation and other cellular mechanisms. Therefore, in this study, we aimed to investigate the protective role of SGK-1 against hyperglycaemia in human umbilical endothelial cells (HUVECs). We used retrovirus to infect HUVECs with either SGK-1, SGK-1Δ60 (lacking of the N-60 amino acids-increase SGK-1 activity) or SGK-1Δ60KD (kinase-dead constructs). We tested our hypothesis in vitro after high glucose and glucosamine incubation. Increase in SGK-1 expression and activity (SGK-1Δ60) resulted in higher production of NO, inhibition of ROS synthesis and lower apoptosis in endothelial cell after either hyperglycaemia or glucosamine treatments. Moreover, in this study, we showed increased GLUT-1 membrane translocation and Na(+)-K(+) ATPase activity in cell infected with SGK-1Δ60 construct. These results suggest that as in endothelial cells, an increased SGK-1 activity and expression reduces oxidative stress, improves cell survival and restores insulin-mediated NO production after different noxae stimuli. Therefore, SGK-1 may represent a specific target to further develop novel therapeutic options against diabetic vascular disease.

  18. Activation of glucocorticoid receptors in Müller glia is protective to retinal neurons and suppresses microglial reactivity

    OpenAIRE

    Gallina, Donika; Zelinka, Christopher Paul; Cebulla, Colleen; Fischer, Andy J.

    2015-01-01

    Reactive microglia and macrophages are prevalent in damaged retinas. Glucocorticoid signaling is known to suppress inflammation and the reactivity of microglia and macrophages. In the vertebrate retina, the glucocorticoid receptor (GCR) is known to be activated and localized to the nuclei of Müller glia (Gallina et al., 2014). Accordingly, we investigated how signaling through GCR influences the survival of neurons using the chick retina in vivo as a model system. We applied intraocular injec...

  19. Glucocorticoids, bone and energy metabolism.

    Science.gov (United States)

    Cooper, Mark S; Seibel, Markus J; Zhou, Hong

    2016-01-01

    Prolonged exposure to excessive levels of endogenous or exogenous glucocorticoids is associated with serious clinical features including altered body composition and the development of insulin resistance, impaired glucose tolerance and diabetes. It had been assumed that these adverse effects were mediated by direct effects of glucocorticoids on tissues such as adipose or liver. Recent studies have however indicated that these effects are, at least in part, mediated through the actions of glucocorticoids on bone and specifically the osteoblast. In mice, targeted abrogation of glucocorticoid signalling in osteoblasts significantly attenuated the changes in body composition and systemic fuel metabolism seen during glucocorticoid treatment. Heterotopic expression of osteocalcin in the liver of normal mice was also able to protect against the metabolic changes induced by glucocorticoids indicating that osteocalcin was the likely factor connecting bone osteoblasts to systemic fuel metabolism. Studies are now needed in humans to determine the extent to which glucocorticoid induced changes in body composition and systemic fuel metabolism are mediated through bone. This article is part of a Special Issue entitled Bone and diabetes. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Fine pathogen discrimination within the APL1 gene family protects Anopheles gambiae against human and rodent malaria species.

    Science.gov (United States)

    Mitri, Christian; Jacques, Jean-Claude; Thiery, Isabelle; Riehle, Michelle M; Xu, Jiannong; Bischoff, Emmanuel; Morlais, Isabelle; Nsango, Sandrine E; Vernick, Kenneth D; Bourgouin, Catherine

    2009-09-01

    Genetically controlled resistance of Anopheles gambiae mosquitoes to Plasmodium falciparum is a common trait in the natural population, and a cluster of natural resistance loci were mapped to the Plasmodium-Resistance Island (PRI) of the A. gambiae genome. The APL1 family of leucine-rich repeat (LRR) proteins was highlighted by candidate gene studies in the PRI, and is comprised of paralogs APL1A, APL1B and APL1C that share > or =50% amino acid identity. Here, we present a functional analysis of the joint response of APL1 family members during mosquito infection with human and rodent Plasmodium species. Only paralog APL1A protected A. gambiae against infection with the human malaria parasite P. falciparum from both the field population and in vitro culture. In contrast, only paralog APL1C protected against the rodent malaria parasites P. berghei and P. yoelii. We show that anti-P. falciparum protection is mediated by the Imd/Rel2 pathway, while protection against P. berghei infection was shown to require Toll/Rel1 signaling. Further, only the short Rel2-S isoform and not the long Rel2-F isoform of Rel2 confers protection against P. falciparum. Protection correlates with the transcriptional regulation of APL1A by Rel2-S but not Rel2-F, suggesting that the Rel2-S anti-parasite phenotype results at least in part from its transcriptional control over APL1A. These results indicate that distinct members of the APL1 gene family display a mutually exclusive protective effect against different classes of Plasmodium parasites. It appears that a gene-for-pathogen-class system orients the appropriate host defenses against distinct categories of similar pathogens. It is known that insect innate immune pathways can distinguish between grossly different microbes such as Gram-positive bacteria, Gram-negative bacteria, or fungi, but the function of the APL1 paralogs reveals that mosquito innate immunity possesses a more fine-grained capacity to distinguish between classes of

  1. Fine pathogen discrimination within the APL1 gene family protects Anopheles gambiae against human and rodent malaria species.

    Directory of Open Access Journals (Sweden)

    Christian Mitri

    2009-09-01

    Full Text Available Genetically controlled resistance of Anopheles gambiae mosquitoes to Plasmodium falciparum is a common trait in the natural population, and a cluster of natural resistance loci were mapped to the Plasmodium-Resistance Island (PRI of the A. gambiae genome. The APL1 family of leucine-rich repeat (LRR proteins was highlighted by candidate gene studies in the PRI, and is comprised of paralogs APL1A, APL1B and APL1C that share > or =50% amino acid identity. Here, we present a functional analysis of the joint response of APL1 family members during mosquito infection with human and rodent Plasmodium species. Only paralog APL1A protected A. gambiae against infection with the human malaria parasite P. falciparum from both the field population and in vitro culture. In contrast, only paralog APL1C protected against the rodent malaria parasites P. berghei and P. yoelii. We show that anti-P. falciparum protection is mediated by the Imd/Rel2 pathway, while protection against P. berghei infection was shown to require Toll/Rel1 signaling. Further, only the short Rel2-S isoform and not the long Rel2-F isoform of Rel2 confers protection against P. falciparum. Protection correlates with the transcriptional regulation of APL1A by Rel2-S but not Rel2-F, suggesting that the Rel2-S anti-parasite phenotype results at least in part from its transcriptional control over APL1A. These results indicate that distinct members of the APL1 gene family display a mutually exclusive protective effect against different classes of Plasmodium parasites. It appears that a gene-for-pathogen-class system orients the appropriate host defenses against distinct categories of similar pathogens. It is known that insect innate immune pathways can distinguish between grossly different microbes such as Gram-positive bacteria, Gram-negative bacteria, or fungi, but the function of the APL1 paralogs reveals that mosquito innate immunity possesses a more fine-grained capacity to distinguish between

  2. THE SURPRISING DUAL ACTION OF GLUCOCORTICOIDS.

    Science.gov (United States)

    Filaretova, Ludmila; Makara, Gábor

    2014-03-30

    Glucocorticoid hormones may have dual action on the stomach: physiological gastroprotective and pathological proulcerogenic one. In physiological conditions, even in acute stress situations, glucocorticoids have an adaptive effect on the stomach and, therefore, are gastroprotective. The findings that we review in this article suggest that glucocorticoids released during acute stress are naturally occurring protective factors that play an important role in maintenance of the gastric mucosal integrity.

  3. When glucocorticoids change from protective to harmful: Lessons from a type 1 diabetes animal model Cuando los glucocorticoides cambian de protectores a dañinos en un modelo animal de diabetes tipo 1

    Directory of Open Access Journals (Sweden)

    Yanina Revsin

    2009-06-01

    Full Text Available A fundamental question in the neuroendocrinology of stress and adaptation is how stress mediators that are crucial for resilience and health can change into harmful signals enhancing vulnerability to disease. To address this question we focus in the rodent on corticosterone as end product of the hypothalamicpituitary- adrenal (HPA axis, which coordinates the behavioural and physiological response to stressors. The action of corticosterone is mediated by mineralocorticoid (MR and glucocorticoid receptors (GR. The receptors are transcription factors regulating gene transcription but recently these nuclear receptors were found to mediate also rapid non-genomic actions. MR participates in the initial stress reaction important for appraisal and coping processes, while management of the later adaptive phase primarily depends on GR. Imbalance in stress mediators is a characteristic feature of a phenotype vulnerable for stressors. This concept calls for recovery of the MR:GR balance as a therapeutic strategy to promote resilience still present in the diseased brain. As an example, we discuss in this article, how the impact of excessive levels of corticosterone in a pharmacological model of type 1 diabetes can be ameliorated after a brief treatment with a GR antagonist.Una cuestión fundamental en la neuroendocrinología del estrés y la adaptación es saber cómo los mediadores del estrés cruciales para la resiliencia y la salud pueden convertirse en señales dañinas que aumentan la vulnerabilidad a las enfermedades. Para responder a esta pregunta nosotros nos centramos en la corticosterona como producto final del eje hipotálamo-hipófisis-glándula adrenal de los ratones, que coordina las respuestas fisiológicas y conductuales hacia los agentes estresantes. La acción de la corticosterona es mediada por los receptores de los mineralocorticoides (MR y glucocorticoides (GR. Estos receptores son factores nucleares que regulan la transcripción de los

  4. Rodent malaria: BCG-induced protection and immunosuppression. [Mice, gamma radiation, Plasmodium berghei

    Energy Technology Data Exchange (ETDEWEB)

    Smrkovski, L.L.; Strickland, G.T.

    1978-10-01

    One dose of 10/sup 7/ viable units of Mycobacterium bovis, strain BCG, protected a significant number of Swiss mice from a primary challenge with 10/sup 4/ thoracic sporozoites of Plasmodium berghei. Immunization with irradiated sporozoites induced greater protection than that observed in BCG-treated animals. Mice treated with BCG and surviving a primary sporozoite challenge were not protected from rechallenge, whereas mice immunized with irradiated sporozoites and surviving initial challenge of sporozoites were solidly immune to further challenge. Immunizing mice with BCG and irradiated sporozoites simulataneously resulted in a synergistic effect of increased protection against a primary challenge of sporozoites only if the two immunogens were administered on the same day and if the mice were challenged 1 to 3 days later. Mice given BCG and irradiated sporozoites and surviving a primary challenge of sporozoites were unable to survive rechallenge. BCG given to mice previously immunized with irradiated sporozoites suppressed their protective immunity against sporozoite challenge.

  5. The respiratory syncytial virus G protein conserved domain induces a persistent and protective antibody response in rodents.

    Directory of Open Access Journals (Sweden)

    Thien N Nguyen

    Full Text Available Respiratory syncytial virus (RSV is an important cause of severe upper and lower respiratory disease in infants and in the elderly. There are 2 main RSV subtypes A and B. A recombinant vaccine was designed based on the central domain of the RSV-A attachment G protein which we had previously named G2Na (aa130-230. Here we evaluated immunogenicity, persistence of antibody (Ab response and protective efficacy induced in rodents by: (i G2Na fused to DT (Diphtheria toxin fragments in cotton rats. DT fusion did not potentiate neutralizing Ab responses against RSV-A or cross-reactivity to RSV-B. (ii G2Nb (aa130-230 of the RSV-B G protein either fused to, or admixed with G2Na. G2Nb did not induce RSV-B-reactive Ab responses. (iii G2Na at low doses. Two injections of 3 µg G2Na in Alum were sufficient to induce protective immune responses in mouse lungs, preventing RSV-A and greatly reducing RSV-B infections. In cotton rats, G2Na-induced RSV-reactive Ab and protective immunity against RSV-A challenge that persisted for at least 24 weeks. (iv injecting RSV primed mice with a single dose of G2Na/Alum or G2Na/PLGA [poly(D,L-lactide-co-glycolide]. Despite the presence of pre-existing RSV-specific Abs, these formulations effectively boosted anti-RSV Ab titres and increased Ab titres persisted for at least 21 weeks. Affinity maturation of these Abs increased from day 28 to day 148. These data indicate that G2Na has potential as a component of an RSV vaccine formulation.

  6. Plasmodium vivax thrombospondin related adhesion protein: immunogenicity and protective efficacy in rodents and Aotus monkeys

    Directory of Open Access Journals (Sweden)

    Angélica Castellanos

    2007-06-01

    Full Text Available The thrombospondin related adhesion protein (TRAP is a malaria pre-erythrocytic antigen currently pursued as malaria vaccine candidate to Plasmodium falciparum. In this study, a long synthetic peptide (LSP representing a P. vivax TRAP fragment involved in hepatocyte invasion was formulated in both Freund and Montanide ISA 720 adjutants and administered by IM and subcutaneous routes to BALB/c mice and Aotus monkeys. We measured specific humoral immune responses in both animal species and performed a sporozoite challenge in Aotus monkeys to assess the protective efficacy of the vaccine. After immunization both mice and Aotus seroconverted as shown by ELISA, and the specific anti-peptide antibodies cross reacted with the parasite in IFAT assays. Only two out of six immunized animals became infected after P. vivax sporozoite challenge as compared with four out of six animals from the control group. These results suggest that this TRAP fragment has protective potential against P. vivax malaria and deserves further studies as vaccine candidate.

  7. Context Modulates Outcome of Perinatal Glucocorticoid Action in the Brain

    Directory of Open Access Journals (Sweden)

    Edo Ronald ede Kloet

    2014-07-01

    Full Text Available Prematurely born infants may be at risk, because of inadequate maturation of tissues. If there are signs of preterm birth, it has become common practice therefore to treat either antenatally the mother or postnatally the infant with glucocorticoids to accelerate tissue development, particularly of the lung. However, this life-saving early glucocorticoid treatment was found to increase the risk of adverse outcome in later life. In one animal study the authors reported a 25% shorter lifespan of rats treated as newborns with the synthetic glucocorticoid dexamethasone, but sofar this finding has not been replicated. After a brief clinical introduction, we discuss studies in rodents designed to examine how perinatal glucocorticoid action affects the developing brain. It appears that the perinatal action of the glucocorticoid depends on the context and the timing as well as the type of administered steroid. The type of steroid is important because the endogenous glucocorticoids cortisol and corticosterone bind to two distinct receptor populations, i.e. mineralocorticoid (MR and glucocorticoid receptors (GR, while synthetic glucocorticoids predominantly bind to the GR. In addition, if given antenatally hydrocortisone is inactivated in the placenta by 11β-HSD type 2, and dexamethasone is not. With respect to timing, the outcome of glucocorticoid effects is different in early vs late phases of brain development. The context refers to the environmental input that can affect the susceptibility to glucocorticoid action in the newborn rodent brain; early handling of pups and maternal care obliterate effects of postnatal dexamethasone treatment. Context also refers to coping with environmental conditions in later life, for which the individual may have been programmed epigenetically by early life experience. This knowledge of determinants affecting the outcome of perinatal glucocorticoid exposure may have clinical implications for the treatment of

  8. Context modulates outcome of perinatal glucocorticoid action in the brain.

    Science.gov (United States)

    de Kloet, E Ronald; Claessens, Sanne E F; Kentrop, Jiska

    2014-01-01

    Prematurely born infants may be at risk, because of inadequate maturation of tissues. If there are signs of preterm birth, it has become common practice therefore to treat either antenatally the mother or postnatally the infant with glucocorticoids to accelerate tissue development, particularly of the lung. However, this life-saving early glucocorticoid treatment was found to increase the risk of adverse outcome in later life. In one animal study, the authors reported a 25% shorter lifespan of rats treated as newborns with the synthetic glucocorticoid dexamethasone, but so far this finding has not been replicated. After a brief clinical introduction, we discuss studies in rodents designed to examine how perinatal glucocorticoid action affects the developing brain. It appears that the perinatal action of the glucocorticoid depends on the context and the timing as well as the type of administered steroid. The type of steroid is important because the endogenous glucocorticoids cortisol and corticosterone bind to two distinct receptor populations, i.e., mineralocorticoid and glucocorticoid receptors (GR), while synthetic glucocorticoids predominantly bind to the GR. In addition, if given antenatally hydrocortisone is inactivated in the placenta by 11β-HSD type 2, and dexamethasone is not. With respect to timing, the outcome of glucocorticoid effects is different in early vs. late phases of brain development. The context refers to the environmental input that can affect the susceptibility to glucocorticoid action in the newborn rodent brain; early handling of pups and maternal care obliterate effects of post-natal dexamethasone treatment. Context also refers to coping with environmental conditions in later life, for which the individual may have been programed epigenetically by early-life experience. This knowledge of determinants affecting the outcome of perinatal glucocorticoid exposure may have clinical implications for the treatment of prematurely born infants.

  9. Synergistic protective effects of escin and low‑dose glucocorticoids on blood‑retinal barrier breakdown in a rat model of retinal ischemia.

    Science.gov (United States)

    Zhang, Fenglan; Li, Yuanbin; Zhang, Leiming; Mu, Guoying

    2013-05-01

    Escin, a natural mixture of triterpenoid saponins isolated from the seed of the horse chestnut (Aesculus hippocastanum), has been demonstrated to possess glucocorticoid (GC)‑like anti‑edematous and anti‑inflammatory effects. The aim of the present study was to investigate whether escin exhibits synergistic protective effects on blood‑retinal barrier (BRB) breakdown when combined with GCs in a rat model of retinal ischemia. Low concentrations of escin and triamcinolone acetonide (TA) alone did not affect BRB permeability. However, when administered together, low‑dose escin and TA significantly reduced BRB permeability following ischemia. Furthermore, low‑dose escin and TA alone did not affect the expression of occludin in the ischemic retina; however, when administered together, they significantly increased occludin expression in the ganglion cell layer of the ischemic retina. This indicates that escin and GCs have synergistic protective effects on BRB breakdown and the molecular mechanisms may be correlated with the upregulation of occludin. Therefore, the administration of escin may allow a reduction in the dose of GCs for the treatment of macular edema. The combination of escin with GCs is potentially a beneficial treatment method for BRB breakdown and warrants further investigation.

  10. 11beta-hydroxysteroid dehydrogenase type 1 regulates glucocorticoid-induced insulin resistance in skeletal muscle.

    LENUS (Irish Health Repository)

    Morgan, Stuart A

    2009-11-01

    Glucocorticoid excess is characterized by increased adiposity, skeletal myopathy, and insulin resistance, but the precise molecular mechanisms are unknown. Within skeletal muscle, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) converts cortisone (11-dehydrocorticosterone in rodents) to active cortisol (corticosterone in rodents). We aimed to determine the mechanisms underpinning glucocorticoid-induced insulin resistance in skeletal muscle and indentify how 11beta-HSD1 inhibitors improve insulin sensitivity.

  11. Brief treatment with the glucocorticoid receptor antagonist mifepristone normalizes the reduction in neurogenesis after chronic stress.

    NARCIS (Netherlands)

    Oomen, C.A.; Mayer, J.L.; de Kloet, E.R.; Joëls, M.; Lucassen, P.J.

    2007-01-01

    In rodents, stress suppresses adult neurogenesis. This is thought to involve activation of glucocorticoid receptors in the brain. In the present study, we therefore questioned whether glucocorticoid receptor blockade by mifepristone can normalize the effects of chronic stress on adult neurogenesis.

  12. Rediscovering the therapeutic use of glucocorticoids in rheumatoid arthritis.

    Science.gov (United States)

    van der Goes, Marlies C; Jacobs, Johannes W G; Bijlsma, Johannes W J

    2016-05-01

    This review will focus on new information obtained on how to apply glucocorticoids in the treatment of rheumatoid arthritis, aiming at an optimal risk-benefit ratio. Moreover, advances in the development of new preparations such as liposomal glucocorticoids will be discussed. In early rheumatoid arthritis, treatment regimens with a disease-modifying drug and initially medium-dose glucocorticoids (>7.5 but ≤30 mg prednisone equivalent) are noninferior compared with regimens with disease-modifying drugs and initially high-dose glucocorticoids (>30 mg prednisone equivalent) and have repeatedly been proven to be more effective than methotrexate monotherapy. Use of glucocorticoids following such a scheme during a period of 6 months to 2 years was not associated with increased mortality, nor with substantial bone loss if bone protective measures had been taken. New drug delivery systems, and in particular long-circulating liposomes, aiming at enhancing the biodistribution and the target site accumulation of glucocorticoids and thereby improving the balance between their efficacy and toxicity, are promising; more results on the effects in rheumatoid arthritis patients are expected to be reported during the years to come. Combination therapy including methotrexate and glucocorticoids should be the initial treatment in patients with early rheumatoid arthritis. Treatment regimens including medium-dose glucocorticoids are noninferior compared with regimens with initially high-dose glucocorticoids. Studies on new glucocorticoid preparations and new drug delivery systems improving the balance between efficacy and toxicity of glucocorticoid therapy are ongoing.

  13. The effect of alphacypermethrin-treated mesh protection against African horse sickness virus vectors on jet stall microclimate, clinical variables and faecal glucocorticoid metabolites of horses.

    Science.gov (United States)

    Page, Patrick; Ganswindt, Andre; Schoeman, Johan; Venter, Gert; Guthrie, Alan

    2017-09-09

    African horse sickness (AHS) is of importance to health and international trade in horses worldwide. During export from and transit through AHS endemic countries or zones, physical and chemical measures to protect horses from the vectors of AHS virus (AHSV) are recommended by the World Organization for Animal Health. Protection of containerized air transport systems for horses (jet stalls) with alphacypermethrin insecticide-treated high density polyethylene mesh is effective in reducing the Culicoides midge vector attack rate. In order to determine the effect of this mesh on jet stall ventilation and horse welfare under temperate climatic conditions, jet stall microclimate, clinical variables and faecal glucocorticoid metabolite (FGM) levels of 12 horses were monitored during overnight housing in either a treated or untreated stall in two blocks of a 2 × 3 randomized crossover design. Temperature difference between the treated stall and outside was significantly higher than the difference between the untreated stall and outside at 1/15 time points only (P = 0.045, r = 0.70). Relative humidity (RH) difference between the treated stall and outside did not differ from the untreated stall and outside. Temperature and RH in the treated stall were highly and significantly correlated with outside temperature (r = 0.96, P < 0.001) and RH (r = 0.95, P < 0.001), respectively. No significant differences were detected between rectal temperatures, pulse and respiratory rates of horses in the treated stall compared to the untreated stall. Mean FGM concentrations for horses housed in the treated stall peaked earlier (24 h) and at a higher concentration than horses housed in the untreated stall (48 h), but were not significantly different from baseline. No significant difference was detected in FGM concentrations when the treated and untreated stall groups were compared at individual time points up to 72 h after exiting the jet stall. Alphacypermethrin

  14. Systemic glucocorticoids: important issues and practical guidelines for the dermatologist.

    Science.gov (United States)

    Dodiuk-Gad, Roni P; Ish-Shalom, Sophia; Shear, Neil H

    2015-06-01

    The potent anti-inflammatory and immunosuppressive effects of systemic glucocorticoids have led to their wide use in the treatment of dermatologic diseases. However, glucocorticoids have been designated the "archetypal double-edged sword of medicine" as a result of their various potential adverse side effects. Dermatologists face major challenges in their usage and require knowledge of both the risks related to their usage and strategies with which to manage them. This brief review includes an evidence-based, strategic approach to the general risk management of systemic glucocorticoids with a focus on preventing glucocorticoid-induced osteoporosis (GIOP). We assess which classes of corticosteroid are most likely to provoke allergic cross-reactions and outline the mechanism for glucocorticoid resistance. We examine how glucocorticoids both help and impair normal physiology. Five reactivity groups are defined, based on the structural and clinical characteristics of glucocorticoids. Tests for allergy reactions and mechanisms for glucocorticoid resistance are described. Guidelines for the prevention and treatment of GIOP are introduced. Glucocorticoids play an important teleologic role in maintaining blood glucose levels adequate for brain function by inducing a catabolic state through the production of carbohydrates at the expense of proteins and fat stores. It is hoped that the various recommendations for the protection of patients treated with systemic glucocorticoids will provide physicians with practical guidelines for prescribing. © 2015 The International Society of Dermatology.

  15. Immune regulation by glucocorticoids.

    Science.gov (United States)

    Cain, Derek W; Cidlowski, John A

    2017-04-01

    Endogenous glucocorticoids are crucial to various physiological processes, including metabolism, development and inflammation. Since 1948, synthetic glucocorticoids have been used to treat various immune-related disorders. The mechanisms that underlie the immunosuppressive properties of these hormones have been intensely scrutinized, and it is widely appreciated that glucocorticoids have pleiotropic effects on the immune system. However, a clear picture of the cellular and molecular basis of glucocorticoid action has remained elusive. In this Review, we distil several decades of intense (and often conflicting) research that defines the interface between the endocrine stress response and the immune system.

  16. Augmented β-Cell Function and Mass in Glucocorticoid-Treated Rodents Are Associated with Increased Islet Ir-β/AKT/mTOR and Decreased AMPK/ACC and AS160 Signaling

    Directory of Open Access Journals (Sweden)

    André O. P. Protzek

    2014-01-01

    Full Text Available Glucocorticoid (GC therapies may adversely cause insulin resistance (IR that lead to a compensatory hyperinsulinemia due to insulin hypersecretion. The increased β-cell function is associated with increased insulin signaling that has the protein kinase B (AKT substrate with 160 kDa (AS160 as an important downstream AKT effector. In muscle, both insulin and AMP-activated protein kinase (AMPK signaling phosphorylate and inactivate AS160, which favors the glucose transporter (GLUT-4 translocation to plasma membrane. Whether AS160 phosphorylation is modulated in islets from GC-treated subjects is unknown. For this, two animal models, Swiss mice and Wistar rats, were treated with dexamethasone (DEX (1 mg/kg body weight for 5 consecutive days. DEX treatment induced IR, hyperinsulinemia, and dyslipidemia in both species, but glucose intolerance and hyperglycemia only in rats. DEX treatment caused increased insulin secretion in response to glucose and augmented β-cell mass in both species that were associated with increased islet content and increased phosphorylation of the AS160 protein. Protein AKT phosphorylation, but not AMPK phosphorylation, was found significantly enhanced in islets from DEX-treated animals. We conclude that the augmented β-cell function developed in response to the GC-induced IR involves inhibition of the islet AS160 protein activity.

  17. Rodent Papillomaviruses.

    Science.gov (United States)

    Uberoi, Aayushi; Lambert, Paul F

    2017-11-27

    Preclinical infection model systems are extremely valuable tools to aid in our understanding of Human Papillomavirus (HPV) biology, disease progression, prevention, and treatments. In this context, rodent papillomaviruses and their respective infection models are useful tools but remain underutilized resources in the field of papillomavirus biology. Two rodent papillomaviruses, MnPV1, which infects the Mastomys species of multimammate rats, and MmuPV1, which infects laboratory mice, are currently the most studied rodent PVs. Both of these viruses cause malignancy in the skin and can provide attractive infection models to study the lesser understood cutaneous papillomaviruses that have been frequently associated with HPV-related skin cancers. Of these, MmuPV1 is the first reported rodent papillomavirus that can naturally infect the laboratory strain of mice. MmuPV1 is an attractive model virus to study papillomavirus pathogenesis because of the ubiquitous availability of lab mice and the fact that this mouse species is genetically modifiable. In this review, we have summarized the knowledge we have gained about PV biology from the study of rodent papillomaviruses and point out the remaining gaps that can provide new research opportunities.

  18. Molecular dynamics of ultradian glucocorticoid receptor action.

    Science.gov (United States)

    Conway-Campbell, Becky L; Pooley, John R; Hager, Gordon L; Lightman, Stafford L

    2012-01-30

    In recent years it has become evident that glucocorticoid receptor (GR) action in the nucleus is highly dynamic, characterized by a rapid exchange at the chromatin template. This stochastic mode of GR action couples perfectly with a deterministic pulsatile availability of endogenous ligand in vivo. The endogenous glucocorticoid hormone (cortisol in man and corticosterone in rodent) is secreted from the adrenal gland with an ultradian rhythm made up of pulses at approximately hourly intervals. These two components - the rapidly fluctuating ligand and the rapidly exchanging receptor - appear to have evolved to establish and maintain a system that is exquisitely responsive to the physiological demands of the organism. In this review, we discuss recent and innovative work that questions the idea of steady state, static hormone receptor responses, and replaces them with new concepts of stochastic mechanisms and oscillatory activity essential for optimal function in molecular and cellular systems. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  19. Glucocorticoids and chronic inflammation.

    Science.gov (United States)

    Straub, Rainer H; Cutolo, Maurizio

    2016-12-01

    Glucocorticoids are steroid hormones that once bound to their receptor interact with the DNA binding domain. Almost 1000-2000 genes are sensitive to their effects, including immune/inflammatory response genes. However, their role in pathophysiology and therapy is still debated. We performed a literature survey using the key words glucocorticoids, inflammation, autoimmune disease, rheumatology and adrenal glands in order to define important targets for this review on glucocorticoids. Considering endogenous/exogenous glucocorticoids in chronic inflammatory diseases brought up five major points for discussion: inadequately low production of endogenous cortisol relative to systemic inflammation (the disproportion principle); changes of the systemic and local cortisol-to-cortisone shuttle (reactivation and degradation of cortisol); inflammation-induced glucocorticoid resistance; highlights of present glucocorticoid therapy; and the role of circadian rhythms in action of cortisol. Much of this information becomes understandable in the context of neurohormonal energy regulation as recently summarized. The optimization of long-term low-dose glucocorticoid therapy in chronic inflammatory diseases arises from the understanding of the above mentioned aspects. Since glucocorticoid resistance is a consequence of inflammation, adequate anti-inflammatory therapy is mandatory. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  20. Glucocorticoids and Cancer

    Science.gov (United States)

    2017-01-01

    Unlike other steroid hormone receptors, the glucocorticoid receptor (GR) is not considered an oncogene. In breast cancer, the estrogen receptor (ER) drives cell growth, proliferation, and metastasis, and the androgen receptor (AR) plays a similar role in prostate cancer. Accordingly, treatment of these diseases has focused on blocking steroid hormone receptor function. In contrast, glucocorticoids (GCs) work through GR to arrest growth and induce apoptosis in lymphoid tissue. Glucocorticoids are amazingly effective in this role, and have been deployed as the cornerstone of lymphoid cancer treatment for decades. Unfortunately, not all patients respond to GCs and dosage is restricted by immediate and long term side effects. In this chapter we review the treatment protocols that employ glucocorticoids as a curative agent, elaborate on what is known about their mechanism of action in these cancers, and also summarize the palliative uses of glucocorticoids for other cancers. PMID:26216001

  1. Anti-Inflammatory Modulation of Microglia via CD163-Targeted Glucocorticoids Protects Dopaminergic Neurons in the 6-OHDA Parkinson's Disease Model

    DEFF Research Database (Denmark)

    Tentillier, Noemie; Etzerodt, Anders; Olesen, Mads N

    2016-01-01

    intravenous CD163-targeted liposomes with Dexa for 3 weeks exhibited better motor performance than the control groups and had minimal glucocorticoid-driven side effects. Furthermore, these animals showed better survival of dopaminergic neurons in substantia nigra and an increased number of microglia...... that CD163+ macrophages can be a target to modulate brain immune response to achieve neuroprotection in the 6-hydroxydopamine model. To do so, we targeted the CD163+ population, which to a low but significant extent infiltrated in the neurodegenerating area of the brain. Specially designed liposomes...... targeted for the CD163 receptor were loaded with glucocorticoids and injected peripherally to modify the infiltrated CD163 cells toward an anti-inflammatory profile. This modification of the CD163 population resulted in a distinctive microglial response that correlated with decreased dopaminergic cell...

  2. Genomic effects of glucocorticoids.

    Science.gov (United States)

    Grbesa, Ivana; Hakim, Ofir

    2017-05-01

    Glucocorticoids and their receptor (GR) have been an important area of research because of their pleiotropic physiological functions and extensive use in the clinic. In addition, the association between GR and glucocorticoids, which is highly specific, leads to rapid nuclear translocation where GR associates with chromatin to regulate gene transcription. This simplified model system has been instrumental for studying the complexity of transcription regulation processes occurring at chromatin. In this review we discuss our current understanding of GR action that has been enhanced by recent developments in genome wide measurements of chromatin accessibility, histone marks, chromatin remodeling and 3D chromatin structure in various cell types responding to glucocorticoids.

  3. Glucocorticoid receptor knockdown decreases the antioxidant protection of B16 melanoma cells: an endocrine system-related mechanism that compromises metastatic cell resistance to vascular endothelium-induced tumor cytotoxicity.

    Science.gov (United States)

    Obrador, Elena; Valles, Soraya L; Benlloch, María; Sirerol, J Antoni; Pellicer, José A; Alcácer, Javier; Coronado, Javier Alcácer-F; Estrela, José M

    2014-01-01

    We previously reported an interorgan system in which stress-related hormones (corticosterone and noradrenaline), interleukin-6, and glutathione (GSH) coordinately regulate metastatic growth of highly aggressive B16-F10 melanoma cells. Corticosterone, at levels measured in tumor-bearing mice, also induces apoptotic cell death in metastatic cells with low GSH content. In the present study we explored the potential role of glucocorticoids in the regulation of metastatic cell death/survival during the early stages of organ invasion. Glucocorticoid receptor (GCR) knockdown decreased the expression and activity of γ-glutamylcysteine synthetase (γ-GCS), the rate-limiting step in GSH synthesis, in metastatic cells in vivo independent of the tumor location (liver, lung, or subcutaneous). The decrease in γ-GCS activity was associated with lower intracellular GSH levels. Nrf2- and p53-dependent down-regulation of γ-GCS was associated with a decrease in the activities of superoxide dismutase 1 and 2, catalase, glutathione peroxidase, and glutathione reductase, but not of the O2--generating NADPH oxidase. The GCR knockdown-induced decrease in antioxidant protection caused a drastic decrease in the survival of metastatic cells during their interaction with endothelial cells, both in vitro and in vivo; only 10% of cancer cells attached to the endothelium survived compared to 90% survival observed in the controls. This very low rate of metastatic cell survival was partially increased (up to 52%) in vivo by inoculating B16-F10 cells preloaded with GSH ester, which enters the cell and delivers free GSH. Taken together, our results indicate that glucocorticoid signaling influences the survival of metastatic cells during their interaction with the vascular endothelium.

  4. Chronic restraint stress upregulates erythropoiesis through glucocorticoid stimulation.

    Directory of Open Access Journals (Sweden)

    Jeffrey L Voorhees

    Full Text Available In response to elevated glucocorticoid levels, erythroid progenitors rapidly expand to produce large numbers of young erythrocytes. Previous work demonstrates hematopoietic changes in rodents exposed to various physical and psychological stressors, however, the effects of chronic psychological stress on erythropoiesis has not be delineated. We employed laboratory, clinical and genomic analyses of a murine model of chronic restraint stress (RST to examine the influence of psychological stress on erythropoiesis. Mice exposed to RST demonstrated markers of early erythroid expansion involving the glucocorticoid receptor. In addition, these RST-exposed mice had increased numbers of circulating reticulocytes and increased erythropoiesis in primary and secondary erythroid tissues. Mice also showed increases in erythroid progenitor populations and elevated expression of the erythroid transcription factor KLF1 in these cells. Together this work reports some of the first evidence of psychological stress affecting erythroid homeostasis through glucocorticoid stimulation.

  5. Role of corticosteroid binding globulin in the fast actions of glucocorticoids on the brain.

    Science.gov (United States)

    Moisan, M P; Minni, A M; Dominguez, G; Helbling, J C; Foury, A; Henkous, N; Dorey, R; Béracochéa, D

    2014-03-01

    Corticosteroid binding globulin (CBG) is a glycoprotein synthesized in liver and secreted in the blood where it binds with a high affinity but low capacity glucocorticoid hormones, cortisol in humans and corticosterone in laboratory rodents. In mammals, 95% of circulating glucocorticoids are bound to either CBG (80%) or albumin (15%) and only the 5% free fraction is able to enter the brain. During stress, the concentration of glucocorticoids rises significantly and the free fraction increases even more because CBG becomes saturated. However, glucocorticoids unbound to CBG are cleared from the blood more quickly. Our studies on mice totally devoid of CBG (Cbg k.o.) showed that during stress these mutant mice display a lower rise of glucocorticoids than the wild-type controls associated with altered emotional reactivity. These data suggested that CBG played a role in the fast actions of glucocorticoids on behavior. Further analyses demonstrated that stress-induced memory retrieval impairment, an example of the fast action of glucocorticoids on the brain is abolished in the Cbg k.o. mice. This effect of stress on memory retrieval could be restored in the Cbg k.o. mice by infusing corticosterone directly in the hippocampus. The mechanisms explaining these effects involved an increased clearance but no difference in corticosterone production. Thus, CBG seems to have an important role in maintaining in blood a glucocorticoid pool that will be able to access the brain for the fast effects of glucocorticoids. Copyright © 2013 Elsevier Ltd. All rights reserved.

  6. Sulforaphane Protects Rodent Retinas against Ischemia-Reperfusion Injury through the Activation of the Nrf2/HO-1 Antioxidant Pathway

    Science.gov (United States)

    Liu, Ruixing; Brecha, Nicholas C.; Yu, Albert Cheung Hoi; Pu, Mingliang

    2014-01-01

    Retinal ischemia-reperfusion (I/R) injury induces oxidative stress, leukocyte infiltration, and neuronal cell death. Sulforaphane (SF), which can be obtained in cruciferous vegetables such as broccoli, exerts protective effects in response to oxidative stress in various tissues. These effects can be initiated through nuclear factor E2-related factor 2 (Nrf2)-mediated induction of heme oxygenase-1 (HO-1). This investigation was designed to elucidate the neural protective mechanisms of SF in the retinal I/R rat model. Animals were intraperitoneally (i.p.) injected with SF (12.5 mg/kg) or vehicle (corn oil) once a day for 7 consecutive days. Then, retinal I/R was made by elevating the intraocular pressure (IOP) to 130 mmHg for 1 h. To determine if HO-1 was involved in the Nrf2 antioxidant pathway, rats were subjected to protoporphyrin IX zinc (II) (ZnPP, 30 mg/kg, i.p.) treatments at 24 h before retinal ischemia. The neuroprotective effects of SF were assessed by determining the morphology of the retina, counting the infiltrating inflammatory cells and the surviving retinal ganglion cells (RGCs) and amacrine cells, and measuring apoptosis in the retinal layers. The expression of Nrf2 and HO-1 was studied by immunofluorescence analysis and western blotting. I/R induced a marked increase of ROS generation, caused pronounced inflammation, increased the apoptosis of RGCs and amacrine cells and caused the thinning of the inner retinal layer (IRL), and these effects were diminished or abolished by SF pretreatment. Meanwhile, SF pretreatment significantly elevated the nuclear accumulation of Nrf2 and the level of HO-1 expression in the I/R retinas; however, ZnPP reversed the protective effects of SF on I/R retinas. Together, we offer direct evidence that SF had protective effects on I/R retinas, which could be attributed, at least in part, to the activation of the Nrf2/HO-1 antioxidant pathway. PMID:25470382

  7. Sulforaphane protects rodent retinas against ischemia-reperfusion injury through the activation of the Nrf2/HO-1 antioxidant pathway.

    Directory of Open Access Journals (Sweden)

    Hong Pan

    Full Text Available Retinal ischemia-reperfusion (I/R injury induces oxidative stress, leukocyte infiltration, and neuronal cell death. Sulforaphane (SF, which can be obtained in cruciferous vegetables such as broccoli, exerts protective effects in response to oxidative stress in various tissues. These effects can be initiated through nuclear factor E2-related factor 2 (Nrf2-mediated induction of heme oxygenase-1 (HO-1. This investigation was designed to elucidate the neural protective mechanisms of SF in the retinal I/R rat model. Animals were intraperitoneally (i.p. injected with SF (12.5 mg/kg or vehicle (corn oil once a day for 7 consecutive days. Then, retinal I/R was made by elevating the intraocular pressure (IOP to 130 mmHg for 1 h. To determine if HO-1 was involved in the Nrf2 antioxidant pathway, rats were subjected to protoporphyrin IX zinc (II (ZnPP, 30 mg/kg, i.p. treatments at 24 h before retinal ischemia. The neuroprotective effects of SF were assessed by determining the morphology of the retina, counting the infiltrating inflammatory cells and the surviving retinal ganglion cells (RGCs and amacrine cells, and measuring apoptosis in the retinal layers. The expression of Nrf2 and HO-1 was studied by immunofluorescence analysis and western blotting. I/R induced a marked increase of ROS generation, caused pronounced inflammation, increased the apoptosis of RGCs and amacrine cells and caused the thinning of the inner retinal layer (IRL, and these effects were diminished or abolished by SF pretreatment. Meanwhile, SF pretreatment significantly elevated the nuclear accumulation of Nrf2 and the level of HO-1 expression in the I/R retinas; however, ZnPP reversed the protective effects of SF on I/R retinas. Together, we offer direct evidence that SF had protective effects on I/R retinas, which could be attributed, at least in part, to the activation of the Nrf2/HO-1 antioxidant pathway.

  8. Baculovirus-vectored multistage Plasmodium vivax vaccine induces both protective and transmission-blocking immunities against transgenic rodent malaria parasites.

    Science.gov (United States)

    Mizutani, Masanori; Iyori, Mitsuhiro; Blagborough, Andrew M; Fukumoto, Shinya; Funatsu, Tomohiro; Sinden, Robert E; Yoshida, Shigeto

    2014-10-01

    A multistage malaria vaccine targeting the pre-erythrocytic and sexual stages of Plasmodium could effectively protect individuals against infection from mosquito bites and provide transmission-blocking (TB) activity against the sexual stages of the parasite, respectively. This strategy could help prevent malaria infections in individuals and, on a larger scale, prevent malaria transmission in communities of endemicity. Here, we describe the development of a multistage Plasmodium vivax vaccine which simultaneously expresses P. vivax circumsporozoite protein (PvCSP) and P25 (Pvs25) protein of this species as a fusion protein, thereby acting as a pre-erythrocytic vaccine and a TB vaccine, respectively. A new-concept vaccine platform based on the baculovirus dual-expression system (BDES) was evaluated. The BDES-Pvs25-PvCSP vaccine displayed correct folding of the Pvs25-PvCSP fusion protein on the viral envelope and was highly expressed upon transduction of mammalian cells in vitro. This vaccine induced high levels of antibodies to Pvs25 and PvCSP and elicited protective (43%) and TB (82%) efficacies against transgenic P. berghei parasites expressing the corresponding P. vivax antigens in mice. Our data indicate that our BDES, which functions as both a subunit and DNA vaccine, can offer a promising multistage vaccine capable of delivering a potent antimalarial pre-erythrocytic and TB response via a single immunization regimen. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  9. Addison disease in patients treated with glucocorticoid therapy.

    LENUS (Irish Health Repository)

    Cronin, C C

    2012-02-03

    Acute adrenal crisis in patients with unrecognized chronic adrenocortical failure is difficult to diagnose and potentially fatal. We describe 2 patients with acute adrenal crisis whose diagnoses were hindered because of concomitant glucocorticoid treatment. Acute adrenal insufficiency is primarily a state of mineralocorticoid deficiency. Prednisolone and prednisone, the most frequently prescribed anti-inflammatory corticosteroid agents, have minimal mineralocorticoid activity. Several conditions that may be treated with pharmacological glucocorticoids are associated with an increased risk of Addison disease. An acute adrenal crisis, against which concurrent glucocorticoid therapy does not confer adequate protection, may develop in such patients.

  10. Amyloid beta and the longest-lived rodent: the naked mole-rat as a model for natural protection from Alzheimer's disease.

    Science.gov (United States)

    Edrey, Yael H; Medina, David X; Gaczynska, Maria; Osmulski, Pawel A; Oddo, Salvatore; Caccamo, Antonella; Buffenstein, Rochelle

    2013-10-01

    Amyloid beta (Aβ) is implicated in Alzheimer's disease (AD) as an integral component of both neural toxicity and plaque formation. Brains of the longest-lived rodents, naked mole-rats (NMRs) approximately 32 years of age, had levels of Aβ similar to those of the 3xTg-AD mouse model of AD. Interestingly, there was no evidence of extracellular plaques, nor was there an age-related increase in Aβ levels in the individuals examined (2-20+ years). The NMR Aβ peptide showed greater homology to the human sequence than to the mouse sequence, differing by only 1 amino acid from the former. This subtle difference led to interspecies differences in aggregation propensity but not neurotoxicity; NMR Aβ was less prone to aggregation than human Aβ. Nevertheless, both NMR and human Aβ were equally toxic to mouse hippocampal neurons, suggesting that Aβ neurotoxicity and aggregation properties were not coupled. Understanding how NMRs acquire and tolerate high levels of Aβ with no plaque formation could provide useful insights into AD, and may elucidate protective mechanisms that delay AD progression. Copyright © 2013 Elsevier Inc. All rights reserved.

  11. Facilitation by endogenous prostaglandins of capsaicin-induced gastric protection in rodents through EP2 and IP receptors.

    Science.gov (United States)

    Takeuchi, Koji; Kato, Shinichi; Takeeda, Masanori; Ogawa, Yoshihiro; Nakashima, Masato; Matsumoto, Masahiro

    2003-03-01

    We investigated the role that prostaglandins (PGs) and EP receptors play in facilitating the gastroprotective action of capsaicin against HCl/ethanol in rats and mice. Male Sprague-Dawley rats and C57BL/6 mice were used after 18 h of fasting. The animals were given HCl/ethanol (60% in 150 mM HCl) p.o. and killed 1 h later. Capsaicin or various EP agonists were given p.o. 30 min or i.v. 10 min before HCl/ethanol. In some cases, indomethacin or various EP agonists were given s.c. 30 min or i.v 10 min before capsaicin, respectively. Gastric lesions induced by HCl/ethanol were significantly inhibited by PGE(2) as well as capsaicin. The effect of PGE(2) was antagonized by ONO-AE-829 (EP1 antagonist), whereas the capsaicin action was mitigated by indomethacin as well as sensory deafferentation but not by ONO-AE-829. The generation of mucosal PGE(2) was not affected by either capsaicin or sensory deafferentation, but was significantly inhibited by indomethacin. Although neither butaprost (EP2), ONO-NT-012 (EP3), nor 11-deoxy PGE1 (EP4) alone had any effect on HCl/ethanol-induced gastric lesions, only butaprost restored the protective action of capsaicin in the presence of indomethacin. Capsaicin provided a protective action against HCl/ethanol-induced gastric lesions in wild-type (+/+) mice in an indomethacin-sensitive manner, and this action was similarly observed in EP1 (-/-) and EP3 (-/-) mice but not in the animals lacking IP receptors. These results suggest that capsaicin exhibits gastric cytoprotection, essentially by stimulating sensory neurons, and this action is facilitated by endogenous PGs through EP2/IP receptors, probably sensitizing the sensory neurons to capsaicin.

  12. The role of glucocorticoids in emotional memory reconsolidation.

    Science.gov (United States)

    Meir Drexler, Shira; Wolf, Oliver T

    2017-07-01

    Glucocorticoids are secreted following exposure to stressful events. Their modulating role on memory reconsolidation, a post-retrieval process of re-stabilization, has been investigated only recently, at times with conflicting results. The goal of this review is twofold. First, to establish the modulating role of glucocorticoids on memory reconsolidation. Second, to point the potential factors and confounds that might explain the seemingly paradoxical findings. Here we review recent pharmacological studies, conducted in rodents and humans, which suggest a critical role of glucocorticoids in this post-retrieval process. In particular, the activation of glucocorticoid receptors in the amygdala and hippocampus is suggested to be involved in emotional memories reconsolidation, pointing to a similarity between post-retrieval reconsolidation and initial memory consolidation. In addition, based on the general reconsolidation literature, we suggest several factors that might play a role in determining the direction and strength of the reconsolidation effect following glucocorticoids treatment: memory-related factors, manipulation-related factors, and individual differences. We conclude that only when taking these additional factors into account can the paradox be resolved. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Occurrence and in vitro bioactivity of estrogen, androgen, and glucocorticoid compounds in a nationwide screen of United States stream waters

    Data.gov (United States)

    U.S. Environmental Protection Agency — In vitro bioactivity concentrations and chemical concentrations of estrogens, androgens, and glucocorticoids from a nationwide screen of United States stream water...

  14. The Role of Glucocorticoids and Neuroinflammation in Mediating the Effects of Stress on Drug Abuse

    Science.gov (United States)

    2013-10-01

    increase in adrenal glucocorticoids (GCs) ( cortisol in the human, corticosterone in the rodent), and it is known that the GC response to stressors...Tocharus et al., 2010. Melatonin attenuates methamphetamine-induced overexpression of pro- inflammatory cytokines in microglial cell lines. J Pineal Res

  15. Synergistic protective effects of escin and low‑dose glucocorticoids against vascular endothelial growth factor‑induced blood‑retinal barrier breakdown in retinal pigment epithelial and umbilical vein endothelial cells.

    Science.gov (United States)

    Zhang, Fenglan; Man, Xuejing; Yu, Huajun; Liu, Limei; Li, Yuanbin

    2015-02-01

    Previous studies have shown that escin possesses glucocorticoid (GC)‑like anti‑edematous and anti‑inflammatory effects. The present study was designed to investigate whether escin exhibits synergistic protective effects against blood‑retinal barrier (BRB) breakdown when combined with GC in an in vitro monolayer BRB model, based on retinal pigment epithelial (RPE) cells and human umbilical vein endothelial cells (HUVECs). The results showed that low concentrations of escin and triamcinolone acetonide (TA) administered separately did not affect BRB trans‑endothelial (epithelium) resistance (TEER). However, when administered together, escin and TA significantly inhibited reduced BRB TEER following treatment with vascular endothelial growth factor (VEGF). Furthermore, low‑concentrations of escin and TA administered together significantly increased the expression levels of occludin and ZO‑1. This demonstrates that escin and GC have synergistic protective effects against BRB breakdown, and the molecular mechanisms may be related to the upregulation of occludin and ZO‑1 expression. The combination of escin with GC indicates a potential beneficial strategy for the treatment of breakdown of the BRB.

  16. Immunogenicity and Protective Efficacy of Brugia malayi Heavy Chain Myosin as Homologous DNA, Protein and Heterologous DNA/Protein Prime Boost Vaccine in Rodent Model.

    Directory of Open Access Journals (Sweden)

    Jyoti Gupta

    Full Text Available We earlier demonstrated the immunoprophylactic efficacy of recombinant heavy chain myosin (Bm-Myo of Brugia malayi (B. malayi in rodent models. In the current study, further attempts have been made to improve this efficacy by employing alternate approaches such as homologous DNA (pcD-Myo and heterologous DNA/protein prime boost (pcD-Myo+Bm-Myo in BALB/c mouse model. The gene bm-myo was cloned in a mammalian expression vector pcDNA 3.1(+ and protein expression was confirmed in mammalian Vero cell line. A significant degree of protection (79.2%±2.32 against L3 challenge in pcD-Myo+Bm-Myo immunized group was observed which was much higher than that exerted by Bm-Myo (66.6%±2.23 and pcD-Myo (41.6%±2.45. In the heterologous immunized group, the percentage of peritoneal leukocytes such as macrophages, neutrophils, B cells and T cells marginally increased and their population augmented further significantly following L3 challenge. pcD-Myo+Bm-Myo immunization elicited robust cellular and humoral immune responses as compared to pcD-Myo and Bm-Myo groups as evidenced by an increased accumulation of CD4+, CD8+ T cells and CD19+ B cells in the mouse spleen and activation of peritoneal macrophages. Though immunized animals produced antigen-specific IgG antibodies and isotypes, sera of mice receiving pcD-Myo+Bm-Myo or Bm-Myo developed much higher antibody levels than other groups and there was profound antibody-dependent cellular adhesion and cytotoxicity (ADCC to B. malayi infective larvae (L3. pcD-Myo+Bm-Myo as well as Bm-Myo mice generated a mixed T helper cell phenotype as evidenced by the production of both pro-inflammatory (IL-2, IFN-γ and anti-inflammatory (IL-4, IL-10 cytokines. Mice receiving pcD-Myo on contrary displayed a polarized pro-inflammatory immune response. The findings suggest that the priming of animals with DNA followed by protein booster generates heightened and mixed pro- and anti-inflammatory immune responses that are capable of

  17. Clinical aspects of glucocorticoid sensitivity

    OpenAIRE

    Lamberts, Steven; Huizenga, Nannette; Lange, Pieter; Jong, Frank; Koper, Jan

    1996-01-01

    textabstractRecent studies demonstrate that primary (hereditary) abnormalities in the glucocorticoid receptor gene make 6.6% of the normal population relatively 'hypersensitive' to glucocorticoids, while 2.3% are relatively 'resistant.' These abnormalities might explain why some individuals develop severe adverse effects during low dose glucocorticoid therapy, while others do not develop side effects even during long-term therapy with a much higher dose. Awareness of this heterogeneity in glu...

  18. Molecular mechanisms of glucocorticoid action and selective glucocorticoid receptor agonists.

    Science.gov (United States)

    Stahn, Cindy; Löwenberg, Mark; Hommes, Daniel W; Buttgereit, Frank

    2007-09-15

    Glucocorticoids (GC) are the most common used anti-inflammatory and immunosuppressive drugs in the treatment of rheumatic and other inflammatory diseases. Their therapeutic effects are considered to be mediated by four different mechanisms of action: the classical genomic mechanism of action caused by the cytosolic glucocorticoid receptor (cGCR); secondary non-genomic effects which are also initiated by the cGCR; membrane-bound glucocorticoid receptor (mGCR)-mediated non-genomic effects; non-specific, non-genomic effects caused by interactions with cellular membranes. The classical, genomic mechanism of GC-action can be divided into two processes: "transrepression", which is responsible for a large number of desirable anti-inflammatory and immunomodulating effects, and "transactivation" which is associated with frequently occurring side effects as well as with some immunosuppressive activities [Ehrchen, J., Steinmuller, L., Barczyk, K., Tenbrock, K., Nacken, W., Eisenacher, M., Nordhues, U., Sorg, C., Sunderkotter, C., Roth, J., 2007. Glucocorticoids induce differentiation of a specifically activated, anti-inflammatory subtype of human monocytes. Blood 109, 1265-1274]. Great efforts have been made to diminish glucocorticoid-induced adverse effects, but the improvement of conventional glucocorticoids has almost reached its limits. As a consequence, new variations of the conventional "good old drugs" are being tested and nitro-steroids and long circulating liposomal glucocorticoids indeed show promising results. Nevertheless, crux of the matter should be the design of qualitatively new drugs, such as selective glucocorticoid receptor agonists (SEGRAs). These innovative steroidal or non-steroidal molecules induce transrepression, while transactivation processes are less affected. First reports on two different GCR ligands, A276575 and ZK216348, show promising results. Here, we review the above-mentioned mechanisms of glucocorticoid action and give particular attention

  19. Glucocorticoids, chronic stress, and obesity

    NARCIS (Netherlands)

    Dallman, Mary F.; Pecoraro, Norman C.; la Fleur, Susanne E.; Warne, James P.; Ginsberg, Abigail B.; Akana, Susan F.; Laugero, Kevin C.; Houshyar, Hani; Strack, Alison M.; Bhatnagar, Seema; Bell, Mary E.

    2006-01-01

    Glucocorticoids either inhibit or sensitize stress-induced activity in the hypothalamo-pituitary-adrenal (HPA) axis, depending on time after their administration, the concentration of the steroids, and whether there is a concurrent stressor input. When there are high glucocorticoids together with a

  20. Clinical aspects of glucocorticoid sensitivity

    NARCIS (Netherlands)

    S.W.J. Lamberts (Steven); N.A.T.M. Huizenga (Nannette); P. de Lange (Pieter); F.H. de Jong (Frank); J.W. Koper (Jan)

    1996-01-01

    textabstractRecent studies demonstrate that primary (hereditary) abnormalities in the glucocorticoid receptor gene make 6.6% of the normal population relatively 'hypersensitive' to glucocorticoids, while 2.3% are relatively 'resistant.' These abnormalities might explain why some individuals develop

  1. Antenatal endogenous and exogenous glucocorticoids and their impact on immune ontogeny and long-term immunity.

    Science.gov (United States)

    Solano, María Emilia; Holmes, Megan C; Mittelstadt, Paul R; Chapman, Karen E; Tolosa, Eva

    2016-11-01

    Endogenous levels of glucocorticoids rise during pregnancy to warrant development and maturation of the fetal organs close to birth. However, during most of the gestation, the fetus is protected from excessive biologically active endogenous glucocorticoids by placental and fetal expression of 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2). Maternal stress, which may overwhelm placental 11β-HSD2 activity with high glucocorticoid levels, or administration of synthetic glucocorticoids to improve the survival chances of the premature newborn, are associated to postnatal increased risk for immune diseases. Fetal exposure to excessive glucocorticoids may underlie this altered postnatal immunity. Here, we revise the role that placental and fetal 11β-HSD2, fetal glucocorticoid exposure, and programming of the offspring's the hypothalamic-pituitary-adrenal (HPA) axis play on concerted steps in immune fetal development. We could identify gaps in knowledge about glucocorticoid-induced programming of immune diseases. Finally, based on current evidence about glucocorticoid and HPA axis-mediated immune regulation, we hypothesize on mechanisms that could drive the enhanced risk for atopies, infections, and type I diabetes in offspring that were prenatally exposed to glucocorticoids.

  2. REDD1 functions at the crossroads between the therapeutic and adverse effects of topical glucocorticoids.

    Science.gov (United States)

    Baida, Gleb; Bhalla, Pankaj; Kirsanov, Kirill; Lesovaya, Ekaterina; Yakubovskaya, Marianna; Yuen, Kit; Guo, Shuchi; Lavker, Robert M; Readhead, Ben; Dudley, Joel T; Budunova, Irina

    2015-01-01

    Cutaneous atrophy is the major adverse effect of topical glucocorticoids; however, its molecular mechanisms are poorly understood. Here, we identify stress-inducible mTOR inhibitor REDD1 (regulated in development and DNA damage response 1) as a major molecular target of glucocorticoids, which mediates cutaneous atrophy. In REDD1 knockout (KO) mice, all skin compartments (epidermis, dermis, subcutaneous fat), epidermal stem, and progenitor cells were protected from atrophic effects of glucocorticoids. Moreover, REDD1 knockdown resulted in similar consequences in organotypic raft cultures of primary human keratinocytes. Expression profiling revealed that gene activation by glucocorticoids was strongly altered in REDD1 KO epidermis. In contrast, the down-regulation of genes involved in anti-inflammatory glucocorticoid response was strikingly similar in wild-type and REDD1 KO mice. Integrative bioinformatics analysis of our and published gene array data revealed similar changes of gene expression in epidermis and in muscle undergoing glucocorticoid-dependent and glucocorticoid-independent atrophy. Importantly, the lack of REDD1 did not diminish the anti-inflammatory effects of glucocorticoids in preclinical model. Our findings suggest that combining steroids with REDD1 inhibitors may yield a novel, safer glucocorticoid-based therapies. © 2014 The Authors. Published under the terms of the CC BY 4.0 license.

  3. [Mechanisms of action of glucocorticoids].

    Science.gov (United States)

    Dejean, C; Richard, D

    2013-05-01

    Glucocorticoids exert their actions at nuclear levels through genomic mechanisms including both transcriptional activation (transactivation) and gene expression repression (transrepression). Transactivation mechanisms are mediated by transcription factors, the main one being the activated glucocorticoid receptor (GR). These mechanisms contribute to both powerful therapeutic effects of glucocorticoids on inflammatory and immune diseases, and adverse effects than can be harmful on vital functions. Non-genomic mechanisms, which act faster than genomic ones, have also been explored. They also involve the GR in different membranous and cytosolic sites. The phenomenon of glucocorticoid resistance is also complex and several different mechanisms may mediate this phenomenon. Among them are alterations in number, binding affinity or phosphorylation status of the GR, changes in capacity of cellular apoptosis, polymorphic changes or expression of proteins involved in the genomic actions of glucocorticoids. Finally, some proteins, which mediate glucocorticoid activity could be therapeutic targets for reducing glucocorticoid-induced adverse effects. Copyright © 2013 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  4. [Glucocorticoids in rheumatology].

    Science.gov (United States)

    Dziurla, R; Buttgereit, F

    2008-11-01

    Glucocorticoids (GC) are effective drugs which are often used in rheumatology. However, they have a considerable potential for frequent and sometimes serious side effects that restrict their use. Their mechanisms of action are either receptor dependent (specific) or independent (unspecific) on the genomic as well as the non-genomic level. Many adverse effects are predominantly caused by transactivation while the desired effects are mostly mediated by transrepression. Treatment strategies are sub-classified into low, medium, high, very high dose and pulse therapy based on criteria such as dose, indication, duration of treatment and potential risk of adverse events. The musculoskeletal, gastrointestinal, neuro-endocrino-immunological, opthalmological and neuropsychiatric systems are examples where adverse effects may occur.

  5. The aryl hydrocarbon receptor and glucocorticoid receptor interact to activate human metallothionein 2A

    Energy Technology Data Exchange (ETDEWEB)

    Sato, Shoko, E-mail: satosho@rs.tus.ac.jp [Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai 981-8555 (Japan); Shirakawa, Hitoshi, E-mail: shirakah@m.tohoku.ac.jp [Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai 981-8555 (Japan); Tomita, Shuhei, E-mail: tomita@med.tottori-u.ac.jp [Division of Molecular Pharmacology, Department of Pathophysiological and Therapeutic Science, Yonago 683-8503 (Japan); Tohkin, Masahiro, E-mail: tohkin@phar.nagoya-cu.ac.jp [Department of Medical Safety Science, Graduate School of Pharmaceutical Science, Nagoya City University, Nagoya 267-8603 (Japan); Gonzalez, Frank J., E-mail: gonzalef@mail.nih.gov [Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States); Komai, Michio, E-mail: mkomai@m.tohoku.ac.jp [Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai 981-8555 (Japan)

    2013-11-15

    Although the aryl hydrocarbon receptor (AHR) and glucocorticoid receptor (GR) play essential roles in mammalian development, stress responses, and other physiological events, crosstalk between these receptors has been the subject of much debate. Metallothioneins are classic glucocorticoid-inducible genes that were reported to increase upon treatment with AHR agonists in rodent tissues and cultured human cells. In this study, the mechanism of human metallothionein 2A (MT2A) gene transcription activation by AHR was investigated. Cotreatment with 3-methylcholanthrene and dexamethasone, agonists of AHR and GR respectively, synergistically increased MT2A mRNA levels in HepG2 cells. MT2A induction was suppressed by RNA interference against AHR or GR. Coimmunoprecipitation experiments revealed a physical interaction between AHR and GR proteins. Moreover, chromatin immunoprecipitation assays indicated that AHR was recruited to the glucocorticoid response element in the MT2A promoter. Thus, we provide a novel mechanism whereby AHR modulates expression of human MT2A via the glucocorticoid response element and protein–protein interactions with GR. - Highlights: • Aryl hydrocarbon receptor forms a complex with glucocorticoid receptor in cells. • Human metallothionein gene is regulated by the AHR and GR interaction. • AHR–GR complex binds to glucocorticoid response element in metallothionein gene. • We demonstrated a novel transcriptional mechanism via AHR and GR interaction.

  6. The aryl hydrocarbon receptor and glucocorticoid receptor interact to activate human metallothionein 2A

    International Nuclear Information System (INIS)

    Sato, Shoko; Shirakawa, Hitoshi; Tomita, Shuhei; Tohkin, Masahiro; Gonzalez, Frank J.; Komai, Michio

    2013-01-01

    Although the aryl hydrocarbon receptor (AHR) and glucocorticoid receptor (GR) play essential roles in mammalian development, stress responses, and other physiological events, crosstalk between these receptors has been the subject of much debate. Metallothioneins are classic glucocorticoid-inducible genes that were reported to increase upon treatment with AHR agonists in rodent tissues and cultured human cells. In this study, the mechanism of human metallothionein 2A (MT2A) gene transcription activation by AHR was investigated. Cotreatment with 3-methylcholanthrene and dexamethasone, agonists of AHR and GR respectively, synergistically increased MT2A mRNA levels in HepG2 cells. MT2A induction was suppressed by RNA interference against AHR or GR. Coimmunoprecipitation experiments revealed a physical interaction between AHR and GR proteins. Moreover, chromatin immunoprecipitation assays indicated that AHR was recruited to the glucocorticoid response element in the MT2A promoter. Thus, we provide a novel mechanism whereby AHR modulates expression of human MT2A via the glucocorticoid response element and protein–protein interactions with GR. - Highlights: • Aryl hydrocarbon receptor forms a complex with glucocorticoid receptor in cells. • Human metallothionein gene is regulated by the AHR and GR interaction. • AHR–GR complex binds to glucocorticoid response element in metallothionein gene. • We demonstrated a novel transcriptional mechanism via AHR and GR interaction

  7. Impact of glucocorticoid on neurogenesis

    Directory of Open Access Journals (Sweden)

    Haruki Odaka

    2017-01-01

    Full Text Available Neurogenesis is currently an area of great interest in neuroscience. It is closely linked to brain diseases, including mental disorders and neurodevelopmental disease. Both embryonic and adult neurogeneses are influenced by glucocorticoids secreted from the adrenal glands in response to a variety of stressors. Moreover, proliferation/differentiation of the neural stem/progenitor cells (NSPCs is affected by glucocorticoids through intracellular signaling pathways such as phosphoinositide 3-kinase (PI3K/Akt, hedgehog, and Wnt. Our review presents recent evidence of the impact of glucocorticoids on NSPC behaviors and the underlying molecular mechanisms; this provides important information for understanding the pathological role of glucocorticoids on neurogenesis-associated brain diseases.

  8. Actions and interactions of estradiol and glucocorticoids in cognition and the brain: Implications for aging women.

    Science.gov (United States)

    Ycaza Herrera, Alexandra; Mather, Mara

    2015-08-01

    Menopause involves dramatic declines in estradiol production and levels. Importantly, estradiol and the class of stress hormones known as glucocorticoids exert countervailing effects throughout the body, with estradiol exerting positive effects on the brain and cognition, glucocorticoids exerting negative effects on the brain and cognition, and estradiol able to mitigate negative effects of glucocorticoids. Although the effects of these hormones in isolation have been extensively studied, the effects of estradiol on the stress response and the neuroprotection offered against glucocorticoid exposure in humans are less well known. Here we review evidence suggesting that estradiol-related protection against glucocorticoids mitigates stress-induced interference with cognitive processes. Animal and human research indicates that estradiol-related mitigation of glucocorticoid damage and interference is one benefit of estradiol supplementation during peri-menopause or soon after menopause. The evidence for estradiol-related protection against glucocorticoids suggests that maintaining estradiol levels in post-menopausal women could protect them from stress-induced declines in neural and cognitive integrity. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Actions and interactions of estradiol and glucocorticoids in cognition and the brain: Implications for aging women.

    Science.gov (United States)

    Herrera, Alexandra Ycaza; Mather, Mara

    2015-01-01

    Menopause involves dramatic declines in estradiol production and levels. Importantly, estradiol and the class of stress hormones known as glucocorticoids exert countervailing effects throughout the body, with estradiol exerting positive effects on the brain and cognition, glucocorticoids exerting negative effects on the brain and cognition, and estradiol able to mitigate negative effects of glucocorticoids. Although the effects of these hormones in isolation have been extensively studied, the effects of estradiol on the stress response and the neuroprotection offered against glucocorticoid exposure in humans are less well known. Here we review evidence suggesting that estradiol-related protection against glucocorticoids mitigates stress-induced interference with cognitive processes. Animal and human research indicates that estradiol-related mitigation of glucocorticoid damage and interference is one benefit of estradiol supplementation during peri-menopause or soon after menopause. The evidence for estradiol-related protection against glucocorticoids suggests that maintaining estradiol levels in post-menopausal women could protect them from stress-induced declines in neural and cognitive integrity. PMID:25929443

  10. From gastroprotective to ulcerogenic effects of glucocorticoids: role of long-term glucocorticoid action.

    Science.gov (United States)

    Filaretova, Ludmila; Podvigina, Tatiana; Bagaeva, Tatiana; Morozova, Olga

    2014-01-01

    Glucocorticoids may have dual action on the gastric mucosa: gastroprotective and ulcerogenic. In this article, we review the data which suggested that an initial action of endogenous glucocorticoids, including stress-produced ones as well as exogenous glucocorticoids is gastroprotective and consider possible mechanisms of the conversion of physiological gastroprotective action of glucocorticoid hormones to their pathological ulcerogenic effect.

  11. Glucocorticoid programming of neuroimmune function.

    Science.gov (United States)

    Walker, David J; Spencer, Karen A

    2018-01-15

    Throughout life physiological systems strive to maintain homeostasis and these systems are susceptible to exposure to maternal or environmental perturbations, particularly during embryonic development. In some cases, these perturbations may influence genetic and physiological processes that permanently alter the functioning of these physiological systems; a process known as developmental programming. In recent years, the neuroimmune system has garnered attention for its fundamental interactions with key hormonal systems, such as the hypothalamic pituitary adrenal (HPA) axis. The ultimate product of this axis, the glucocorticoid hormones, play a key role in modulating immune responses within the periphery and the CNS as part of the physiological stress response. It is well-established that elevated glucocorticoids induced by developmental stress exert profound short and long-term physiological effects, yet there is relatively little information of how these effects are manifested within the neuroimmune system. Pre and post-natal periods are prime candidates for manipulation in order to uncover the physiological mechanisms that underlie glucocorticoid programming of neuroimmune responses. Understanding the potential programming role of glucocorticoids may be key in uncovering vulnerable windows of CNS susceptibility to stressful experiences during embryonic development and improve our use of glucocorticoids as therapeutics in the treatment of neurodegenerative diseases. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

  12. Investigations of Glucocorticoid Action in GN

    NARCIS (Netherlands)

    Kuppe, C.; Roeyen, C. van; Leuchtle, K.; Kabgani, N.; Vogt, M.; Zandvoort, M. Van; Smeets, B.; Floege, J.; Grone, H.J.; Moeller, M.J.

    2017-01-01

    For several decades, glucocorticoids have been used empirically to treat rapid progressive GN. It is commonly assumed that glucocorticoids act primarily by dampening the immune response, but the mechanisms remain incompletely understood. In this study, we inactivated the glucocorticoid receptor (GR)

  13. Towards sustainable management of rodents in organic animal husbandry

    NARCIS (Netherlands)

    Meerburg, B.G.; Bonde, M.; Brom, F.W.A.; Endepols, S.; Jensen, A.N.; Leirs, H.; Lodal, J.; Singleton, G.R.; Pelz, H.J.; Rodenburg, T.B.; Kijlstra, A.

    2004-01-01

    From 26 to 28 May 2004 an international seminar was held in Wageningen, the Netherlands, about current knowledge and advice on rodent management on organic pig and poultry farms in Western Europe. This paper summarizes the discussions. Rodent management is necessary to protect the food production

  14. A Herbal Composition of Semen Hoveniae, Radix Puerariae, and Fructus Schisandrae Shows Potent Protective Effects on Acute Alcoholic Intoxication in Rodent Models

    Directory of Open Access Journals (Sweden)

    Jie Xiong

    2012-01-01

    Full Text Available This study is designed to evaluate the effects of a herbal composition of Semen Hoveniae, Radix Puerariae and Fructus Schisandrae (SRF against acute alcoholic intoxication. The animals were treated with SRF extract (SRFE for 14 days, and ethanol was conducted subsequent to the final treatment. The effects of SRFE on righting reflex, inebriety rates, kinetic parameters of blood ethanol and acetaldehyde were determined. In addition; levels of alcohol dehydrogenase (ADH and aldehyde dehydrogenase (ALDH, the activities of cytochrome P450 2E1 (CYP2E1, selected antioxidative enzymes, and the contents of malonaldehyde (MDA were measured. SRFE-pretreated rodents exhibited lower rates of intoxication, longer times to loss of righting reflex, and shortened times to recovery of righting reflex than in controls. The peak concentrations and area under the time-concentration curves were lower in the pretreated animals than in controls, which corresponded to higher levels of ADH and ALDH in both gastrointestines and livers of the SRFE-treated animals. The activities of CYP2E1 were lower in SRFE-pretreated animals, which also exhibited higher activities of some antioxidant enzymes and lower hepatic MDA levels. These findings suggest that the anti-inebriation effects of SRFE may involve inhibition of ethanol absorption, promotion of ethanol metabolism, and enhancing hepatic anti-oxidative functions.

  15. Molecular mechanisms of glucocorticoid action and selective glucocorticoid receptor agonists

    NARCIS (Netherlands)

    Stahn, Cindy; Löwenberg, Mark; Hommes, Daniel W.; Buttgereit, Frank

    2007-01-01

    Glucocorticoids (GC) are the most common used anti-inflammatory and immunosuppressive drugs in the treatment of rheumatic and other inflammatory diseases. Their therapeutic effects are considered to be mediated by four different mechanisms of action: the classical genomic mechanism of action caused

  16. Rodent models of osteoporosis

    OpenAIRE

    Sophocleous, Antonia; Idris, Aymen I

    2014-01-01

    The aim of this protocol is to provide a detailed description of male and female rodent models of osteoporosis. In addition to indications on the methods of performing the surgical procedures, the choice of reliable and safe anaesthetics is also described. Post-operative care, including analgesia administration for pain management, is also discussed. Ovariectomy in rodents is a procedure where ovaries are surgically excised. Hormonal changes resulting from ovary removal lead to an oestrogen-d...

  17. Glucocorticoids in nephrology II: indications and dosage

    Directory of Open Access Journals (Sweden)

    Jernej Pajek

    2015-05-01

    Full Text Available Present article describes glucocorticoid prescriptions in nephrology and renal transplantation, the dosages in induction and maintenance treatment phases and discontinuation. Key evidence and landmark trials are referenced, to establish the basis for modern glucocorticoid application in specific kidney disease indications. The glucocorticoid regimens in IgA glomerulonephritis, major primary glomerular diseases with nephrotic syndrome, vasculitides and tubulointerstitial nephritis are described. Various schemes for glucocorticoid dosage in lupus nephritis are given. The evolution of glucocorticoid usage in kidney transplantation is delineated and the modern role of these drugs in renal transplantation is defined. There are attempts to replace glucocorticoids with adrenocorticotrophic hormone in some glomerular diseases. Despite being relatively old drugs and having numerous side effects, glucocorticoids still function as major therapeutic agents for specific immunosuppressive treatment in nephrology.

  18. Mechanisms of Glucocorticoid Action During Development.

    Science.gov (United States)

    Busada, Jonathan T; Cidlowski, John A

    2017-01-01

    Glucocorticoids are primary stress hormones produced by the adrenal cortex. The concentration of serum glucocorticoids in the fetus is low throughout most of gestation but surge in the weeks prior to birth. While their most well-known function is to stimulate differentiation and functional development of the lungs, glucocorticoids also play crucial roles in the development of several other organ systems. Mothers at risk of preterm delivery are administered glucocorticoids to accelerate fetal lung development and prevent respiratory distress. Conversely, excessive glucocorticoid signaling is detrimental for fetal development; slowing fetal and placental growth and programming the individual for disease later in adult life. This review explores the mechanisms that control glucocorticoid signaling during pregnancy and provides an overview of the impact of glucocorticoid signaling on fetal development. © 2017 Elsevier Inc. All rights reserved.

  19. Glucocorticoid programming of intrauterine development.

    Science.gov (United States)

    Fowden, A L; Valenzuela, O A; Vaughan, O R; Jellyman, J K; Forhead, A J

    2016-07-01

    Glucocorticoids (GCs) are important environmental and maturational signals during intrauterine development. Toward term, the maturational rise in fetal glucocorticoid receptor concentrations decreases fetal growth and induces differentiation of key tissues essential for neonatal survival. When cortisol levels rise earlier in gestation as a result of suboptimal conditions for fetal growth, the switch from tissue accretion to differentiation is initiated prematurely, which alters the phenotype that develops from the genotype inherited at conception. Although this improves the chances of survival should delivery occur, it also has functional consequences for the offspring long after birth. Glucocorticoids are, therefore, also programming signals that permanently alter tissue structure and function during intrauterine development to optimize offspring fitness. However, if the postnatal environmental conditions differ from those signaled in utero, the phenotypical outcome of early-life glucocorticoid receptor overexposure may become maladaptive and lead to physiological dysfunction in the adult. This review focuses on the role of GCs in developmental programming, primarily in farm species. It examines the factors influencing GC bioavailability in utero and the effects that GCs have on the development of fetal tissues and organ systems, both at term and earlier in gestation. It also discusses the windows of susceptibility to GC overexposure in early life together with the molecular mechanisms and long-term consequences of GC programming with particular emphasis on the cardiovascular, metabolic, and endocrine phenotype of the offspring. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Activation of the Nrf2/HO-1 antioxidant pathway contributes to the protective effects of Lycium barbarum polysaccharides in the rodent retina after ischemia-reperfusion-induced damage.

    Directory of Open Access Journals (Sweden)

    Meihua He

    Full Text Available Lycium barbarum polysaccharides (LBP, extracts from the wolfberries, are protective to retina after ischemia-reperfusion (I/R. The antioxidant response element (ARE-mediated antioxidant pathway plays an important role in maintaining the redox status of the retina. Heme oxygenase-1 (HO-1, combined with potent AREs in its promoter, is a highly effective therapeutic target for the protection against neurodegenerative diseases, including I/R-induced retinal damage. The aim of our present study was to investigate whether the protective effect of LBP after I/R damage was mediated via activation of the Nrf2/HO-1-antioxidant pathway in the retina. Retinal I/R was induced by an increase in intraocular pressure to 130 mm Hg for 60 minutes. Prior to the induction of ischemia, rats were orally treated with either vehicle (PBS or LBP (1 mg/kg once a day for 1 week. For specific experiments, zinc protoporphyrin (ZnPP, 20 mg/kg, an HO-1 inhibitor, was intraperitoneally administered at 24 h prior to ischemia. The protective effects of LBP were evaluated by quantifying ganglion cell and amacrine cell survival, and by measuring cell apoptosis in the retinal layers. In addition, HO-1 expression was examined using Western blotting and immunofluorescence analyses. Cytosolic and nuclear Nrf2 was measured using immunofluorescent staining. LBP treatment significantly increased Nrf2 nuclear accumulation and HO-1 expression in the retina after I/R injury. Increased apoptosis and a decrease in the number of viable cells were observed in the ganglion cell layer (GCL and inner nuclear layer (INL in the I/R retina, which were reversed by LBP treatment. The HO-1 inhibitor, ZnPP, diminished the LBP treatment-induced protective effects in the retina after I/R. Taken together, these results suggested that LBP partially exerted its beneficial neuroprotective effects via the activation of Nrf2 and an increase in HO-1 protein expression.

  1. Glucocorticoids Acutely Increase Brown Adipose Tissue Activity in Humans, Revealing Species-Specific Differences in UCP-1 Regulation.

    Science.gov (United States)

    Ramage, Lynne E; Akyol, Murat; Fletcher, Alison M; Forsythe, John; Nixon, Mark; Carter, Roderick N; van Beek, Edwin J R; Morton, Nicholas M; Walker, Brian R; Stimson, Roland H

    2016-07-12

    The discovery of brown adipose tissue (BAT) in adult humans presents a new therapeutic target for metabolic disease; however, little is known about the regulation of human BAT. Chronic glucocorticoid excess causes obesity in humans, and glucocorticoids suppress BAT activation in rodents. We tested whether glucocorticoids regulate BAT activity in humans. In vivo, the glucocorticoid prednisolone acutely increased (18)fluorodeoxyglucose uptake by BAT (measured using PET/CT) in lean healthy men during mild cold exposure (16°C-17°C). In addition, prednisolone increased supraclavicular skin temperature (measured using infrared thermography) and energy expenditure during cold, but not warm, exposure in lean subjects. In vitro, glucocorticoids increased isoprenaline-stimulated respiration and UCP-1 in human primary brown adipocytes, but substantially decreased isoprenaline-stimulated respiration and UCP-1 in primary murine brown and beige adipocytes. The highly species-specific regulation of BAT function by glucocorticoids may have important implications for the translation of novel treatments to activate BAT to improve metabolic health. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  2. Mode of Glucocorticoid Actions in Airway Disease

    Directory of Open Access Journals (Sweden)

    Kazuhiro Ito

    2006-01-01

    Full Text Available Synthetic glucocorticoids are the most potent anti-inflammatory agents used to treat chronic inflammatory disease, such as asthma. However, a small number (<5% of asthmatic patients and almost all patients with chronic obstructive pulmonary disease (COPD do not respond well, or at all, to glucocorticoid therapy. If the molecular mechanism of glucocorticoid insensitivity is uncovered, it may in turn provide insight into the key mechanism of glucocorticoid action and allow a rational way to implement treatment regimens that restore glucocorticoid sensitivity. Glucocorticoids exert their effects by binding to a cytoplasmic glucocorticoid receptor (GR, which is subjected to post-translational modifications. Receptor phosphorylation, acetylation, nitrosylation, ubiquitinylation, and other modifications influence hormone binding, nuclear translocation, and protein half-life. Analysis of GR interactions to other molecules, such as coactivators or corepressors, may explain the genetic specificity of GR action. Priming with inflammatory cytokine or oxidative/nitrative stress is a mechanism for the glucocorticoid resistance observed in chronic inflammatory airway disease via reduction of corepressors or GR modification. Therapies targeting these aspects of the GR activation pathway may reverse glucocorticoid resistance in patients with glucocorticoid-insensitive airway disease and some patients with other inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease.

  3. Chemotherapy of Rodent Malaria.

    Science.gov (United States)

    1985-07-01

    resistant strains. Rodent malaria strains resistant to Halofantrine and to quinine nave been deve’oped and these will be inclided in future bcod...of rodent malaria continues to expand with the inclusion of strains resistant to Halofantrine, quinine and artemisinin. In addition, we are producing...report, st :Jies cve ’t~P-ntrhe ’ crrs.’.on 9f resistano r c I ris 2 ro - lJ ln Il ll lh- - malaria to two compounds, halofantrine and quinine , using our

  4. New dimension of glucocorticoids in cancer treatment.

    Science.gov (United States)

    Lin, Kai-Ti; Wang, Lu-Hai

    2016-07-01

    Glucocorticoids have been used in clinical oncology for over half a century. The clinical applications of glucocorticoids in oncology are mainly dependent on their pro-apoptotic action to treat lymphoproliferative disorders, and also on alleviating side effects induced by chemotherapy or radiotherapy in non-hematologic cancer types. Researches in the past few years have begun to unveil the profound complexity of glucocorticoids signaling and have contributed remarkably on therapeutic strategies. However, it remains striking and puzzling how glucocorticoids use different mechanisms in different cancer types and different targets to promote or inhibit tumor progression. In this review, we provide an update on glucocorticoids and its receptor, GR-mediated signaling and highlight some of the latest findings on the actions of glucocorticoids signaling during tumor progression and metastasis. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  5. The Skeletal Effects of Inhaled Glucocorticoids.

    Science.gov (United States)

    Sutter, Stephanie A; Stein, Emily M

    2016-06-01

    The skeletal effects of inhaled glucocorticoids are poorly understood. Children with asthma treated with inhaled glucocorticoids have lower growth velocity, bone density, and adult height. Studies of adults with asthma have reported variable effects on BMD, although prospective studies have demonstrated bone loss after initiation of inhaled glucocorticoids in premenopausal women. There is a dose-response relationship between inhaled glucocorticoids and fracture risk in asthmatics; the risk of vertebral and non-vertebral fractures is greater in subjects treated with the highest doses in the majority of studies. Patients with COPD have lower BMD and higher fracture rates compared to controls, however, the majority of studies have not found an additional detrimental effect of inhaled glucocorticoids on bone. While the evidence is not conclusive, it supports using the lowest possible dose of inhaled glucocorticoids to treat patients with asthma and COPD and highlights the need for further research on this topic.

  6. Xenobiotics and the Glucocorticoid Receptor.

    Science.gov (United States)

    Gulliver, Linda S M

    2017-03-15

    Glucocorticoid Receptor (GR) is present in virtually every human cell type. Representing a nuclear receptor superfamily, GR has several different isoforms essentially acting as ligand-dependent transcription factors, regulating glucocorticoid-responsive gene expression in both a positive and a negative manner. Although the natural ligand of the Glucocorticoid Receptor, glucocorticoids (GC) represent only some of the multiple ligands for GR. Xenobiotics, ubiquitous in the environment, bind to GR and are also capable of activating or repressing GR gene expression, thereby modulating GR cell and tissue-specific downstream effects in a multitude of ways that include responses to inflammatory, allergic, metabolic, neoplastic and autoimmune processes. Many xenobiotics, if inadequately metabolized by xenobiotic metabolizing enzymes and not wholly eliminated, could have deleterious toxic effects with potentially lethal consequences. This review examines GR, the genomic and non-genomic actions of natural and synthetic GC and the body's handling of xenobiotic compounds, before reviewing what is presently known about GR's interactions with many of the more commonly encountered and some of the less well known GR-associated xenobiotics. GR promiscuity and crosstalk with other signaling pathways is discussed, alongside novel roles for GR that include mood disorder and addiction. A knowledge of GR interactions with xenobiotics is increasingly relevant when considering aging populations and the related prevalence of neoplastic disease, together with growing concerns around human exposure to mixtures of chemicals in the environment. Furthermore, escalating rates of obesity, Type 2 diabetes; autoimmune, allergy, addiction and mood disorder-related pathologies, require novel targeted interventions and GR appears a promising pharmacological candidate. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Glucocorticoid control of gene transcription in neural tissue

    NARCIS (Netherlands)

    Morsink, Maarten Christian

    2007-01-01

    Glucocorticoid hormones exert modulatory effects on neural function in a delayed genomic fashion. The two receptor types that can bind glucocorticoids, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR), are ligand-inducible transcription factors. Therefore, changes in gene

  8. The effects of glucocorticoids on feeding behavior in rats

    NARCIS (Netherlands)

    la Fleur, Susanne E.

    2006-01-01

    Glucocorticoids have major effects on food intake, however, the underlying mechanisms are poorly understood. This article highlights data on the changes that occur when glucocorticoids are removed by adrenalectomy, and the effects of central and systemic administered glucocorticoids on feeding

  9. Involvement of the insular cortex in regulating glucocorticoid effects on memory consolidation of inhibitory avoidance training.

    Science.gov (United States)

    Fornari, Raquel V; Wichmann, Romy; Atucha, Erika; Desprez, Tifany; Eggens-Meijer, Ellie; Roozendaal, Benno

    2012-01-01

    Glucocorticoids are known to enhance the consolidation of memory of emotionally arousing experiences by acting upon a network of interconnected brain regions. Although animal studies typically do not consider the insular cortex (IC) to be part of this network, the present findings indicate that the IC is importantly involved in regulating glucocorticoid effects on memory consolidation of emotionally arousing inhibitory avoidance training. The specific glucocorticoid receptor (GR) agonist RU 28362 (3 or 10 ng in 0.5 μl) infused bilaterally into the IC of male Sprague-Dawley rats immediately after one-trial inhibitory avoidance training dose-dependently enhanced 48 h retention performance. Moreover, training on the inhibitory avoidance task increased neuronal activity of the IC, as assessed by an increased number of cells expressing immunoreactivity for phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2). However, systemic administration of a memory-enhancing dose of corticosterone (1 mg/kg) after inhibitory avoidance training rapidly reduced the number of pERK1/2-positive cells in the IC, suggesting that glucocorticoid administration reduces overall neuronal activity of the IC. To investigate which components of the inhibitory avoidance training experience were influenced by the intra-IC glucocorticoid administration, in the last experiment rats were trained on a modified inhibitory avoidance task in which context exposure and footshock training occur on two sequential days. RU 28362 administration into the IC enhanced later retention when infused immediately after either the context or footshock training. Thus, these findings indicate that the IC mediates glucocorticoid effects on the consolidation of memory of different components of inhibitory avoidance training and suggest that the IC might be an important element of the rodent brain network involved in emotional regulation of learning and memory.

  10. Involvement of the insular cortex in regulating glucocorticoid effects on memory consolidation of inhibitory avoidance training

    Directory of Open Access Journals (Sweden)

    Raquel eFornari

    2012-03-01

    Full Text Available Glucocorticoids are known to enhance the consolidation of memory of emotionally arousing experiences by acting upon a network of interconnected brain regions. Although animal studies typically do not consider the insular cortex (IC to be part of this network, the present findings indicate that the IC is importantly involved in regulating glucocorticoid effects on memory consolidation of emotionally arousing inhibitory avoidance training. The specific glucocorticoid receptor agonist RU 28362 (3 or 10 ng in 0.5 l infused bilaterally into the IC of male Sprague-Dawley rats immediately after one-trial inhibitory avoidance training dose-dependently enhanced 48-h retention performance. Moreover, training on the inhibitory avoidance task increased neuronal activity of the IC, as assessed by an increased number of cells expressing immunoreactivity for phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2. However, systemic administration of a memory-enhancing dose of corticosterone (1 mg/kg after inhibitory avoidance training rapidly reduced the number of pERK1/2-positive cells in the IC, suggesting that glucocorticoid administration reduces overall neuronal activity of the IC. To investigate which components of the inhibitory avoidance training experience were influenced by the intra-IC glucocorticoid administration, in the last experiment rats were trained on a modified inhibitory avoidance task in which context exposure and footshock training occur on two sequential days. RU 28362 administration into the IC enhanced later retention when infused immediately after either the context or footshock training. Thus, these findings indicate that the IC mediates glucocorticoid effects on the consolidation of memory of different components of inhibitory avoidance training and suggest that the IC might be an important element of the rodent brain network involved in emotional regulation of learning and memory.

  11. 11β-hydroxysteroid dehydrogenases: intracellular gate-keepers of tissue glucocorticoid action.

    Science.gov (United States)

    Chapman, Karen; Holmes, Megan; Seckl, Jonathan

    2013-07-01

    Glucocorticoid action on target tissues is determined by the density of "nuclear" receptors and intracellular metabolism by the two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD) which catalyze interconversion of active cortisol and corticosterone with inert cortisone and 11-dehydrocorticosterone. 11β-HSD type 1, a predominant reductase in most intact cells, catalyzes the regeneration of active glucocorticoids, thus amplifying cellular action. 11β-HSD1 is widely expressed in liver, adipose tissue, muscle, pancreatic islets, adult brain, inflammatory cells, and gonads. 11β-HSD1 is selectively elevated in adipose tissue in obesity where it contributes to metabolic complications. Similarly, 11β-HSD1 is elevated in the ageing brain where it exacerbates glucocorticoid-associated cognitive decline. Deficiency or selective inhibition of 11β-HSD1 improves multiple metabolic syndrome parameters in rodent models and human clinical trials and similarly improves cognitive function with ageing. The efficacy of inhibitors in human therapy remains unclear. 11β-HSD2 is a high-affinity dehydrogenase that inactivates glucocorticoids. In the distal nephron, 11β-HSD2 ensures that only aldosterone is an agonist at mineralocorticoid receptors (MR). 11β-HSD2 inhibition or genetic deficiency causes apparent mineralocorticoid excess and hypertension due to inappropriate glucocorticoid activation of renal MR. The placenta and fetus also highly express 11β-HSD2 which, by inactivating glucocorticoids, prevents premature maturation of fetal tissues and consequent developmental "programming." The role of 11β-HSD2 as a marker of programming is being explored. The 11β-HSDs thus illuminate the emerging biology of intracrine control, afford important insights into human pathogenesis, and offer new tissue-restricted therapeutic avenues.

  12. 11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

    Science.gov (United States)

    Chapman, Karen; Holmes, Megan

    2013-01-01

    Glucocorticoid action on target tissues is determined by the density of “nuclear” receptors and intracellular metabolism by the two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD) which catalyze interconversion of active cortisol and corticosterone with inert cortisone and 11-dehydrocorticosterone. 11β-HSD type 1, a predominant reductase in most intact cells, catalyzes the regeneration of active glucocorticoids, thus amplifying cellular action. 11β-HSD1 is widely expressed in liver, adipose tissue, muscle, pancreatic islets, adult brain, inflammatory cells, and gonads. 11β-HSD1 is selectively elevated in adipose tissue in obesity where it contributes to metabolic complications. Similarly, 11β-HSD1 is elevated in the ageing brain where it exacerbates glucocorticoid-associated cognitive decline. Deficiency or selective inhibition of 11β-HSD1 improves multiple metabolic syndrome parameters in rodent models and human clinical trials and similarly improves cognitive function with ageing. The efficacy of inhibitors in human therapy remains unclear. 11β-HSD2 is a high-affinity dehydrogenase that inactivates glucocorticoids. In the distal nephron, 11β-HSD2 ensures that only aldosterone is an agonist at mineralocorticoid receptors (MR). 11β-HSD2 inhibition or genetic deficiency causes apparent mineralocorticoid excess and hypertension due to inappropriate glucocorticoid activation of renal MR. The placenta and fetus also highly express 11β-HSD2 which, by inactivating glucocorticoids, prevents premature maturation of fetal tissues and consequent developmental “programming.” The role of 11β-HSD2 as a marker of programming is being explored. The 11β-HSDs thus illuminate the emerging biology of intracrine control, afford important insights into human pathogenesis, and offer new tissue-restricted therapeutic avenues. PMID:23899562

  13. Aging, glucocorticoids and developmental programming.

    Science.gov (United States)

    Zambrano, E; Reyes-Castro, L A; Nathanielsz, P W

    2015-06-01

    Glucocorticoids are pleiotropic regulators of multiple cell types with critical roles in physiological systems that change across the life-course. Although glucocorticoids have been associated with aging, available data on the aging trajectory in basal circulating glucocorticoids are conflicting. A literature search reveals sparse life-course data. We evaluated (1) the profile of basal circulating corticosterone across the life-course from weaning (postnatal day-PND 21), young adult PND 110, adult PND 450, mature adult PND 650 to aged phase PND 850 in a well-characterized homogeneous rat colony to determine existence of significant changes in trajectory in the second half of life; (2) sex differences; and (3) whether developmental programming of offspring by exposure to maternal obesity during development alters the later-life circulating corticosterone trajectory. We identified (1) a fall in corticosterone between PND 450 and 650 in both males and females (p age but from higher levels in male and female offspring of obese mothers. In all four groups studied, there was a second half of life fall in corticosterone. Higher corticosterone levels in offspring of obese mothers may play a role in their shorter life-span, but the age-associated fall occurs at a similar time to control offspring. Although even more life-course time-points would be useful, a five life-course time-point analysis provides important new information on normative and programmed aging of circulating corticosterone.

  14. AMPK regulates metabolic actions of glucocorticoids by phosphorylating the glucocorticoid receptor through p38 MAPK.

    Science.gov (United States)

    Nader, Nancy; Ng, Sinnie Sin Man; Lambrou, George I; Pervanidou, Panagiota; Wang, Yonghong; Chrousos, George P; Kino, Tomoshige

    2010-09-01

    Glucocorticoids play central roles in the regulation of energy metabolism by shifting it toward catabolism, whereas AMP-activated protein kinase (AMPK) is the master regulator of energy homeostasis, sensing energy depletion and stimulating pathways of increasing fuel uptake and saving on peripheral supplies. We showed here that AMPK regulates glucocorticoid actions on carbohydrate metabolism by targeting the glucocorticoid receptor (GR) and modifying transcription of glucocorticoid-responsive genes in a tissue- and promoter-specific fashion. Activation of AMPK in rats reversed glucocorticoid-induced hepatic steatosis and suppressed glucocorticoid-mediated stimulation of glucose metabolism. Transcriptomic analysis in the liver suggested marked overlaps between the AMPK and glucocorticoid signaling pathways directed mostly from AMPK to glucocorticoid actions. AMPK accomplishes this by phosphorylating serine 211 of the human GR indirectly through phosphorylation and consequent activation of p38 MAPK and by altering attraction of transcriptional coregulators to DNA-bound GR. In human peripheral mononuclear cells, AMPK mRNA expression positively correlated with that of glucocorticoid-responsive glucocorticoid-inducible leucine zipper protein, which correlated also positively with the body mass index of subjects. These results indicate that the AMPK-mediated energy control system modulates glucocorticoid action at target tissues. Because increased action of glucocorticoids is associated with the development of metabolic disorders, activation of AMPK could be a promising target for developing pharmacological interventions to these pathologies.

  15. Long-term side effects of glucocorticoids.

    Science.gov (United States)

    Oray, Merih; Abu Samra, Khawla; Ebrahimiadib, Nazanin; Meese, Halea; Foster, C Stephen

    2016-01-01

    Glucocorticoids represent the standard therapy for reducing inflammation and immune activation in various diseases. However, as with any potent medication, they are not without side effects. Glucocorticoid-associated side effects may involve most major organ systems. Musculoskeletal, gastrointestinal, cardiovascular, endocrine, neuropsychiatric, dermatologic, ocular, and immunologic side effects are all possible. This article analyzes English-language literature and provides an update on the most recent literature regarding side effects of systemic glucocorticoid treatment. The risk/benefit ratio of glucocorticoid therapy can be improved by proper use. Careful monitoring and using appropriate preventive strategies can potentially minimize side effects.

  16. Uus Multiphonic Rodent

    Index Scriptorium Estoniae

    2009-01-01

    Tartus tegutsenud eksperimentaal-rock-duo Opium Flirt Eestisse jäänud liige Erki Hõbe (paarimees Ervin Trofimov tegutseb Ungaris) annab välja oma teise sooloalbumi nime all Multiphonic Rodent, heliplaadi "Astral Dance" esitluskontsert toimub 5. veebruaril Tallinnas baaris Juuksur

  17. NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells

    NARCIS (Netherlands)

    S.W. Paugh (Steven); E.J. Bonten (Erik J.); D. Savic (Daniel); L.B. Ramsey (Laura B.); W.E. Thierfelder (William E.); P. Gurung (Prajwal); R.K.S. Malireddi (R. K. Subbarao); M. Actis (Marcelo); A. Mayasundari (Anand); J. Min (Jaeki); D.R. Coss (David R.); L.T. Laudermilk (Lucas T.); J.C. Panetta (John); J.R. McCorkle (J. Robert); Y. Fan (Yiping); K.R. Crews (Kristine R.); G. Stocco (Gabriele); M.R. Wilkinson (Mark R.); A.M. Ferreira (Antonio M.); C. Cheng (Cheng); W. Yang (Wenjian); S.E. Karol (Seth E.); C.A. Fernandez (Christian A.); B. Diouf (Barthelemy); C. Smith (Colton); J.K. Hicks (J Kevin); A. Zanut (Alessandra); A. Giordanengo (Audrey); D.J. Crona; J.J. Bianchi (Joy J.); L. Holmfeldt (Linda); C.G. Mullighan (Charles); M.L. den Boer (Monique); R. Pieters (Rob); S. Jeha (Sima); T.L. Dunwell (Thomas L.); F. Latif (Farida); D. Bhojwani (Deepa); W.L. Carroll (William L.); C.-H. Pui (Ching-Hon); R.M. Myers (Richard M.); R.K. Guy (R Kiplin); T.-D. Kanneganti (Thirumala-Devi); M.V. Relling (Mary); W.E. Evans (William)

    2015-01-01

    textabstractGlucocorticoids are universally used in the treatment of acute lymphoblastic leukemia (ALL), and resistance to glucocorticoids in leukemia cells confers poor prognosis. To elucidate mechanisms of glucocorticoid resistance, we determined the prednisolone sensitivity of primary leukemia

  18. Harvesting behaviour of three central European rodents: Identifying the rodent pest in cereals

    Czech Academy of Sciences Publication Activity Database

    Heroldová, Marta; Tkadlec, Emil

    2011-01-01

    Roč. 30, č. 1 (2011), s. 82-84 ISSN 0261-2194 R&D Projects: GA MZe QH72075 Institutional research plan: CEZ:AV0Z60930519 Keywords : Apodemus sylvaticus * Apodemus uralensis * feeding behaviour * lab experiments * Microtus arvalis * rodent pest control Subject RIV: GF - Plant Pathology, Vermin, Weed, Plant Protection Impact factor: 1.402, year: 2011

  19. Muscle atrophy in response to cytotoxic chemotherapy is dependent on intact glucocorticoid signaling in skeletal muscle.

    Directory of Open Access Journals (Sweden)

    Theodore P Braun

    Full Text Available Cancer cachexia is a syndrome of weight loss that results from the selective depletion of skeletal muscle mass and contributes significantly to cancer morbidity and mortality. The driver of skeletal muscle atrophy in cancer cachexia is systemic inflammation arising from both the cancer and cancer treatment. While the importance of tumor derived inflammation is well described, the mechanism by which cytotoxic chemotherapy contributes to cancer cachexia is relatively unexplored. We found that the administration of chemotherapy to mice produces a rapid inflammatory response. This drives activation of the hypothalamic-pituitary-adrenal axis, which increases the circulating level of corticosterone, the predominant endogenous glucocorticoid in rodents. Additionally, chemotherapy administration results in a significant loss of skeletal muscle mass 18 hours after administration with a concurrent induction of genes involved with the ubiquitin proteasome and autophagy lysosome systems. However, in mice lacking glucocorticoid receptor expression in skeletal muscle, chemotherapy-induced muscle atrophy is completely blocked. This demonstrates that cytotoxic chemotherapy elicits significant muscle atrophy driven by the production of endogenous glucocorticoids. Further, it argues that pharmacotherapy targeting the glucocorticoid receptor, given in concert with chemotherapy, is a viable therapeutic strategy in the treatment of cancer cachexia.

  20. Gamma-secretase inhibitors reverse glucocorticoid resistance in T-ALL

    Science.gov (United States)

    Real, Pedro J.; Tosello, Valeria; Palomero, Teresa; Castillo, Mireia; Hernando, Eva; de Stanchina, Elisa; Sulis, Maria Luisa; Barnes, Kelly; Sawai, Catherine; Homminga, Irene; Meijerink, Jules; Aifantis, Iannis; Basso, Giuseppe; Cordon-Cardo, Carlos; Ai, Walden; Ferrando, Adolfo

    2009-01-01

    Summary Gamma-secretase inhibitors (GSIs) block the activation of oncogenic NOTCH1 in T-cell acute lymphoblastic leukemia (T-ALL). However, limited antileukemic cytotoxicity and severe gastrointestinal toxicity have restricted the clinical application of these targeted drugs. Here we show that combination therapy with GSIs plus glucocorticoids can improve the antileukemic effects of GSIs and reduce their gut toxicity in vivo. Inhibition of NOTCH1 signaling in glucocorticoid-resistant T-ALL restored glucocorticoid receptor auto-up-regulation and induced apoptotic cell death through induction of BIM expression. GSI treatment resulted in cell cycle arrest and accumulation of goblet cells in the gut mediated by upregulation of Klf4, a negative regulator of cell cycle required for goblet cell differentiation. In contrast, glucocorticoid treatment induced transcriptional upregulation of Ccnd2 and protected mice from developing intestinal goblet cell metaplasia typically induced by inhibition of NOTCH signaling with GSIs. These results support a role for glucocorticoids plus GSIs in the treatment of glucocorticoid-resistant T-ALL. PMID:19098907

  1. Thymus as a target tissue of glucocorticoid action: what are the consequences of glucocorticoids thymectomy?

    Science.gov (United States)

    Bjelaković, Gordana; Stojanovic, Ivana; Jevtovic-Stoimenov, Tatjana; Pavlović, Dusica; Kocić, Gordana; Kamenov, Borisav; Saranac, Ljiljana; Nikolić, Jelenka; Bjelaković, Bojko; Sokolović, Dusan; Basić, Jelena

    2009-01-01

    Glucocorticoids represent the most powerful endogenous anti-inflammatory and immunosuppressive effectors, interfering with virtually every step of immunoinflammatory responses. Glucocorticoids are often the most effective therapy in the prevention or suppression of inflammation and other immunologically mediated processes, but their use is limited by systemic side effects induced by the over-production of reactive oxygen species, causing dysregulation of physiological processes. The thymus is an organ with both endocrine and immune functions. Glucocorticoids induce thymocyte apoptosis, causing a profound reduction in thymic mass and volume and inducing hormonal thymectomy. The clinical aspects of glucocorticoid thymectomy are not under enough investigation. These unwanted systemic side effects may be the consequence of prolonged therapeutic application of glucocorticoids and prolonged or chronic activation of the hypothalamic-pituitary adrenal axis, which may lead to increased and prolonged secretion of glucocorticoids. This review will discuss the metabolic effects of glucocorticoids in the context of thymic physiology asthe primary sex hormone-responsive organ.

  2. Behavioral neuroadaptation to alcohol : from glucocorticoids to histone acetylation

    Directory of Open Access Journals (Sweden)

    Daniel Beracochea

    2016-10-01

    Full Text Available A prime mechanism that contributes to the development and maintenance of alcoholism is the dysregulation of the hypothalamic-pituitary-adrenal (HPA axis activity and the release of glucocorticoids (cortisol in humans and primates, corticosterone in rodents from the adrenal glands. In the brain, sustained, local elevation of glucocorticoid concentration even long after cessation of chronic alcohol consumption compromises functional integrity of a circuit including the prefrontal cortex, the hippocampus and the amygdala. These structures are implicated in learning and memory processes as well as in orchestrating neuroadaptive responses to stress and anxiety responses. Thus, potentiation of anxiety-related neuroadaptation by alcohol is characterized by an abnormally amygdala hyperactivity coupled with a hypofunction of the prefrontal cortex and the hippocampus. This review describes research on molecular and epigenetic mechanisms by which alcohol causes distinct region-specific adaptive changes in gene expression patterns and ultimately, leads to a variety of cognitive and behavioral impairments on prefrontal- and hippocampal-based tasks. Alcohol-induced neuroadaptations involve the dysregulation of numerous signaling cascades, leading to long-term changes in transcriptional profiles of genes, through the actions of transcription factors such as CREB (cAMP response element binding protein and chromatin remodeling due to post-translational modifications of histone proteins. We describe the role of prefrontal-hippocampus-amygdala circuit in mediating the effects of acute and chronic alcohol on learning and memory, and region-specific molecular and epigenetic mechanisms involved in this process. This review first discusses the importance of brain region-specific dysregulation of glucocorticoid concentration in the development of alcohol dependence and describes on how persistently increased glucocorticoid levels in prefrontal cortex may be involved in

  3. Advances in Glucocorticoid-induced Osteoporosis

    NARCIS (Netherlands)

    den Uyl, D.; Bultink, I.E.M.; Lems, W.F.

    2011-01-01

    Glucocorticoid-induced osteoporosis (GIOP) is one of the most important side effects of glucocorticoid use, as it leads to an increased risk of fractures. Recently, many published studies have focused on the cellular and molecular mechanisms of bone metabolism, the pathophysiology of GIOP, and the

  4. Glucocorticoid pulsatility : implications for brain functioning

    NARCIS (Netherlands)

    Sarabdjitsingh, Ratna Angela

    2010-01-01

    Pronounced ultradian and circadian rhythms in the hormones of the hypothalamic-pituitary-adrenal (HPA) axis (i.e. glucocorticoids), one of the body’s major neuroendocrine axes, were already demonstrated several decades ago. Until now, the clinical relevance of the pulsatile nature of glucocorticoids

  5. Primary generalized glucocorticoid resistance and hypersensitivity.

    Science.gov (United States)

    Charmandari, Evangelia

    2011-01-01

    The human glucocorticoid receptor (hGR) is a ubiquitously expressed intracellular, ligand-dependent transcription factor, which mediates the action of glucocorticoids and influences physiological functions essential for life. Alterations in the molecular mechanisms of hGR action impair glucocorticoid signal transduction and alter tissue sensitivity to glucocorticoids. This review summarizes the pathophysiology, molecular mechanisms and clinical aspects of primary generalized glucocorticoid resistance (PGGR) and hypersensitivity (PGGH). A systematic review of the published, peer-reviewed medical literature (PubMed: 1975 through May 2011) was conducted to identify original articles and reviews on this topic. Evidence synthesis was relied upon the experience of a number of experts in the field, including our extensive personal experience. The molecular basis of PGGR and PGGH has been ascribed to mutations in the hGR gene, which alter tissue sensitivity to glucocorticoids. The stochastic nature of glucocorticoid signaling pathways in association with the variable effect that hGR gene mutations/polymorphisms might have on glucocorticoid signal transduction indicates that alterations in hGR action may have important implications for many critical biological processes, such as the behavioral and physiological responses to stress, the immune and inflammatory reaction, as well as growth and reproduction. Copyright © 2011 S. Karger AG, Basel.

  6. An early warning system for IPM-based rodent control in smallholder farming systems in Tanzania

    DEFF Research Database (Denmark)

    Mwanjabe, Patrick S.; Leirs, Herwig

    1997-01-01

    We conducted a four-year study in Tanzania to test a method for predicting outbreaks of Mastomys natalensis rats and verify whether such method, based on rainfall variability, could be used in an integrated Pest Management strategy for rodent control. Temporal fluctuations in rodent numbers...... that the effects of a single control action undertaken at planting time do not persist long enough to protect seedlings, probably due to quick reinvasion of the treated fields by rodents from the surroundings. These observations are formulated into a rodent control package whose steps are to predict rodent...... outbreaks, to warn farmers and the government of the outbreaks, and to organise control measures in advance....

  7. Optimal glucocorticoid replacement in adrenal insufficiency.

    Science.gov (United States)

    Øksnes, Marianne; Ross, Richard; Løvås, Kristian

    2015-01-01

    Adrenal insufficiency (glucocorticoid deficiency) comprises a group of rare diseases, including primary adrenal insufficiency, secondary adrenal insufficiency and congenital adrenal hyperplasia. Lifesaving glucocorticoid therapy was introduced over 60 years ago, but since then a number of advances in treatment have taken place. Specifically, little is known about short- and long-term treatment effects, and morbidity and mortality. Over the past decade, systematic cohort and registry studies have described reduced health-related quality of life, an unfavourable metabolic profile and increased mortality in patients with adrenal insufficiency, which may relate to unphysiological glucocorticoid replacement. This has led to the development of new modes of replacement that aim to mimic normal glucocorticoid physiology. Here, evidence for the inadequacy of conventional glucocorticoid therapy and recent developments in treatment are reviewed, with an emphasis on primary adrenal insufficiency. Copyright © 2014 Elsevier Ltd. All rights reserved.

  8. Exogenous Cushing's syndrome and glucocorticoid withdrawal.

    Science.gov (United States)

    Hopkins, Rachel L; Leinung, Matthew C

    2005-06-01

    Glucocorticoid therapy in various forms is extremely common for a wide range of inflammatory, autoimmune, and neoplastic disorders. It is therefore important for the physician to be aware of the possibility of both iatrogenic and factitious Cushing's syndrome. Although most common with oral therapy, it is also important to be alert to the fact that all forms of glucocorticoid delivery have the potential to cause Cushing's syndrome. Withdrawal from chronic glucocorticoid therapy presents significant challenges. These include the possibility of adrenal insufficiency after discontinuation of steroid therapy, recurrence of underlying disease as the glucocorticoid is being withdrawn, and the possibility of steroid withdrawal symptoms. Nonetheless, with patience and persistence, a reasonable approach to withdrawal of glucocorticoid therapy can be achieved.

  9. Glucocorticoids as mediators of developmental programming effects.

    Science.gov (United States)

    Khulan, Batbayar; Drake, Amanda J

    2012-10-01

    Epidemiological evidence suggests that exposure to an adverse environment in early life is associated with an increased risk of cardio-metabolic and behavioral disorders in adulthood, a phenomenon termed 'early life programming'. One major hypothesis for early life programming is fetal glucocorticoid overexposure. In animal studies, prenatal glucocorticoid excess as a consequence of maternal stress or through exogenous administration to the mother or fetus is associated with programming effects on cardiovascular and metabolic systems and on the brain. These effects can be transmitted to subsequent generations. Studies in humans provide some evidence that prenatal glucocorticoid exposure may exert similar programming effects on glucose/insulin homeostasis, blood pressure and neurodevelopment. The mechanisms by which glucocorticoids mediate these effects are unclear but may include a role for epigenetic modifications. This review discusses the evidence for glucocorticoid programming in animal models and in humans. Copyright © 2012 Elsevier Ltd. All rights reserved.

  10. Rodents of the Caribbean

    DEFF Research Database (Denmark)

    Fabre, Pierre-Henri; Mouatt, Julia Thidamarth Vilstrup; Raghavan, Maanasa

    2014-01-01

    The Capromyidae (hutias) are endemic rodents of the Caribbean and represent a model of dispersal for non-flying mammals in the Greater Antilles. This family has experienced severe extinctions during the Holocene and its phylogenetic affinities with respect to other caviomorph relatives are still ...... (Bahamas, Cuba, Jamaica) hutias. Recent divergences among these western hutias suggest Plio-Pleistocene dispersal waves associated with glacial cycles....

  11. Anti-inflammatory glucocorticoids: changing concepts.

    Science.gov (United States)

    Newton, Robert

    2014-02-05

    Despite being the most effective anti-inflammatory treatment for chronic inflammatory diseases, the mechanisms by which glucocorticoids (corticosteroids) effect repression of inflammatory gene expression remain incompletely understood. Direct interaction of the glucocorticoid receptor (NR3C1) with inflammatory transcription factors to repress transcriptional activity, i.e. transrepression, represents one mechanism of action. However, transcriptional activation, or transactivation, by NR3C1 also represents an important mechanism of glucocorticoid action. Glucocorticoids rapidly and profoundly increase expression of multiple genes, many with properties consistent with the repression of inflammatory gene expression. For example: the dual specificity phosphatase, DUSP1, reduces activation of mitogen-activated protein kinases; glucocorticoid-induced leucine zipper (TSC22D3) represses nuclear factor-κB (NF-κB) and activator protein 1 (AP-1) transcriptional responses; inhibitor of κBα (NFKBIA) inhibits NF-κB; tristraprolin (ZFP36) destabilises and translationally represses inflammatory mRNAs; CDKN1C, a cell cycle regulator, may attenuate JUN N-terminal kinase signalling; and regulator of G-protein signalling 2 (RGS2), by reducing signalling from Gαq-linked G protein-coupled receptors (GPCRs), is bronchoprotective. While glucocorticoid-dependent transrepression can co-exist with transactivation, transactivation may account for the greatest level and most potent repression of inflammatory genes. Equally, NR3C1 transactivation is enhanced by β2-adrenoceptor agonists and may explain the enhanced clinical efficacy of β2-adrenoceptor/glucocorticoid combination therapies in asthma and chronic obstructive pulmonary disease. Finally, NR3C1 transactivation is reduced by inflammatory stimuli, including respiratory syncytial virus and human rhinovirus. This provides an explanation for glucocorticoid resistance. Continuing efforts to understand roles for glucocorticoid

  12. Antenatal glucocorticoid treatment and polymorphisms of the glucocorticoid and mineralocorticoid receptors are associated with IQ and behavior in young adults born very preterm

    NARCIS (Netherlands)

    Voorn, B. van der; Pal, S.M. van der; Rotteveel, J.; Finken, M.J.

    2015-01-01

    Context: Preterm survivors exhibit neurodevelopmental impairments. Whether this association is influenced by antenatal glucocorticoid treatment and glucocorticoid sensitivity is unknown. Objectives: To study the effects of antenatal glucocorticoid treatment and glucocorticoid receptor (GR) and

  13. Macrophage migration inhibitory factor inhibits the antiinflammatory effects of glucocorticoids via glucocorticoid-induced leucine zipper.

    Science.gov (United States)

    Fan, Huapeng; Kao, Wenping; Yang, Yuan H; Gu, Ran; Harris, James; Fingerle-Rowson, Günter; Bucala, Richard; Ngo, Devi; Beaulieu, Elaine; Morand, Eric F

    2014-08-01

    Glucocorticoids remain a mainstay in the treatment of rheumatoid arthritis (RA). Dose-dependent adverse effects highlight the need for therapies that regulate glucocorticoid sensitivity to enable dosage reduction. Macrophage migration inhibitory factor (MIF) is a proinflammatory protein that has been implicated in the pathogenesis of RA; it impairs glucocorticoid sensitivity via MAPK phosphatase 1 (MKP-1) inhibition. The intracellular protein glucocorticoid-induced leucine zipper (GILZ) mimics the effects of glucocorticoids in models of RA, but whether it represents a target for the modulation of glucocorticoid sensitivity remains unknown. We undertook this study to investigate whether GILZ is involved in the regulation of glucocorticoid sensitivity by MIF. GILZ expression was studied in the presence and absence of MIF, and the role of GILZ in the MIF-dependent regulation of the glucocorticoid sensitivity mediator MKP-1 was studied at the level of expression and function. GILZ expression was significantly inhibited by endogenous MIF, both basally and during responses to glucocorticoid treatment. The effects of MIF on GILZ were dependent on the expression and Akt-induced nuclear translocation of the transcription factor FoxO3A. GILZ was shown to regulate the expression of MKP-1 and consequent MAPK phosphorylation and cytokine release. MIF exerts its effects on MKP-1 expression and MAPK activity through inhibitory effects on GILZ. These findings suggest a previously unsuspected interaction between MIF and GILZ and identify GILZ as a potential target for the therapeutic regulation of glucocorticoid sensitivity. Copyright © 2014 by the American College of Rheumatology.

  14. Estrogen inhibits glucocorticoid action via protein phosphatase 5 (PP5)-mediated glucocorticoid receptor dephosphorylation.

    Science.gov (United States)

    Zhang, Yong; Leung, Donald Y M; Nordeen, Steven K; Goleva, Elena

    2009-09-04

    Although glucocorticoids suppress proliferation of many cell types and are used in the treatment of certain cancers, trials of glucocorticoid therapy in breast cancer have been a disappointment. Another suggestion that estrogens may affect glucocorticoid action is that the course of some inflammatory diseases tends to be more severe and less responsive to corticosteroid treatment in females. To date, the molecular mechanism of cross-talk between estrogens and glucocorticoids is poorly understood. Here we show that, in both MCF-7 and T47D breast cancer cells, estrogen inhibits glucocorticoid induction of the MKP-1 (mitogen-activated protein kinase phosphatase-1) and serum/glucocorticoid-regulated kinase genes. Estrogen did not affect glucocorticoid-induced glucocorticoid receptor (GR) nuclear translocation but reduced ligand-induced GR phosphorylation at Ser-211, which is associated with the active form of GR. We show that estrogen increases expression of protein phosphatase 5 (PP5), which mediates the dephosphorylation of GR at Ser-211. Gene knockdown of PP5 abolished the estrogen-mediated suppression of GR phosphorylation and induction of MKP-1 and serum/glucocorticoid-regulated kinase. More importantly, after PP5 knockdown estrogen-promoted cell proliferation was significantly suppressed by glucocorticoids. This study demonstrates cross-talk between estrogen-induced PP5 and GR action. It also reveals that PP5 inhibition may antagonize estrogen-promoted events in response to corticosteroid therapy.

  15. Dynamic regulation of glucocorticoid signalling in health and disease

    OpenAIRE

    Biddie, Simon C.; Conway-Campbell, Becky L.; Lightman, Stafford L.

    2011-01-01

    Activation of the glucocorticoid receptor (GR) by endogenous and synthetic glucocorticoids regulates hundreds of genes to control regulatory networks in development, metabolism, cognition and inflammation. Elucidation of the mechanisms that regulate glucocorticoid action has highlighted the dynamic nature of hormone signalling and provides novel insights into genomic glucocorticoid actions. The major factors that regulate GR function include chromatin structure, epigenetics, genetic variation...

  16. Effects of elevated glucocorticoids on reproduction and development: relevance to endocrine disruptor screening.

    Science.gov (United States)

    Witorsch, Raphael J

    2016-01-01

    This article reviews the influence of the hypothalamo-pituitary-adrenocortical (HPA) axis on mammalian male and female reproduction and development of offspring and its potential impact on the identification of endocrine disruptive chemicals by in vivo assays. In the adult male rat and baboon, stress suppresses testosterone secretion via a direct inhibitory effect of elevated glucocorticoids on Leydig cells. In adult female sheep, stress disrupts reproductive function via multi-stage mechanisms involving glucocorticoid-mediated suppression of LH secretion, LH action on the ovary and the action of estradiol on its target cells (e.g., uterus). While physiological concentrations of endogenous glucocorticoids are supportive of fetal development, excessive glucocorticoids in utero (i.e., maternal stress) adversely affect mammalian offspring by "programing" abnormalities that are primarily manifest postpartum. The influence of stress on reproduction and development can also be mediated by 11β-hydroxysteroid dehydrogenase (HSD), a bi-directional oxidative:reductive pathway, which governs the balance between biologically active (reduced) endogenous glucocorticoid and inactive (oxidized) metabolites. This pathway is mediated primarily by two isozymes, 11β - HSD1 (reductase) and 11β-HSD2 (oxidase) which act both in an intracrine (intracellular) and endocrine (systemic) fashion. The 11β-HSD pathway appears to play a variety of physiological roles in mammalian reproduction and development and is a target for selected xenobiotics. The effects of the HPA axis on mammalian reproduction and development are potential confounders for in vivo bioassays in rodents employed to identify endocrine disruptive chemicals. Accordingly, consideration of the impact of the HPA axis should be incorporated into the design of bioassays for evaluating endocrine disruptors.

  17. Rodent models for studying empathy.

    Science.gov (United States)

    Keum, Sehoon; Shin, Hee-Sup

    2016-11-01

    Empathy is the important capacity to recognize and share emotions with others. Recent evidence shows that rodents possess a remarkable affective sensitivity to the emotional state of others and that primitive forms of empathy exist in social lives of rodents. However, due to the ambiguous definitional boundaries between empathy, emotional contagion and other related terms, distinct components of empathic behaviors in rodents need to be clarified. Hence, we review recent experimental studies demonstrating that rodents are able to share emotions with others. Specifically, we highlight several behavioral models that examine different aspects of rodent empathic behaviors in response to the various distress of conspecifics. Experimental approaches using rodent behavioral models will help elucidate the neural circuitry of empathy and its neurochemical association. Integrating these findings with corresponding experiments in humans will ultimately provide novel insights into therapeutic interventions for mental disorders associated with empathy. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Glucocorticoids, epigenetic control and stress resilience

    Directory of Open Access Journals (Sweden)

    Johannes M.H.M. Reul

    2015-01-01

    Full Text Available Glucocorticoid hormones play a pivotal role in the response to stressful challenges. The surge in glucocorticoid hormone secretion after stress needs to be tightly controlled with characteristics like peak height, curvature and duration depending on the nature and severity of the challenge. This is important as chronic hyper- or hypo-responses are detrimental to health due to increasing the risk for developing a stress-related mental disorder. Proper glucocorticoid responses to stress are critical for adaptation. Therefore, the tight control of baseline and stress-evoked glucocorticoid secretion are important constituents of an organism's resilience. Here, we address a number of mechanisms that illustrate the multitude and complexity of measures safeguarding the control of glucocorticoid function. These mechanisms include the control of mineralocorticoid (MR and glucocorticoid receptor (GR occupancy and concentration, the dynamic control of free glucocorticoid hormone availability by corticosteroid-binding globulin (CBG, and the control exerted by glucocorticoids at the signaling, epigenetic and genomic level on gene transcriptional responses to stress. We review the beneficial effects of regular exercise on HPA axis and sleep physiology, and cognitive and anxiety-related behavior. Furthermore, we describe that, possibly through changes in the GABAergic system, exercise reduces the impact of stress on a signaling pathway specifically in the dentate gyrus that is strongly implicated in the behavioral response to that stressor. These observations underline the impact of life style on stress resilience. Finally, we address how single nucleotide polymorphisms (SNPs affecting glucocorticoid action can compromise stress resilience, which becomes most apparent under conditions of childhood abuse.

  19. Circumvention of glucocorticoid resistance in childhood leukemia.

    Science.gov (United States)

    Haarman, E G; Kaspers, G J L; Pieters, R; Rottier, M M A; Veerman, A J P

    2008-09-01

    In this study, we determined if in vitro resistance to prednisolone and dexamethasone could be circumvented by cortivazol or methylprednisolone, or reversed by meta-iodobenzylguanidine in pediatric lymphoblastic and myeloid leukemia. As there were strong correlations between the LC50 values (drug concentration inducing 50% leukemic cell kill, LCK) of the different glucocorticoids and median prednisolone/methylprednisolone, prednisolone/dexamethasone and prednisolone/cortivazol LC50 ratios did not differ between the leukemia subtypes, we conclude that none of the glucocorticoids had preferential anti-leukemic activity. Meta-iodobenzylguanidine however, partially reversed glucocorticoid resistance in 19% of the lymphoblastic leukemia samples.

  20. Timing of glucocorticoid therapy for liver failure

    Directory of Open Access Journals (Sweden)

    MENG Qinghua

    2017-09-01

    Full Text Available There are still controversies over the use of glucocorticoids in the treatment of liver failure, and current guidelines for liver failure recommend that glucocorticoids should be used with great caution. However, some latest studies have shown that the use of glucocorticoid therapy in the early stage of liver failure can bring more benefits to patients. Age, disease progression rate and severity, and complications of liver failure may affect the treatment outcome. Further studies are still needed for the selection of right patients, drugs and dose, and treatment timing.

  1. GLUCOCORTICOID RECEPTOR REGULATION IN THE RAT EMBRYO: A POTENTIAL SITE FOR DEVELOPMENTAL TOXICITY?

    Science.gov (United States)

    Glucocorticoid receptor regulation in the rat embryo: a potential site for developmental toxicity?Ghosh B, Wood CR, Held GA, Abbott BD, Lau C.National Research Council, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.

  2. Vitamin D Deficiency in BALB/c Mouse Pregnancy Increases Placental Transfer of Glucocorticoids.

    Science.gov (United States)

    Tesic, Dijana; Hawes, Jazmin E; Zosky, Graeme R; Wyrwoll, Caitlin S

    2015-10-01

    The prevalence of vitamin D deficiency in pregnancy is increasing and implicated in adverse consequences for the health of offspring in later life. The aim of this study was to determine whether vitamin D deficiency increases fetal exposure to glucocorticoids, which are known to alter fetal development and result in adverse adult health outcomes. Female BALB/c mice were placed on either a vitamin D control (2195 IU/kg) or deficient (0 IU/kg) diet for 5 weeks before and during pregnancy. Maternal serum, placentas and fetal brains were collected at embryonic day 14.5 or 17.5 for morphological and gene expression analysis. Vitamin D deficiency during pregnancy increased maternal corticosterone concentrations and reduced placental weight. Maternal vitamin D deficiency decreased placental expression of 11β-hydroxysteroid dehydrogenase type II, which inactivates glucocorticoids thereby protecting the fetus from inappropriate glucocorticoid exposure. There was a corresponding increase in placental and fetal expression of the highly glucocorticoid-sensitive factor glucocorticoid-induced leucine zipper. Furthermore, placental expression of the angiogenic factor vascular endothelial growth factor-A was reduced in vitamin D-deficient pregnancies, with a corresponding decline in fetal capillary volume within the placenta. Overall, we show that prenatal vitamin D deficiency leads to an increase in maternal corticosterone, alterations in genes indicative of increased fetal glucocorticoid exposure and impairment in placental vascular development. Thus, the long-term adverse health consequences of vitamin D deficiency during early development may not just be due to alteration in direct vitamin D-related pathways but also altered fetal glucocorticoid exposure.

  3. Glucocorticoids Suppress Mitochondrial Oxidant Production via Upregulation of Uncoupling Protein 2 in Hyperglycemic Endothelial Cells.

    Science.gov (United States)

    Gerö, Domokos; Szabo, Csaba

    2016-01-01

    Diabetic complications are the leading cause of morbidity and mortality in diabetic patients. Elevated blood glucose contributes to the development of endothelial and vascular dysfunction, and, consequently, to diabetic micro- and macrovascular complications, because it increases the mitochondrial proton gradient and mitochondrial oxidant production. Therapeutic approaches designed to counteract glucose-induced mitochondrial reactive oxygen species (ROS) production in the vasculature are expected to show efficacy against all diabetic complications, but direct pharmacological targeting (scavenging) of mitochondrial oxidants remains challenging due to the high reactivity of some of these oxidant species. In a recent study, we have conducted a medium-throughput cell-based screening of a focused library of well-annotated pharmacologically active compounds and identified glucocorticoids as inhibitors of mitochondrial superoxide production in microvascular endothelial cells exposed to elevated extracellular glucose. The goal of the current study was to investigate the mechanism of glucocorticoids' action. Our findings show that glucocorticoids induce the expression of the mitochondrial UCP2 protein and decrease the mitochondrial potential. UCP2 silencing prevents the protective effect of the glucocorticoids on ROS production. UCP2 induction also increases the oxygen consumption and the "proton leak" in microvascular endothelial cells. Furthermore, glutamine supplementation augments the effect of glucocorticoids via further enhancing the expression of UCP2 at the translational level. We conclude that UCP2 induction represents a novel experimental therapeutic intervention in diabetic vascular complications. While direct repurposing of glucocorticoids may not be possible for the therapy of diabetic complications due to their significant side effects that develop during chronic administration, the UCP2 pathway may be therapeutically targetable by other, glucocorticoid

  4. Glucocorticoids Suppress Mitochondrial Oxidant Production via Upregulation of Uncoupling Protein 2 in Hyperglycemic Endothelial Cells.

    Directory of Open Access Journals (Sweden)

    Domokos Gerö

    Full Text Available Diabetic complications are the leading cause of morbidity and mortality in diabetic patients. Elevated blood glucose contributes to the development of endothelial and vascular dysfunction, and, consequently, to diabetic micro- and macrovascular complications, because it increases the mitochondrial proton gradient and mitochondrial oxidant production. Therapeutic approaches designed to counteract glucose-induced mitochondrial reactive oxygen species (ROS production in the vasculature are expected to show efficacy against all diabetic complications, but direct pharmacological targeting (scavenging of mitochondrial oxidants remains challenging due to the high reactivity of some of these oxidant species. In a recent study, we have conducted a medium-throughput cell-based screening of a focused library of well-annotated pharmacologically active compounds and identified glucocorticoids as inhibitors of mitochondrial superoxide production in microvascular endothelial cells exposed to elevated extracellular glucose. The goal of the current study was to investigate the mechanism of glucocorticoids' action. Our findings show that glucocorticoids induce the expression of the mitochondrial UCP2 protein and decrease the mitochondrial potential. UCP2 silencing prevents the protective effect of the glucocorticoids on ROS production. UCP2 induction also increases the oxygen consumption and the "proton leak" in microvascular endothelial cells. Furthermore, glutamine supplementation augments the effect of glucocorticoids via further enhancing the expression of UCP2 at the translational level. We conclude that UCP2 induction represents a novel experimental therapeutic intervention in diabetic vascular complications. While direct repurposing of glucocorticoids may not be possible for the therapy of diabetic complications due to their significant side effects that develop during chronic administration, the UCP2 pathway may be therapeutically targetable by other

  5. Molecular mechanisms of glucocorticoid receptor signaling

    Directory of Open Access Journals (Sweden)

    Marta Labeur

    2010-10-01

    Full Text Available This review highlights the most recent findings on the molecular mechanisms of the glucocorticoid receptor (GR. Most effects of glucocorticoids are mediated by the intracellular GR which is present in almost every tissue and controls transcriptional activation via direct and indirect mechanisms. Nevertheless the glucocorticoid responses are tissue -and gene- specific. GR associates selectively with corticosteroid ligands produced in the adrenal gland in response to changes of humoral homeostasis. Ligand interaction with GR promotes either GR binding to genomic glucocorticoid response elements, in turn modulating gene transcription, or interaction of GR monomers with other transcription factors activated by other signalling pathways leading to transrepression. The GR regulates a broad spectrum of physiological functions, including cell differentiation, metabolism and inflammatory responses. Thus, disruption or dysregulation of GR function will result in severe impairments in the maintenance of homeostasis and the control of adaptation to stress.

  6. Effects of Glucocorticoids in the Immune System.

    Science.gov (United States)

    Oppong, Emmanuel; Cato, Andrew C B

    2015-01-01

    Glucocorticoids (GCs) are steroid hormones with widespread effects. They control intermediate metabolism by stimulating gluconeogenesis in the liver, mobilize amino acids from extra hepatic tissues, inhibit glucose uptake in muscle and adipose tissue, and stimulate fat breakdown in adipose tissue. They also mediate stress response. They exert potent immune-suppressive and anti-inflammatory effects particularly when administered pharmacologically. Understanding these diverse effects of glucocorticoids requires a detailed knowledge of their mode of action. Research over the years has uncovered several details on the molecular action of this hormone, especially in immune cells. In this chapter, we have summarized the latest findings on the action of glucocorticoids in immune cells with a view of identifying important control points that may be relevant in glucocorticoid therapy.

  7. Glucocorticoids as regulatory signals during intrauterine development.

    Science.gov (United States)

    Fowden, Abigail L; Forhead, Alison J

    2015-12-01

    What is the topic of this review? This review discusses the role of the glucocorticoids as regulatory signals during intrauterine development. It examines the functional significance of these hormones as maturational, environmental and programming signals in determining offspring phenotype. What advances does it highlight? It focuses on the extensive nature of the regulatory actions of these hormones. It highlights the emerging data that these actions are mediated, in part, by the placenta, other endocrine systems and epigenetic modifications of the genome. Glucocorticoids are important regulatory signals during intrauterine development. They act as maturational, environmental and programming signals that modify the developing phenotype to optimize offspring viability and fitness. They affect development of a wide range of fetal tissues by inducing changes in cellular expression of structural, transport and signalling proteins, which have widespread functional consequences at the whole organ and systems levels. Glucocorticoids, therefore, activate many of the physiological systems that have little function in utero but are vital at birth to replace the respiratory, nutritive and excretory functions previously carried out by the placenta. However, by switching tissues from accretion to differentiation, early glucocorticoid overexposure in response to adverse conditions can programme fetal development with longer term physiological consequences for the adult offspring, which can extend to the next generation. The developmental effects of the glucocorticoids can be direct on fetal tissues with glucocorticoid receptors or mediated by changes in placental function or other endocrine systems. At the molecular level, glucocorticoids can act directly on gene transcription via their receptors or indirectly by epigenetic modifications of the genome. In this review, we examine the role and functional significance of glucocorticoids as regulatory signals during intrauterine

  8. Glucocorticoids are ineffective in alcoholic hepatitis

    DEFF Research Database (Denmark)

    Christensen, E; Gluud, C

    1995-01-01

    The aim of this study was to perform a meta-analysis of controlled clinical trials of glucocorticoid treatment in clinical alcoholic hepatitis, adjusting for prognostic variables and their possible interaction with therapy, because these trials have given appreciably different results. Weighted...... may be different (beneficial or harmful) in special patient subgroups. These results do not support the routine use of glucocorticoids in patients with alcoholic hepatitis, including those with encephalopathy. Whether other subgroups may benefit needs further investigation using the individual patient...

  9. Hypothalamic-Pituitary-Adrenal Axis Modulation of Glucocorticoids in the Cardiovascular System

    Science.gov (United States)

    Burford, Natalie G.; Webster, Natalia A.; Cruz-Topete, Diana

    2017-01-01

    The collective of endocrine organs acting in homeostatic regulation—known as the hypothalamic-pituitary-adrenal (HPA) axis—comprises an integration of the central nervous system as well as peripheral tissues. These organs respond to imminent or perceived threats that elicit a stress response, primarily culminating in the release of glucocorticoids into the systemic circulation by the adrenal glands. Although the secretion of glucocorticoids serves to protect and maintain homeostasis in the typical operation at baseline levels, inadequate regulation can lead to physiologic and psychologic pathologies. The cardiovascular system is especially susceptible to prolonged dysregulation of the HPA axis and glucocorticoid production. There is debate about whether cardiovascular health risks arise from the direct detrimental effects of stress axis activation or whether pathologies develop secondary to the accompanying metabolic strain of excess glucocorticoids. In this review, we will explore the emerging research that indicates stress does have direct effects on the cardiovascular system via the HPA axis activation, with emphasis on the latest research on the impact of glucocorticoids signaling in the vasculature and the heart. PMID:29035323

  10. Hypothalamic-Pituitary-Adrenal Axis Modulation of Glucocorticoids in the Cardiovascular System.

    Science.gov (United States)

    Burford, Natalie G; Webster, Natalia A; Cruz-Topete, Diana

    2017-10-16

    The collective of endocrine organs acting in homeostatic regulation-known as the hypothalamic-pituitary-adrenal (HPA) axis-comprises an integration of the central nervous system as well as peripheral tissues. These organs respond to imminent or perceived threats that elicit a stress response, primarily culminating in the release of glucocorticoids into the systemic circulation by the adrenal glands. Although the secretion of glucocorticoids serves to protect and maintain homeostasis in the typical operation at baseline levels, inadequate regulation can lead to physiologic and psychologic pathologies. The cardiovascular system is especially susceptible to prolonged dysregulation of the HPA axis and glucocorticoid production. There is debate about whether cardiovascular health risks arise from the direct detrimental effects of stress axis activation or whether pathologies develop secondary to the accompanying metabolic strain of excess glucocorticoids. In this review, we will explore the emerging research that indicates stress does have direct effects on the cardiovascular system via the HPA axis activation, with emphasis on the latest research on the impact of glucocorticoids signaling in the vasculature and the heart.

  11. Hypothalamic-Pituitary-Adrenal Axis Modulation of Glucocorticoids in the Cardiovascular System

    Directory of Open Access Journals (Sweden)

    Natalie G. Burford

    2017-10-01

    Full Text Available The collective of endocrine organs acting in homeostatic regulation—known as the hypothalamic-pituitary-adrenal (HPA axis—comprises an integration of the central nervous system as well as peripheral tissues. These organs respond to imminent or perceived threats that elicit a stress response, primarily culminating in the release of glucocorticoids into the systemic circulation by the adrenal glands. Although the secretion of glucocorticoids serves to protect and maintain homeostasis in the typical operation at baseline levels, inadequate regulation can lead to physiologic and psychologic pathologies. The cardiovascular system is especially susceptible to prolonged dysregulation of the HPA axis and glucocorticoid production. There is debate about whether cardiovascular health risks arise from the direct detrimental effects of stress axis activation or whether pathologies develop secondary to the accompanying metabolic strain of excess glucocorticoids. In this review, we will explore the emerging research that indicates stress does have direct effects on the cardiovascular system via the HPA axis activation, with emphasis on the latest research on the impact of glucocorticoids signaling in the vasculature and the heart.

  12. Perioperative glucocorticoids in hip and knee surgery - benefit vs. harm?

    DEFF Research Database (Denmark)

    Lunn, T H; Kehlet, H

    2013-01-01

    glucocorticoid administration analogous to > 10 mg or ≤ 10 mg dexamethasone, and local glucocorticoid administration. Seventeen studies with data from 1081 patients were included in the final qualitative synthesis. Benefit (of any kind) with glucocorticoid vs. placebo was reported in 15 studies. PONV was reduced...... with systemic glucocorticoid. Pain was reduced with high-dose systemic and local glucocorticoid, but not with low-dose systemic glucocorticoid. Systemic inflammatory markers were reduced with low-dose and high-dose systemic glucocorticoid, and with local glucocorticoid. Functional recovery was improved...... with local glucocorticoid. All studies were small-sized and none sufficiently powered to meaningfully evaluate uncommon adverse events. Most of the local administration studies had poor scientific quality (high risk of bias). Due to clinical heterogeneity and poor scientific quality, no meta...

  13. Glucocorticoids and fetal programming part 2: Mechanisms.

    Science.gov (United States)

    Moisiadis, Vasilis G; Matthews, Stephen G

    2014-07-01

    The lifelong health of an individual is shaped during critical periods of development. The fetus is particularly susceptible to internal and external stimuli, many of which can alter developmental trajectories and subsequent susceptibility to disease. Glucocorticoids are critical in normal development of the fetus, as they are involved in the growth and maturation of many organ systems. The surge in fetal glucocorticoid levels that occurs in most mammalian species over the last few days of pregnancy is an important developmental switch leading to fundamental changes in gene regulation in many organs, including the brain. These changes are important for the transition to postnatal life. Exposure of the fetus to increased levels of glucocorticoids, resulting from maternal stress or treatment with synthetic glucocorticoids, can lead to long-term 'programming' of hypothalamic-pituitary-adrenal function and behaviours. Glucocorticoids act at multiple levels within the fetal brain. Growing evidence indicates that they can exert powerful effects on the epigenome, including on DNA methylation, histone acetylation and microRNA, to influence gene expression. Such influences probably represent a critical component of the 'programming' process, and might be partly responsible for the transgenerational effects of antenatal glucocorticoid exposure on neurologic, cardiovascular and metabolic function.

  14. The multiple facets of glucocorticoid action in rheumatoid arthritis.

    Science.gov (United States)

    Baschant, Ulrike; Lane, Nancy E; Tuckermann, Jan

    2012-11-01

    Glucocorticoids have potent anti-inflammatory effects and have been used to treat patients with rheumatoid arthritis for more than 60 years. However, severe adverse effects of glucocorticoid treatment, including loss of bone mass and increased risk of fractures, are common. Data from studies of glucocorticoid-mediated gene regulation, which utilized conditional knockout mice in animal models of arthritis or glucocorticoid-induced osteoporosis, have substantially increased our understanding of the mechanisms by which glucocorticoids act via the glucocorticoid receptor. Following glucocorticoid binding, the receptor regulates gene expression either by interacting with DNA-bound transcription factors as a monomer or by binding directly to DNA as a dimer. In contrast to the old hypothesis that transrepression mechanisms involving monomeric glucocorticoid receptor actions were responsible for the anti-inflammatory effects of glucocorticoids, whereas dimeric glucocorticoid receptor binding resulted in adverse effects, data from animal models have shown that the anti-inflammatory and adverse effects of glucocorticoids are mediated by both monomeric and dimeric glucocorticoid receptor binding. This improved knowledge of the molecular mechanisms that underlie the beneficial and adverse effects of glucocorticoid therapy might lead to the development of rationales for novel glucocorticoid receptor ligands that could potentially have anti-inflammatory efficacy without adverse effects on bone.

  15. Glucocorticoid-like effects of antihepatocarcinogen Rotenone are mediated via enhanced serum corticosterone levels: Molecular Fitting and Receptor Activation Studies

    Directory of Open Access Journals (Sweden)

    Youssef Jihan

    2003-02-01

    diminished similarity with a value of 1 or higher excluding any such similarities. Results Although the stimulatory effect exerted by rotenone on hepatocellular apoptosis was in the opposite direction of that produced by the glucocorticoid antagonist RU 486, data suggested that rotenone does not directly activate the glucocorticoid receptor. Molecular fitting of rotenone to glucocorticoid receptor agonists and antagonists as well as examination of the transcriptional activation of a glucocorticoid-responsive reporter gene (Mouse MammaryTumorVirus in response to rotenone indicated that it is highly unlikely that rotenone interacts directly with the glucocorticoid receptor. However, feeding male B6C3F1 mice a diet containing rotenone (600 ppm for 7 days resulted in a 3-fold increase in serum levels of corticosterone relative to control animals. Corticosterone is the major glucocorticoid in rodents. Conclusion Rotenone does not interact directly with the glucocorticoid receptor. Elevation of serum corticosterone levels in response to rotenone may explain the glucocorticoid-like effects of this compound, and may play a role in its anti-hepatocarcinogenic effect.

  16. MicroRNA-29a mitigates glucocorticoid induction of bone loss and fatty marrow by rescuing Runx2 acetylation.

    Science.gov (United States)

    Ko, Jih-Yang; Chuang, Pei-Chin; Ke, Huei-Jin; Chen, Yu-Shan; Sun, Yi-Chih; Wang, Feng-Sheng

    2015-12-01

    detrimental effects of glucocorticoid on mineralization and lipogenesis reactions in bone tissue microenvironments. This study highlighted emerging skeletal-anabolic actions of miR-29a signaling in the progression of glucocorticoid-induced bone tissue destruction. Sustaining miR-29a actions is beneficial in protecting against glucocorticoid-mediated osteoporosis. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Role of glucocorticoids and the glucocorticoid receptor in metabolism: insights from genetic manipulations.

    Science.gov (United States)

    Rose, Adam J; Vegiopoulos, Alexandros; Herzig, Stephan

    2010-10-01

    Since the discovery of the beneficial effects of adrenocortical extracts for treating adrenal insufficiency more than 80 years ago, glucocorticoids and their cognate, intracellular receptor, the glucocorticoid receptor have been characterized as critical checkpoints in the delicate hormonal control of energy homeostasis in mammals. Whereas physiological levels of glucocorticoids are required for proper metabolic control, aberrant glucocorticoid action has been linked to a variety of pandemic metabolic diseases, such as type II diabetes and obesity. Based on its importance for human health, studies of the molecular mechanisms of within the glucocorticoid signaling axis have become a major focus in biomedical research. In particular, the understanding of tissue-specific functions of the glucocorticoid receptor pathway has been proven to be of substantial value for the development of novel therapies in the treatment of chronic metabolic disorders. Therefore, this review focuses on the consequences of endogenous and experimental modulation of glucocorticoid receptor expression for metabolic homeostasis and dysregulation, particularly emphasizing tissue-specific contributions of the glucocorticoid pathway to the control of energy metabolism. Copyright © 2010 Elsevier Ltd. All rights reserved.

  18. Sensory, hormonal, and neural control of maternal aggression in laboratory rodents.

    Science.gov (United States)

    Lonstein, Joseph S; Gammie, Stephen C

    2002-12-01

    Parental animals of many rodent species display fierce and persistent aggression toward unfamiliar conspecifics that appears to protect their often altricial and defenseless young. We herein review studies of the sensory, hormonal, neuroanatomical, and neurochemical mechanisms underlying maternal aggression in laboratory rodents. The relationship between maternal aggression and fearfulness or anxiety is also discussed.

  19. NALP3 inflammasome up-regulation and CASP1 cleavage of the glucocorticoid receptor causes glucocorticoid resistance in leukemia cells

    Science.gov (United States)

    Paugh, Steven W.; Bonten, Erik J.; Savic, Daniel; Ramsey, Laura B.; Thierfelder, William E.; Gurung, Prajwal; Malireddi, R. K. Subbarao; Actis, Marcelo; Mayasundari, Anand; Min, Jaeki; Coss, David R.; Laudermilk, Lucas T.; Panetta, John C.; McCorkle, J. Robert; Fan, Yiping; Crews, Kristine R.; Stocco, Gabriele; Wilkinson, Mark R.; Ferreira, Antonio M.; Cheng, Cheng; Yang, Wenjian; Karol, Seth E.; Fernandez, Christian A.; Diouf, Barthelemy; Smith, Colton; Hicks, J. Kevin; Zanut, Alessandra; Giordanengo, Audrey; Crona, Daniel; Bianchi, Joy J.; Holmfeldt, Linda; Mullighan, Charles G.; den Boer, Monique L.; Pieters, Rob; Jeha, Sima; Dunwell, Thomas L.; Latif, Farida; Bhojwani, Deepa; Carroll, William L.; Pui, Ching-Hon; Myers, Richard M.; Guy, R. Kiplin; Kanneganti, Thirumala-Devi; Relling, Mary V.; Evans, William E.

    2015-01-01

    Glucocorticoids are universally used in the treatment of acute lymphoblastic leukemia (ALL), and leukemia cell resistant to glucocorticoids confers a poor prognosis. To elucidate mechanisms of glucocorticoid resistance, we determined the sensitivity to prednisolone of primary leukemia cells from 444 newly diagnosed ALL patients, revealing significantly higher expression of caspase 1 (CASP1) and its activator NLRP3 in glucocorticoid resistant leukemia cells, due to significantly lower somatic methylation of CASP1 and NLRP3 promoters. Over-expression of CASP1 resulted in cleavage of the glucocorticoid receptor, diminished glucocorticoid-induced transcriptional response and increased glucocorticoid resistance. Knockdown or inhibition of CASP1 significantly increased glucocorticoid receptor levels and mitigated glucocorticoid resistance in CASP1 overexpressing ALL. Our findings establish a new mechanism by which the NLRP3/CASP1 inflammasome modulates cellular levels of the glucocorticoid receptor and diminishes cell sensitivity to glucocorticoids. The broad impact on glucocorticoid transcriptional response suggests this mechanism could also modify glucocorticoid effects in other diseases. PMID:25938942

  20. Glucocorticoid Receptors and the Pattern of Steroid Response in ...

    African Journals Online (AJOL)

    CD3+) expression of glucocorticoid receptors (GCR) and the response to glucocorticoid treatment in children with idiopathic nephrotic syndrome (NS). The aim of the current study is to determine whether steroid responsiveness is dependent on ...

  1. Glucocorticoids and Reproduction: Traffic Control on the Road to Reproduction.

    Science.gov (United States)

    Whirledge, Shannon; Cidlowski, John A

    2017-06-01

    Glucocorticoids are steroid hormones that regulate diverse cellular functions and are essential to facilitate normal physiology. However, stress-induced levels of glucocorticoids result in several pathologies including profound reproductive dysfunction. Compelling new evidence indicates that glucocorticoids are crucial to the establishment and maintenance of reproductive function. The fertility-promoting or -inhibiting activity of glucocorticoids depends on timing, dose, and glucocorticoid responsiveness within a given tissue, which is mediated by the glucocorticoid receptor (GR). The GR gene and protein are subject to cellular processing, contributing to signaling diversity and providing a mechanism by which both physiological and stress-induced levels of glucocorticoids function in a cell-specific manner. Understanding how glucocorticoids regulate fertility and infertility may lead to novel approaches to the regulation of reproductive function. Published by Elsevier Ltd.

  2. Glucocorticoids and the regulation of memory in health and disease

    NARCIS (Netherlands)

    de Quervain, Dominique J. -F; Aerni, Amanda; Schelling, Gustav; Roozendaal, Benno

    Over the last decades considerable evidence has accumulated indicating that glucocorticoids - stress hormones released from the adrenal cortex - are crucially involved in the regulation of memory. Specifically, glucocorticoids have been shown to enhance memory consolidation of emotionally arousing

  3. Mechanisms of glucocorticoid action and insensitivity in airways disease

    NARCIS (Netherlands)

    Boardman, C.; Chachi, L.; Gavrila, A.; Keenan, C. R.; Perry, M. M.; Xia, Y. C.; Meurs, H.; Sharma, P.

    2014-01-01

    Glucocorticoids are the mainstay for the treatment of chronic inflammatory diseases including asthma and chronic obstructive pulmonary disease (COPD). However, it has been recognized that glucocorticoids do not work well in certain patient populations suggesting reduced sensitivity. The ultimate

  4. Adverse consequences of glucocorticoid medication: psychological, cognitive, and behavioral effects

    NARCIS (Netherlands)

    Judd, L.L.; Schettler, P.J.; Brown, E.S.; Wolkowitz, O.M.; Sternberg, E.M.; Bender, B.G.; Bulloch, K.; Cidlowski, J.A.; Kloet, E.R. de; Fardet, L.; Joels, M.; Leung, D.Y.; McEwen, B.S.; Roozendaal, B.; Rossum, E.F. van; Ahn, J.; Brown, D.W.; Plitt, A.; Singh, G.

    2014-01-01

    Glucocorticoids are the most commonly prescribed anti-inflammatory/immunosuppressant medications worldwide. This article highlights the risk of clinically significant and sometimes severe psychological, cognitive, and behavioral disturbances that may be associated with glucocorticoid use, as well as

  5. Investigations of Glucocorticoid Action in GN.

    Science.gov (United States)

    Kuppe, Christoph; van Roeyen, Claudia; Leuchtle, Katja; Kabgani, Nazanin; Vogt, Michael; Van Zandvoort, Marc; Smeets, Bart; Floege, Jürgen; Gröne, Hermann-Josef; Moeller, Marcus J

    2017-05-01

    For several decades, glucocorticoids have been used empirically to treat rapid progressive GN. It is commonly assumed that glucocorticoids act primarily by dampening the immune response, but the mechanisms remain incompletely understood. In this study, we inactivated the glucocorticoid receptor (GR) specifically in kidney epithelial cells using Pax8-Cre/GR fl/fl mice. Pax8-Cre/GR fl/fl mice did not exhibit an overt spontaneous phenotype. In mice treated with nephrotoxic serum to induce crescentic nephritis (rapidly progressive GN), this genetic inactivation of the GR in kidney epithelial cells exerted renal benefits, including inhibition of albuminuria and cellular crescent formation, similar to the renal benefits observed with high-dose prednisolone in control mice. However, genetic inactivation of the GR in kidney epithelial cells did not induce the immunosuppressive effects observed with prednisolone. In vitro , prednisolone and the pharmacologic GR antagonist mifepristone each acted directly on primary cultures of parietal epithelial cells, inhibiting cellular outgrowth and proliferation. In wild-type mice, pharmacologic treatment with the GR antagonist mifepristone also attenuated disease as effectively as high-dose prednisolone without the systemic immunosuppressive effects. Collectively, these data show that glucocorticoids act directly on activated glomerular parietal epithelial cells in crescentic nephritis. Furthermore, we identified a novel therapeutic approach in crescentic nephritis, that of glucocorticoid antagonism, which was at least as effective as high-dose prednisolone with potentially fewer adverse effects. Copyright © 2017 by the American Society of Nephrology.

  6. Islet-cell dysfunction induced by glucocorticoid treatment

    DEFF Research Database (Denmark)

    van Raalte, Daniël H; Kwa, Kelly A A; van Genugten, Renate E

    2013-01-01

    Glucocorticoids impair glucose tolerance by inducing insulin resistance. We investigated the dose-dependent effects of glucocorticoid treatment on islet-cell function in healthy males and studied the role of the autonomic nervous system.......Glucocorticoids impair glucose tolerance by inducing insulin resistance. We investigated the dose-dependent effects of glucocorticoid treatment on islet-cell function in healthy males and studied the role of the autonomic nervous system....

  7. Virtual reality systems for rodents.

    Science.gov (United States)

    Thurley, Kay; Ayaz, Aslı

    2017-02-01

    Over the last decade virtual reality (VR) setups for rodents have been developed and utilized to investigate the neural foundations of behavior. Such VR systems became very popular since they allow the use of state-of-the-art techniques to measure neural activity in behaving rodents that cannot be easily used with classical behavior setups. Here, we provide an overview of rodent VR technologies and review recent results from related research. We discuss commonalities and differences as well as merits and issues of different approaches. A special focus is given to experimental (behavioral) paradigms in use. Finally we comment on possible use cases that may further exploit the potential of VR in rodent research and hence inspire future studies.

  8. Tissue glucocorticoid sensitivity: beyond stochastic regulation on the diverse actions of glucocorticoids.

    Science.gov (United States)

    Kino, T

    2007-06-01

    Glucocorticoids have a broad array of life-sustaining functions, such as for the maintenance of the basal- and stress-related organ homeostasis. They are also frequently used as therapeutic compounds for many pathologic conditions. Thus, changes of tissue sensitivity to glucocorticoids play important roles in the physiologic conditions and are associated with and influence the course of numerous pathologic states. Changes in tissue glucocorticoid sensitivity may present on either side of an optimal range, respectively as glucocorticoid resistance or hypersensitivity, and may be generalized or tissue-specific. Recent insights into the mechanisms of the glucocorticoid receptor (GR) action indicated that the glucocorticoid signaling system is highly stochastic. Indeed, numerous factors contribute to the hormonal action at each step of the GR signaling cascade, such as ligand availability, receptor isoform expression, intracellular circulation, promoter association, attraction of cofactors, and finally clearance of the receptor from the target genes. Importantly, these regulatory mechanisms appear to be functional in tissue-, gene- and cellular biologic state-specific fashions. As an example of such phase-specific factors, we discussed influence of the cyclin-dependent kinase 5 to the GR transcriptional activity, which specifically functions in the central nervous system and may thus play an important role in the regulation of glucocorticoid action in this organ.

  9. Glucocorticoids regulate metallothionein-1/2 expression in rat choroid plexus: effects on apoptosis.

    Science.gov (United States)

    Martinho, A; Gonçalves, I; Santos, C R

    2013-04-01

    The choroid plexus (CP) participates in the synthesis, secretion and regulation of the cerebrospinal fluid, in the removal of its toxic compounds and in the regulation of the availability of essential metal ions to the brain. It expresses and secretes metallothioneins 1/2 (MT-1/2) which are key components in the maintenance of the central nervous system metal homeostasis and have anti-apoptotic properties, thereby protecting the brain. Glucocorticoids regulate MT-1/2 expression in several brain regions, but within the choroid plexuses (CPs) it remains unknown. Glucocorticoid levels increase in response to stress with implications in apoptosis. Further, CP expresses glucocorticoid (GR) and mineralocorticoid receptors (MR) turning it into likely glucocorticoid responsive structure. Data prompted us to study the regulation of MT-1/2 expression in response to glucocorticoids in the rat CP, and to investigate its implications in apoptosis. MT-1/2 protein and mRNA expression analysis showed that hydrocortisone up-regulates MT-1/2 expression in rat choroid plexus (RCP) cell line and in primary cultures of choroid plexus epithelial cells (CPEC) cultures via GR and MR. Also, incubation of RCP cells with hydrocortisone significantly diminished apoptosis, an effect eliminated by the addition of a MT-1/2 antibody. Moreover, induction of psychosocial stress, with concomitant rise of corticosterone levels, increased MT-1/2 expression in liver and in CP of male and female rats, with an exception observed in CP from males subjected to acute stress in which down-regulation in MT-1/2 expression occurred. Altogether, the results obtained demonstrated that stress/glucocorticoids regulate MT-1/2 expression in rat CP, with implications on apoptosis.

  10. Resistin in Rodents and Humans

    OpenAIRE

    Park, Hyeong Kyu; Ahima, Rexford S.

    2013-01-01

    Obesity is characterized by excess accumulation of lipids in adipose tissue and other organs, and chronic inflammation associated with insulin resistance and an increased risk of type 2 diabetes. Obesity, type 2 diabetes, and cardiovascular diseases are major health concerns. Resistin was first discovered as an adipose-secreted hormone (adipokine) linked to obesity and insulin resistance in rodents. Adipocyte-derived resistin is increased in obese rodents and strongly related to insulin resis...

  11. Tachyphylaxis to topical glucocorticoids; what is the evidence?

    OpenAIRE

    Taheri, Arash; Cantrell, Jacob; Feldman, Steven R.

    2013-01-01

    Background: Common belief holds that as topical glucocorticoids are used over time the less effective they become, a phenomenon called tolerance or tachyphylaxis. Objective: To determine what evidence supports the concept of tachyphylaxis to glucocorticoids. Methods: We searched Medline and Google Scholar for articles on tachyphylaxis to glucocorticoids published through October 2012. Results: Rapid tolerance, tac...

  12. Perinatal glucocorticoid treatment and perspectives for antioxidat therapy

    NARCIS (Netherlands)

    Tijsseling, D.|info:eu-repo/dai/nl/338666885

    2014-01-01

    Pre- and postnatal glucocorticoids are a life-saving therapy for prematurely born infants. However, glucocorticoids also trigger unwanted side effects. In part I we investigated the effects of antenatal glucocorticoids on hippocampal development. First in a mice model using a clinically relevant

  13. Withdrawal of inhaled glucocorticoids and exacerbations of COPD

    DEFF Research Database (Denmark)

    Magnussen, Helgo; Disse, Bernd; Rodriguez-Roisin, Roberto

    2014-01-01

    exacerbations was similar among those who discontinued inhaled glucocorticoids and those who continued glucocorticoid therapy. However, there was a greater decrease in lung function during the final step of glucocorticoid withdrawal. (Funded by Boehringer Ingelheim Pharma; WISDOM ClinicalTrials.gov number, NCT...

  14. Glucocorticoids and fetal programming part 1: Outcomes.

    Science.gov (United States)

    Moisiadis, Vasilis G; Matthews, Stephen G

    2014-07-01

    Fetal development is a critical period for shaping the lifelong health of an individual. However, the fetus is susceptible to internal and external stimuli that can lead to adverse long-term health consequences. Glucocorticoids are an important developmental switch, driving changes in gene regulation that are necessary for normal growth and maturation. The fetal hypothalamic-pituitary-adrenal (HPA) axis is particularly susceptible to long-term programming by glucocorticoids; these effects can persist throughout the life of an organism. Dysfunction of the HPA axis as a result of fetal programming has been associated with impaired brain growth, altered behaviour and increased susceptibility to chronic disease (such as metabolic and cardiovascular disease). Moreover, the effects of glucocorticoid-mediated programming are evident in subsequent generations, and transmission of these changes can occur through both maternal and paternal lineages.

  15. An Approach to Greater Specificity for Glucocorticoids

    Directory of Open Access Journals (Sweden)

    Carson C. Chow

    2018-03-01

    Full Text Available Glucocorticoid steroids are among the most prescribed drugs each year. Nonetheless, the many undesirable side effects, and lack of selectivity, restrict their greater usage. Research to increase glucocorticoid specificity has spanned many years. These efforts have been hampered by the ability of glucocorticoids to both induce and repress gene transcription and also by the lack of success in defining any predictable properties that control glucocorticoid specificity. Correlations of transcriptional specificity have been observed with changes in steroid structure, receptor and chromatin conformation, DNA sequence for receptor binding, and associated cofactors. However, none of these studies have progressed to the point of being able to offer guidance for increased specificity. We summarize here a mathematical theory that allows a novel and quantifiable approach to increase selectivity. The theory applies to all three major actions of glucocorticoid receptors: induction by agonists, induction by antagonists, and repression by agonists. Simple graphical analysis of competition assays involving any two factors (steroid, chemical, peptide, protein, DNA, etc. yields information (1 about the kinetically described mechanism of action for each factor at that step where the factor acts in the overall reaction sequence and (2 about the relative position of that step where each factor acts. These two pieces of information uniquely provide direction for increasing the specificity of glucocorticoid action. Consideration of all three modes of action indicate that the most promising approach for increased specificity is to vary the concentrations of those cofactors/pharmaceuticals that act closest to the observed end point. The potential for selectivity is even greater when varying cofactors/pharmaceuticals in conjunction with a select class of antagonists.

  16. Glucocorticoid pharmacogenetics in pediatric idiopathic nephrotic syndrome.

    Science.gov (United States)

    Cuzzoni, Eva; De Iudicibus, Sara; Franca, Raffaella; Stocco, Gabriele; Lucafò, Marianna; Pelin, Marco; Favretto, Diego; Pasini, Andrea; Montini, Giovanni; Decorti, Giuliana

    2015-01-01

    Idiopathic nephrotic syndrome represents the most common type of primary glomerular disease in children: glucocorticoids (GCs) are the first-line therapy, even if considerable interindividual differences in their efficacy and side effects have been reported. Immunosuppressive and anti-inflammatory effects of these drugs are mainly due to the GC-mediated transcription regulation of pro- and anti-inflammatory genes. This mechanism of action is the result of a complex multistep pathway that involves the glucocorticoid receptor and several other proteins, encoded by polymorphic genes. Aim of this review is to highlight the current knowledge on genetic variants that could affect GC response, particularly focusing on children with idiopathic nephrotic syndrome.

  17. Glucocorticoid Induced Leucine Zipper inhibits apoptosis of cardiomyocytes by doxorubicin

    Energy Technology Data Exchange (ETDEWEB)

    Aguilar, David; Strom, Joshua; Chen, Qin M., E-mail: qchen@email.arizona.edu

    2014-04-01

    Doxorubicin (Dox) is an indispensable chemotherapeutic agent for the treatment of various forms of neoplasia such as lung, breast, ovarian, and bladder cancers. Cardiotoxicity is a major concern for patients receiving Dox therapy. Previous work from our laboratory indicated that glucocorticoids (GCs) alleviate Dox-induced apoptosis in cardiomyocytes. Here we have found Glucocorticoid-Induced Leucine Zipper (GILZ) to be a mediator of GC-induced cytoprotection. GILZ was found to be induced in cardiomyocytes by GC treatment. Knocking down of GILZ using siRNA resulted in cancelation of GC-induced cytoprotection against apoptosis by Dox treatment. Overexpressing GILZ by transfection was able to protect cells from apoptosis induced by Dox as measured by caspase activation, Annexin V binding and morphologic changes. Western blot analyses indicate that GILZ overexpression prevented cytochrome c release from mitochondria and cleavage of caspase-3. When bcl-2 family proteins were examined, we found that GILZ overexpression causes induction of the pro-survival protein Bcl-xL. Since siRNA against Bcl-xL reverses GC induced cytoprotection, Bcl-xL induction represents an important event in GILZ-induced cytoprotection. Our data suggest that GILZ functions as a cytoprotective gene in cardiomyocytes. - Highlights: • Corticosteroids act as a cytoprotective agent in cardiomyocytes • Corticosteroids induce GILZ expression in cardiomyocytes • Elevated GILZ results in resistance against apoptosis induced by doxorubicin • GILZ induces Bcl-xL protein without inducing Bcl-xL mRNA.

  18. Rodent diversity and habitat use in a protected area of Buenos Aires province, Argentina Diversidad y uso del hábitat por roedores en un área protegida de Buenos Aires, Argentina

    Directory of Open Access Journals (Sweden)

    Isabel E. Gómez-Villafañe

    2012-09-01

    Full Text Available Habitat use of rodents is associated to environmental variables, species requirements and biological interactions. The aim of this study was to analyse the macro and microhabitat use and spatial variation in the abundance of small wild rodents that inhabit Otamendi Natural Reserve, Argentina. We studied the rodent communities in 6 habitats: riparian forest, Celtis tala forest, lowland grassland, salt marsh and 2 highland grasslands. We captured a total of 153 individual of Scapteromys aquaticus, Akodon azarae, Oxymycterus rufus, Oligoryzomys flavescens, Deltamys kempi and O. nigripes, with a trapping effort of 3636 trap-nights. The species richness is maintained by the presence of different habitats that satisfy specific requirements from specialist and generalist species, using differentially the reserve and forming communities of different specific composition in each habitat. A differential macrohabitat use was observed by all species, and a certain level of selectivity at microhabitat scale was observed in individuals of 2 species. This study shows that the diversity of environments in the Otamendi Natural Reserve, which allows the maintenance of many wild species of small rodents; confirming the high ecological and conservational value of the reserves inside an urban region.El uso del habitat de los roedores está asociado a variables ambientales, requerimientos específicos e interacciones biológicas. El objetivo de este estudio fue analizar el uso del macro y microhábitat y la variación espacial en la abundancia de pequeños roedores que habitan la Reserva Natural Otamendi, Argentina. Estudiamos la comunidad de roedores en 6 ambientes: bosque ribereño, talares, pastizales bajos, pastizal salino y 2 pastizales altos. Capturamos 153 individuos de Scapteromys aquaticus, Akodon azarae, Oxymycterus rufus, Oligoryzomys flavescens, Deltamys kempi y O. nigripes, con un esfuerzo de 3 636 trampas-noche. La riqueza de especies se mantiene

  19. [Management and Treatment of Glucocorticoid-Induced Hyperglycemia].

    Science.gov (United States)

    Paredes, Sílvia; Alves, Marta

    2016-09-01

    Glucocorticoids have been associated to several side effects, specially a diabetogenic action, the most common and representative effect. Glucocorticoid-induced hyperglycemia is a common medical condition, with general associated morbidity and mortality. It was performed a literature review about the management and treatment of glucocorticoid-induced hyperglycemia. Through numerous not quite fully understood mechanics, glucocorticoids promote hyperglycemia in non-diabetic patients and worsen diabetes control in diabetic individuals. Glucocorticoid-induced hyperglycemia presents key patterns, enhanced in the postprandial period and scheduled-dependent. Despite the existence of guidelines for hyperglycemia treatment in non-critic hospitalized and non-hospitalized patients, there are no guidelines respecting glucocorticoid-induced hyperglycemia. Nevertheless, it is known that glucocorticoid-induced hyperglycemia is complex and demanding, requiring a specific approach. Indeed, glucocorticoid-induced hyperglycemia treatment depends on the glucocorticoid used, its dose, frequency and schedule. Furthermore, the scheme of treatment previously used by diabetic individuals also influences the choice of the new scheme. The authors reviewed the glucocorticoid induced-hyperglycemia thematic and propose strategies to approach and treat glucocorticoid induced-hyperglycemia in diabetic and non-diabetic individuals. This review is expected to be useful in different settings and crosswise to all medical specialties.

  20. Mechanisms of glucocorticoid action and insensitivity in airways disease.

    Science.gov (United States)

    Boardman, C; Chachi, L; Gavrila, A; Keenan, C R; Perry, M M; Xia, Y C; Meurs, H; Sharma, P

    2014-12-01

    Glucocorticoids are the mainstay for the treatment of chronic inflammatory diseases including asthma and chronic obstructive pulmonary disease (COPD). However, it has been recognized that glucocorticoids do not work well in certain patient populations suggesting reduced sensitivity. The ultimate biologic responses to glucocorticoids are determined by not only the concentration of glucocorticoids but also the differences between individuals in glucocorticoid sensitivity, which is influenced by multiple factors. Studies are emerging to understand these mechanisms in detail, which would help in increasing glucocorticoid sensitivity in patients with chronic airways disease. This review aims to highlight both classical and emerging concepts of the anti-inflammatory mechanisms of glucocorticoids and also review some novel strategies to overcome steroid insensitivity in airways disease. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. On the retinal toxicity of intraocular glucocorticoids.

    Science.gov (United States)

    Torriglia, Alicia; Valamanesh, Fatemeh; Behar-Cohen, Francine

    2010-12-15

    Corticosteroids are hormones involved in many physiological responses such as stress, immune modulation, protein catabolism and water homeostasis. The subfamily of glucocorticoids is used systemically in the treatment of inflammatory diseases or allergic reactions. In the eye, glucocorticoides are used to treat macular edema, inflammation and neovascularization. The most commonly used glucocorticoid is triamcinolone acetonide (TA). The pharmaceutical formulation of TA is not adapted for intravitreal administration but has been selected by ophthalmologists because its very low intraocular solubility provides sustained effect. Visual benefits of intraocular TA do not clearly correlate with morpho-anatomical improvements, suggesting potential toxicity. We therefore studied, non-common, but deleterious effects of glucocorticoids on the retina. We found that the intravitreal administration of TA is beneficial in the treatment of neovascularization because it triggers cell death of endothelial cells of neovessels by a caspase-independent mechanism. However, this treatment is toxic for the retina because it induces a non-apoptotic, caspase-independent cell death related to paraptosis, mostly in the retinal pigmented epithelium cells and the Müller cells. Copyright © 2010 Elsevier Inc. All rights reserved.

  2. Bisphosphonates and glucocorticoid-induced osteoporosis: cons

    NARCIS (Netherlands)

    Lems, W.F.; Saag, K.

    2015-01-01

    During the use of glucocorticoids (GCs), both vertebral and nonvertebral fracture risk are increased, due to the direct and indirect negative effects of GCs on bone, muscles, and the activity of the underlying inflammatory diseases. Inhibition of bone formation and increased apoptosis of osteocytes

  3. Glucocorticoid receptor knockdown and adult hippocampal neurogenesis

    NARCIS (Netherlands)

    Hooijdonk, Leonarda Wilhelmina Antonia van

    2010-01-01

    The research in this thesis is aimed at the elucidation of the role of the glucocorticoid receptor (GR) in hippocampal neuroplasticity and functioning. To achieve this, we have developed a novel method to specifically knockdown GR in a discrete cell population of the mouse brain. In this thesis I

  4. Are BDNF and glucocorticoid activities calibrated?

    Science.gov (United States)

    Jeanneteau, Freddy; Chao, Moses V.

    2012-01-01

    One hypothesis to account for the onset and severity of neurological disorders is the loss of trophic support. Indeed, changes in the levels and activities of brain-derived neurotrophic factor (BDNF) occur in numerous neurodegenerative and neuropsychiatric diseases. A deficit promotes vulnerability whereas a gain of function facilitates recovery by enhancing survival, synapse formation and synaptic plasticity. Implementation of ‘BDNF therapies’, however, faces numerous methodological and pharmacokinetic issues. Identifying BDNF mimetics that activate the BDNF receptor or downstream targets of BDNF signaling represent an alternative approach. One mechanism that shows great promise is to study the interplay of BDNF and glucocorticoid hormones, a major class of natural steroid secreted during stress reactions and in synchrony with circadian rhythms. While small amounts of glucocorticoids support normal brain function, excess stimulation by these steroid hormones precipitate stress-related affective disorders. To date, however, because of the paucity of knowledge of underlying cellular mechanisms, deleterious effects of glucocorticoids are not prevented following extreme stress. In the present review, we will discuss the complementary roles share by BDNF and glucocorticoids in synaptic plasticity, and delineate possible signaling mechanisms mediating these effects. PMID:23022538

  5. Glucocorticoid Regulation of the Vitamin D Receptor

    Science.gov (United States)

    Hidalgo, Alejandro A.; Trump, Donald L.; Johnson, Candace S.

    2010-01-01

    Many studies indicate calcitriol has potent anti-tumor activity in different types of cancers. However, high levels of vitamin D can produce hypercalcemia in some patients. Glucocorticoids are used to ameliorate hypercalcemia and to enhance calcitriol anti-tumor activity. Calcitriol in combination with the glucocorticoid dexamethasone (Dex) increased vitamin D receptor (VDR) protein levels and ligand binding in squamous cell carcinoma VII (SCC). In this study we found that both calcitriol and Dex induce VDR- and glucocorticoid receptor (GR)-mediated transcription respectively, indicating both hormone receptors are active in SCC. Pre-treatment with Dex increases VDR-mediated transcription at the human CYP24A1 promoter. Whereas, pre-treatment with other steroid hormones, including dihydrotestosterone and R1881, has no effect on VDR-mediated transcription. Real-time PCR indicates treatment with Dex increases Vdr transcripts in a time-dependent manner, suggesting Dex may directly regulate expression of Vdr. Numerous putative glucocorticoid response elements (GREs) were found in the Vdr gene. Chromatin immunoprecipitation (ChIP) assay demonstrated GR binding at several putative GREs located within the mouse Vdr gene. However, none of the putative GREs studied increase GR-mediated transcription in luciferase reporter assays. In an attempt to identify the response element responsible for Vdr transcript regulation, future studies will continue to analyze newly identified GREs more distal from the Vdr gene promoter. PMID:20398752

  6. Altered placental development in undernourished rats: role of maternal glucocorticoids

    Directory of Open Access Journals (Sweden)

    Chen Chun-Hung

    2011-08-01

    Full Text Available Abstract Maternal undernutrition (MUN during pregnancy may lead to fetal intrauterine growth restriction (IUGR, which itself predisposes to adult risk of obesity, hypertension, and diabetes. IUGR may stem from insufficient maternal nutrient supply or reduced placental nutrient transfer. In addition, a critical role for maternal stress-induced glucocorticoids (GCs has been suggested to contribute to both IUGR and the ensuing risk of adult metabolic syndrome. While GC-induced fetal organ defects have been examined, there have been few studies on placental responses to MUN-induced maternal stress. Therefore, we hypothesize that 50% MUN associates with increased maternal GC levels and decreased placental HSD11B. This in turn leads to decreased placental and fetal growth, hence the need to investigate nutrient transporters. We measured maternal serum levels of corticosterone, and the placental basal and labyrinth zone expression of glucocorticoid receptor (NR3C1, 11-hydroxysteroid dehydrogenase B 1 (HSD11B-1 predominantly activates cortisone to cortisol and 11-dehydrocorticosterone (11-DHC to corticosterone, although can sometimes drive the opposing (inactivating reaction, and HSD11B-2 (only inactivates and converts corticosterone to 11-DHC in rodents in control and MUN rats at embryonic day 20 (E20. Moreover, we evaluated the expression of nutrient transporters for glucose (SLC2A1, SLC2A3 and amino acids (SLC38A1, 2, and 4. Our results show that MUN dams displayed significantly increased plasma corticosterone levels compared to control dams. Further, a reduction in fetal and placental weights was observed in both the mid-horn and proximal-horn positions. Notably, the placental labyrinth zone, the site of feto-maternal exchange, showed decreased expression of HSD11B1-2 in both horns, and increased HSD11B-1 in proximal-horn placentas, but no change in NR3C1. The reduced placental GCs catabolic capacity was accompanied by downregulation of SLC2A3, SLC

  7. Prepubertal glucocorticoid status and pubertal timing.

    Science.gov (United States)

    Shi, Lijie; Wudy, Stefan A; Buyken, Anette E; Maser-Gluth, Christiane; Hartmann, Michaela F; Remer, Thomas

    2011-06-01

    Whether prepubertal glucocorticoid status impacts on the timing of puberty is not clear. The objective of the study was to examine the relationship between prepubertal glucocorticoid status and early or late pubertal markers, independent of adrenarchal and nutritional status. Prospective cohort study of healthy Caucasian children (n = 111, 56 boys) who provided both 24-h urine samples and weighed dietary records 1 and 2 yr before the start of pubertal growth spurt [age at take-off (ATO)]. Major urinary glucocorticoid and androgen metabolites determined by gas chromatography-mass spectrometry analysis were summed to assess daily overall cortisol (ΣC21) and adrenal androgen secretion; urinary free cortisol and cortisone measured by RIA were summed (UFF+UFE) as an indicator of potentially bioactive free glucocorticoids. The main outcomes included ATO, age at peak height velocity, age at menarche/voice break, ages at Tanner stage 2 for breast (girls) and genital (boys) development, and pubic hair. In girls ΣC21, but not UFF+UFE, was associated with pubertal markers after adjusting for overall adrenal androgen, urinary nitrogen, and body fat. Girls with higher ΣC21 (fourth quartile) reached ATO 0.7 yr (P = 0.01) and menarche 0.9 yr later (P = 0.006) than girls with lower ΣC21 (first quartile). The ΣC21 tended to be also positively associated with age at Tanner stage 2 for breast (P = 0.1), Tanner stage 2 for pubic hair (P = 0.1), and age at peak height velocity (P = 0.06). In boys, neither the ΣC21 nor UFF+UFE was related to pubertal timing. An individually higher prepubertal glucocorticoid secretion level, even in physiological range, appears to delay early and late pubertal timing of healthy girls, particularly their onset of pubertal growth spurt and menarche.

  8. Sensitivity of depression-like behavior to glucocorticoids and antidepressants is independent of forebrain glucocorticoid receptors.

    Science.gov (United States)

    Vincent, Melanie Y; Hussain, Rifat J; Zampi, Michael E; Sheeran, Katherine; Solomon, Matia B; Herman, James P; Khan, Anum; Jacobson, Lauren

    2013-08-07

    The location of glucocorticoid receptors (GR) implicated in depression symptoms and antidepressant action remains unclear. Forebrain glucocorticoid receptor deletion on a C57B/6×129×CBA background (FBGRKO-T50) reportedly produces increased depression-like behavior and elevated glucocorticoids. We further hypothesized that forebrain GR deletion would reduce behavioral sensitivity to glucocorticoids and to antidepressants. We have tested this hypothesis in mice with calcium calmodulin kinase IIα-Cre-mediated forebrain GR deletion derived from a new founder on a pure C57BL/6 background (FBGRKO-T29-1). We measured immobility in forced swim or tail suspension tests after manipulating glucocorticoids or after dose response experiments with tricyclic or monoamine oxidase inhibitor antidepressants. Despite forebrain GR deletion that was at least as rapid and more extensive than reported in the mixed-strain FBGRKO-T50 mice (Boyle et al. 2005), and possibly because of their different founder, our FBGRKO-T29-1 mice did not exhibit increases in depression-like behavior or adrenocortical axis hormones. Nevertheless, FBGRKO-T29-1 mice were at least as sensitive as floxed GR controls to the depressive effects of glucocorticoids and the effects of two different classes of antidepressants. FBGRKO-T29-1 mice also unexpectedly exhibited increased mineralocorticoid receptor (MR) gene expression. Our results reinforce prior evidence that antidepressant action does not require forebrain GR, and suggest a correlation between the absence of depression-like phenotype and combined MR up-regulation and central amygdala GR deficiency. Our findings demonstrate that GR outside the areas targeted in FBGRKO-T29-1 mice are involved in the depressive effects of glucocorticoids, and leave open the possibility that these GR populations also contribute to antidepressant action. Copyright © 2013 Elsevier B.V. All rights reserved.

  9. Use of topical glucocorticoids: a population-based cohort study.

    Science.gov (United States)

    El-Khoury, M; Thay, R; N'Diaye, M; Fardet, L

    2017-06-01

    Little is known about the prescriptions of topical glucocorticoids in the general population. To report an overall picture of topical glucocorticoid prescriptions in France. This study used the Echantillon Généraliste de Bénéficiaires (EGB) database, a 1/97th random sampling of the French population covered by the main national healthcare insurance system (approximately 90% of the whole population). All patients prescribed topical glucocorticoids over a 5-year period (1 January 2011 to 31 December 2015) were identified using a specific code list for topical glucocorticoids. Over the 5-year study period, 662 531 individuals were recorded for at least 1 day in the EGB. Among them, 220 345 (33.3%) were prescribed at least once topical glucocorticoid. The prevalence of topical glucocorticoid prescription increased regularly from 2011 (11.7%) to 2015 (12.5%). A total of 922 026 tubes of topical glucocorticoids were dispensed, mainly high-potency glucocorticoids, and were mainly prescribed by general practitioners (73.1%). A total of 1713 (0.8%) patients were prescribed at least 24 tubes over a calendar year. These patients were more frequently men (P glucocorticoids. The 124 844 tubes prescribed to these patients had stronger potency than those prescribed to the overall population (P glucocorticoids at least once each year. Most prescriptions are issued by general practitioners, dermatologists being the prescribers in less than one-quarter of cases. © 2017 European Academy of Dermatology and Venereology.

  10. Extensive Regulation of Diurnal Transcription and Metabolism by Glucocorticoids.

    Directory of Open Access Journals (Sweden)

    Benjamin D Weger

    2016-12-01

    Full Text Available Altered daily patterns of hormone action are suspected to contribute to metabolic disease. It is poorly understood how the adrenal glucocorticoid hormones contribute to the coordination of daily global patterns of transcription and metabolism. Here, we examined diurnal metabolite and transcriptome patterns in a zebrafish glucocorticoid deficiency model by RNA-Seq, NMR spectroscopy and liquid chromatography-based methods. We observed dysregulation of metabolic pathways including glutaminolysis, the citrate and urea cycles and glyoxylate detoxification. Constant, non-rhythmic glucocorticoid treatment rescued many of these changes, with some notable exceptions among the amino acid related pathways. Surprisingly, the non-rhythmic glucocorticoid treatment rescued almost half of the entire dysregulated diurnal transcriptome patterns. A combination of E-box and glucocorticoid response elements is enriched in the rescued genes. This simple enhancer element combination is sufficient to drive rhythmic circadian reporter gene expression under non-rhythmic glucocorticoid exposure, revealing a permissive function for the hormones in glucocorticoid-dependent circadian transcription. Our work highlights metabolic pathways potentially contributing to morbidity in patients with glucocorticoid deficiency, even under glucocorticoid replacement therapy. Moreover, we provide mechanistic insight into the interaction between the circadian clock and glucocorticoids in the transcriptional regulation of metabolism.

  11. Extensive Regulation of Diurnal Transcription and Metabolism by Glucocorticoids.

    Science.gov (United States)

    Weger, Benjamin D; Weger, Meltem; Görling, Benjamin; Schink, Andrea; Gobet, Cédric; Keime, Céline; Poschet, Gernot; Jost, Bernard; Krone, Nils; Hell, Rüdiger; Gachon, Frédéric; Luy, Burkhard; Dickmeis, Thomas

    2016-12-01

    Altered daily patterns of hormone action are suspected to contribute to metabolic disease. It is poorly understood how the adrenal glucocorticoid hormones contribute to the coordination of daily global patterns of transcription and metabolism. Here, we examined diurnal metabolite and transcriptome patterns in a zebrafish glucocorticoid deficiency model by RNA-Seq, NMR spectroscopy and liquid chromatography-based methods. We observed dysregulation of metabolic pathways including glutaminolysis, the citrate and urea cycles and glyoxylate detoxification. Constant, non-rhythmic glucocorticoid treatment rescued many of these changes, with some notable exceptions among the amino acid related pathways. Surprisingly, the non-rhythmic glucocorticoid treatment rescued almost half of the entire dysregulated diurnal transcriptome patterns. A combination of E-box and glucocorticoid response elements is enriched in the rescued genes. This simple enhancer element combination is sufficient to drive rhythmic circadian reporter gene expression under non-rhythmic glucocorticoid exposure, revealing a permissive function for the hormones in glucocorticoid-dependent circadian transcription. Our work highlights metabolic pathways potentially contributing to morbidity in patients with glucocorticoid deficiency, even under glucocorticoid replacement therapy. Moreover, we provide mechanistic insight into the interaction between the circadian clock and glucocorticoids in the transcriptional regulation of metabolism.

  12. Exogenous glucocorticoids and adverse cerebral effects in children.

    Science.gov (United States)

    Damsted, Sara K; Born, A P; Paulson, Olaf B; Uldall, Peter

    2011-11-01

    Glucocorticoids are commonly used in treatment of paediatric diseases, but evidence of associated adverse cerebral effects is accumulating. The various pharmacokinetic profiles of the exogenous glucocorticoids and the changes in pharmacodynamics during childhood, result in different exposure of nervous tissue to exogenous glucocorticoids. Glucocorticoids activate two types of intracellular receptors, the mineralocorticoid receptor and the glucocorticoid receptor. The two receptors differ in cerebral distribution, affinity and effects. Exogenous glucocorticoids favor activation of the glucocorticoid receptor, which is associated with unfavorable cellular outcomes. Prenatal treatment with glucocorticoids can compromise brain growth and is associated with periventricular leukomalacia, attentions deficits and poorer cognitive performance. In the neonatal period exposure to glucocorticoids reduces neurogenesis and cerebral volume, impairs memory and increases the incidence of cerebral palsy. Cerebral effects of glucocorticoids in later childhood have been less thoroughly studied, but apparent brain atrophy, reduced size of limbic structures and neuropsychiatric symptoms have been reported. Glucocortioids affect several cellular structures and functions, which may explain the observed adverse effects. Glucocorticoids can impair neuronal glucose uptake, decrease excitability, cause atrophy of dendrites, compromise development of myelin-producing oligodendrocytes and disturb important cellular structures involved in axonal transport, long-term potentiation and neuronal plasticity. Significant maturation of the brain continues throughout childhood and we hypothesize that exposure to exogenous glucocorticoids during preschool and school age causes adverse cerebral effects. It is our opinion that studies of associations between exposure to glucocorticoids during childhood and impaired neurodevelopment are highly relevant. Copyright © 2011 European Paediatric Neurology

  13. Protective

    Directory of Open Access Journals (Sweden)

    Wessam M. Abdel-Wahab

    2013-10-01

    Full Text Available Many active ingredients extracted from herbal and medicinal plants are extensively studied for their beneficial effects. Antioxidant activity and free radical scavenging properties of thymoquinone (TQ have been reported. The present study evaluated the possible protective effects of TQ against the toxicity and oxidative stress of sodium fluoride (NaF in the liver of rats. Rats were divided into four groups, the first group served as the control group and was administered distilled water whereas the NaF group received NaF orally at a dose of 10 mg/kg for 4 weeks, TQ group was administered TQ orally at a dose of 10 mg/kg for 5 weeks, and the NaF-TQ group was first given TQ for 1 week and was secondly administered 10 mg/kg/day NaF in association with 10 mg/kg TQ for 4 weeks. Rats intoxicated with NaF showed a significant increase in lipid peroxidation whereas the level of reduced glutathione (GSH and the activity of superoxide dismutase (SOD, catalase (CAT, glutathione S-transferase (GST and glutathione peroxidase (GPx were reduced in hepatic tissues. The proper functioning of the liver was also disrupted as indicated by alterations in the measured liver function indices and biochemical parameters. TQ supplementation counteracted the NaF-induced hepatotoxicity probably due to its strong antioxidant activity. In conclusion, the results obtained clearly indicated the role of oxidative stress in the induction of NaF toxicity and suggested hepatoprotective effects of TQ against the toxicity of fluoride compounds.

  14. The Ethics of Rodent Control

    NARCIS (Netherlands)

    Meerburg, B.G.; Brom, F.W.A.; Kijlstra, A.

    2008-01-01

    Because western societies generally see animals as objects of moral concern, demands have been made on the way they are treated, e.g. during animal experimentation. In the case of rodent pests, however, inhumane control methods are often applied. This inconsistency in the human-animal relationship

  15. Forecasting rodent outbreaks in Africa

    DEFF Research Database (Denmark)

    Leirs, Herwig; Verhagen, Ron; Verheyen, Walter

    1996-01-01

    1. Rainfall data were collated for years preceding historical outbreaks of Mastomys rats in East Africa in order to test the hypothesis that such outbreaks occur after long dry periods. 2. Rodent outbreaks were generally not preceded by long dry periods. 3. Population dynamics of Mastomys...

  16. Resistin in Rodents and Humans

    Directory of Open Access Journals (Sweden)

    Hyeong Kyu Park

    2013-12-01

    Full Text Available Obesity is characterized by excess accumulation of lipids in adipose tissue and other organs, and chronic inflammation associated with insulin resistance and an increased risk of type 2 diabetes. Obesity, type 2 diabetes, and cardiovascular diseases are major health concerns. Resistin was first discovered as an adipose-secreted hormone (adipokine linked to obesity and insulin resistance in rodents. Adipocyte-derived resistin is increased in obese rodents and strongly related to insulin resistance. However, in contrast to rodents, resistin is expressed and secreted from macrophages in humans and is increased in inflammatory conditions. Some studies have also suggested an association between increased resistin levels and insulin resistance, diabetes and cardiovascular disease. Genetic studies have provided additional evidence for a role of resistin in insulin resistance and inflammation. Resistin appears to mediate the pathogenesis of atherosclerosis by promoting endothelial dysfunction, vascular smooth muscle cell proliferation, arterial inflammation, and formation of foam cells. Indeed, resistin is predictive of atherosclerosis and poor clinical outcomes in patients with coronary artery disease and ischemic stroke. There is also growing evidence that elevated resistin is associated with the development of heart failure. This review will focus on the biology of resistin in rodents and humans, and evidence linking resistin with type 2 diabetes, atherosclerosis, and cardiovascular disease.

  17. A biometric approach to laboratory rodent identification.

    Science.gov (United States)

    Cameron, Jens; Jacobson, Christina; Nilsson, Kenneth; Rögnvaldsson, Thorsteinn

    2007-03-01

    Individual identification of laboratory rodents typically involves invasive methods, such as tattoos, ear clips, and implanted transponders. Beyond the ethical dilemmas they may present, these methods may cause pain or distress that confounds research results. The authors describe a prototype device for biometric identification of laboratory rodents that would allow researchers to identify rodents without the complications of other methods. The device, which uses the rodent's ear blood vessel pattern as the identifier, is fast, automatic, noninvasive, and painless.

  18. Endogenous glucocorticoids exacerbate cholestasis-associated liver injury and hypercholesterolemia in mice

    International Nuclear Information System (INIS)

    Geest, Rick van der; Ouweneel, Amber B.; Sluis, Ronald J. van der; Groen, Albert K.; Van Eck, Miranda; Hoekstra, Menno

    2016-01-01

    Cholestatic liver disease is characterized by a disruption of bile flow, bile acid toxicity, liver injury, and hypercholesterolemia. Relatively high secretion of glucocorticoids by the adrenals has been observed under cholestatic conditions. Here we investigated a contribution of the rise in endogenous glucocorticoids to initial stage cholestasis pathology. Adrenalectomized or sham-operated control C57BL/6 mice were given an oral dose of alpha-naphthylisothiocyanate to induce cholestasis. Adrenalectomy effectively lowered plasma corticosterone levels (18 ± 5 ng/ml vs 472 ± 58 ng/ml; P < 0.001) and disrupted the metabolic and anti-inflammatory glucocorticoid function. Adrenal removal did not exacerbate the cholestasis extent. In contrast, the cholestasis-associated liver injury was markedly lower in adrenalectomized mice as compared to controls as evidenced by a 84%–93% decrease in liver necrosis and plasma alanine aminotransferase and bile acid levels (P < 0.001 for all). Gene expression analysis on livers from adrenalectomized mice suggested the absence of bile acid toxicity-associated farnesoid X receptor signaling in the context of a 44% (P < 0.01) and 82% (P < 0.001) reduction in sodium/bile acid cotransporter member 1 transcript level as compared to respectively control and non-diseased mice. Adrenalectomy reduced the expression of the cholesterol synthesis gene HMG-CoA reductase by 70% (P < 0.05), which translated into a 73% lower plasma total cholesterol level (P < 0.05). Treatment of C57BL/6 mice with the glucocorticoid receptor antagonist RU-486 recapitulated the protective effect of adrenalectomy on indices of liver injury and hypercholesterolemia. In conclusion, we have shown that endogenous glucocorticoids exacerbate the liver injury and hypercholesterolemia associated with acute cholestasis in mice. - Highlights: • Cholestasis is associated with increased plasma glucocorticoid levels in mice. • Adrenalectomy lowers cholestasis-associated liver

  19. IL-17A Monoclonal Antibody Partly Reverses the Glucocorticoids Insensitivity in Mice Exposed to Ozonec.

    Science.gov (United States)

    Fei, Xia; Zhang, Peng-Yu; Zhang, Xue; Zhang, Guo-Qing; Bao, Wu-Ping; Zhang, Ying-Ying; Zhang, Min; Zhou, Xin

    2017-06-01

    Exposure to ozone has been associated with airway inflammation and glucocorticoid insensitivity. This study aimed to observe the capacity of anti-murine interleukin-17A monoclonal antibody (IL-17mAb) to reverse ozone-induced glucocorticoid insensitivity and to detect its effects with glucocorticoids in protecting against airway inflammation. After C57/BL6 mice were exposed to ozone (2.5 ppm; 3 h) for 12 times over 6 weeks, PBS, IL-17mAb (50 ug/ml), dexamethasone (2 mg/kg), and combination administration of IL-17mAb (50 ug/ml) and dexamethasone (2 mg/kg) were intraperitoneally injected into mice at a dose of 0.1 ml, respectively, for 10 times over 5 weeks. At sacrifice, lung histology, airway inflammatory cells, levels of related cytokines in bronchoalveolar lavage fluid (BALF), and serum were analyzed, airway inflammatory cell infiltration density and mean linear intercept (Lm) were measured, the expression of IL-17A mRNA, glucocorticoid receptors (GR), NF-κB, and p38 mitogen-activated protein kinase (MAPK) phosphorylation were determined. We found that combination administration markedly reduced ozone-induced total inflammatory cells, especially neutrophils; inhibited levels of cytokines, including IL-8, IL-17A, and TNF-α in BALF; and suppressed airway inflammatory cell infiltration density and Lm. Additionally, combination administration significantly elevated levels of IFN-γ in BALF, decreased the dexamethasone-induced increase of IL-17A mRNA, and increased the expression of GR and decrement of NF-κB and p38MAPK phosphorylation, which are also related to glucocorticoids insensitivity. Collectively, combination administration shows profound efficacy in inhibiting certain cytokines, and IL-17 mAb partly improved the glucocorticoids insensitivity via modulating the enhanced production rate and improving expression of IL-17A induced by glucocorticoids administration and p38MAPK, NF-κB signaling pathway.

  20. Glucocorticoid excess and the developmental origins of disease: two decades of testing the hypothesis--2012 Curt Richter Award Winner.

    Science.gov (United States)

    Reynolds, Rebecca M

    2013-01-01

    Low birthweight, a marker of an adverse in utero environment, is associated with cardiometabolic disease and brain disorders in adulthood. The adaptive changes made by the fetus in response to the intra-uterine environment result in permanent changes in physiology, structure and metabolism, a phenomenon termed early life programming. One of the key hypotheses to explain programming, namely over exposure of the developing fetus to glucocorticoids, was proposed nearly two decades ago, following the observation that the fetus was protected from high glucocorticoid levels in the mother by the actions of the placental barrier enzyme, 11β-hydroxysteroid dehydrogenase, which converts active glucocorticoids into inactive products. Numerous mechanistic studies in animal models have been carried out to test this hypothesis using manipulations to increase maternal glucocorticoids. Overall, these have resulted in offspring of lower birthweight, with an activated hypothalamic-pituitary-adrenal (HPA) axis and an adverse metabolic profile and behavioural phenotype in adulthood. Altered glucocorticoid activity or action is a good candidate mechanism in humans to link low birthweight with cardiometabolic and brain disorders. We have carried out detailed studies in men and women showing that high levels of endogenous glucocorticoids, or treatment with exogenous glucocorticoids, is associated with an adverse metabolic profile, increased cardiovascular disease and altered mood and cognitive decline. Our laboratory carried out the first translational studies in humans to test the glucocorticoid hypothesis, firstly demonstrating in studies of adult men and women, that low birthweight was associated with high fasting cortisol levels. We went on to dissect the mechanisms underlying the high fasting cortisol, demonstrating activation of the HPA axis, with increased cortisol responses to stimulation with exogenous adrenocorticotrophin hormone, lack of habituation to the stress of

  1. 21 CFR 1250.96 - Rodent control.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Rodent control. 1250.96 Section 1250.96 Food and... SANITATION Sanitation Facilities and Conditions on Vessels § 1250.96 Rodent control. Vessels shall be... of rodent control. ...

  2. Bone safety of low-dose glucocorticoids in rheumatic diseases.

    Science.gov (United States)

    Saag, Kenneth G

    2014-05-01

    Glucocorticoids are widely used internationally for the treatment of inflammatory disease, such as rheumatoid arthritis (RA). Although the benefit of glucocorticoids in RA on both disease activity and severity are well known, there remain unanswered questions about the overall bone safety of chronic low-dose glucocorticoids in RA. Debate exists about the merits of glucocorticoids for bone health on the basis of their benefits in promoting activity and reducing proinflammatory cytokines. Overall current evidence supports the view that bone loss is a disease related both to RA and to glucocorticoid use independently. Calcium and vitamin D, along with prescription antiosteoporosis therapies, particularly bisphosphonates and teriparatide, play an important role in stabilizing bone mineral density and potentially lowering spinal fracture risk at the spine. International guidelines provide pathways for appropriate prevention of glucocorticoid-induced osteoporosis (GIOP). Despite the evidence and these guidelines, many patients do not receive adequate management to prevent GIOP. © 2014 New York Academy of Sciences.

  3. [Dual effects of glucocorticoids on the gastric mucosa].

    Science.gov (United States)

    Podvigina, T T; Filaretova, L P

    2014-01-01

    In this review we systematise and analyze data of literature about the effect of glucocorticoids on the gastric mucosa. There are convincing results that show the adaptive gastoprotective nature of endogenous glucocorticoids, which are produced during acute stress-induced activation of the HPA axis. The role glucocorticoid hormones play in the effect of chronic stress remains little-studied. We have seen that after single administration of glucocorticoids, there can arise gastroprotective and ulcerogenic effects. Although. the question about the effect of therapy using glucocorticoid hormones on gastric ulceration is being debated, the data confirm the ulcerogenic influence that large doses of these hormones have on experimental animals. The initial gastroprotective effect that glucocorticoid hormones have, even after their single administration can be transformed into an ulcerogenic effect with a prolongation of the hormonal action, but not of the hormone dose. We are discussing the possible mechanism behind the transformation.

  4. [Glucocorticoids in neurology: mechanism of action, applications and side effects].

    Science.gov (United States)

    Finsterer, J; Frank, M

    2014-06-01

    Glucocorticoids represent a cornerstone in the therapy for many neurological disorders. Even though their mechanism of action is still not completely understood, synthetic glucocorticoids are given as first line drugs in a number of immunological and non-immunological disorders of the central or peripheral nervous system. For most of these disorders, however, the level of evidence that glucocorticoids are truly effective is still not sufficient. This is why treatment with glucocorticoids cannot be recommended on an evidenced-based level for many of these disorders. Due to the huge number of acute or chronic side effects, it is essential that the effects are documented by more randomised placebo-controlled cross-over trials. Generally, glucocorticoids can no longer be omitted in the treatment of neurological disorders, the indication to apply glucocorticoids, however, needs to be thoroughly balanced in the light of their many side effects. © Georg Thieme Verlag KG Stuttgart · New York.

  5. Obestatin controls the ubiquitin-proteasome and autophagy-lysosome systems in glucocorticoid-induced muscle cell atrophy.

    Science.gov (United States)

    Cid-Díaz, Tania; Santos-Zas, Icía; González-Sánchez, Jessica; Gurriarán-Rodríguez, Uxía; Mosteiro, Carlos S; Casabiell, Xesús; García-Caballero, Tomás; Mouly, Vincent; Pazos, Yolanda; Camiña, Jesús P

    2017-12-01

    Many pathological states characterized by muscle atrophy are associated with an increase in circulating glucocorticoids and poor patient prognosis, making it an important target for treatment. The development of treatments for glucocorticoid-induced and wasting disorder-related skeletal muscle atrophy should be designed based on how the particular transcriptional program is orchestrated and how the balance of muscle protein synthesis and degradation is deregulated. Here, we investigated whether the obestatin/GPR39 system, an autocrine/paracrine signaling system acting on myogenesis and with anabolic effects on the skeletal muscle, could protect against glucocorticoid-induced muscle cell atrophy. In the present study, we have utilized mouse C2C12 myotube cultures to examine whether the obestatin/GPR39 signaling pathways can affect the atrophy induced by the synthetic glucocorticoid dexamethasone. We have extended these findings to in vitro effects on human atrophy using human KM155C25 myotubes. The activation of the obestatin/GPR39 system protects from glucocorticoid-induced atrophy by regulation of Akt, PKD/PKCμ, CAMKII and AMPK signaling and its downstream targets in the control of protein synthesis, ubiquitin-proteasome system and autophagy-lysosome system in mouse cells. We compared mouse and human myotube cells in their response to glucocorticoid and identified differences in both the triggering of the atrophic program and the response to obestatin stimulation. Notably, we demonstrate that specific patterns of post-translational modifications of FoxO4 and FoxO1 play a key role in directing FoxO activity in response to obestatin in human myotubes. Our findings emphasize the function of the obestatin/GPR39 system in coordinating a variety of pathways involved in the regulation of protein degradation during catabolic conditions. © 2017 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on

  6. Glucocorticoid Availability in Colonic Inflammation of Rat

    Czech Academy of Sciences Publication Activity Database

    Ergang, Peter; Leden, Pavel; Bryndová, Jana; Žbánková, Šárka; Mikšík, Ivan; Kment, M.; Pácha, Jiří

    2008-01-01

    Roč. 53, č. 8 (2008), s. 2160-2167 ISSN 0163-2116 R&D Projects: GA MZd(CZ) NR8576; GA ČR GA305/07/0328 Grant - others:Univerzita Karlova(CZ) 77/2006C Institutional research plan: CEZ:AV0Z50110509 Keywords : glucocorticoids * 11beta hydroxisteroid dehydrogenase 1 Subject RIV: ED - Physiology Impact factor: 1.583, year: 2008

  7. Biochemical endpoints of glucocorticoid hormone action

    Energy Technology Data Exchange (ETDEWEB)

    Young, D.A.; Nicholson, M.L.; Guyette, W.A.; Giddings, S.J.; Mendelsohn, S.L.; Nordeen, S.K.; Lyons, R.T.

    1978-01-01

    Both the rapidly evolving metabolic effects of glucocorticoids and the more slowly developing lethal actions appear to be initiated via the synthesis of new mRNAs and proteins. The chronic suppression of cell growth may be the consequence of suppression of overall rates of protein synthesis (and probably RNA and DNA synthesis as well) that in turn may represent the cellular response to the small changes in ratios of adenine nucleotides that result from the suppression of oxidative ATP production. The inhibition of glucose transport may also play a role here to prevent a compensatory increase in glycolytic ATP production. Some other hormone actions, the decrease in the ability of cells to concentrate AIB and the increase in nuclear fragility are unrelated to, and evolve separately from, the hormonal inhibitions on energy production. Cell killing is not the result of suppression of protein synthesis, nor of hormone-induced increases in calcium uptake. While the mechanisms are unknown, the increase in nuclear fragility appears to be the earliest measure of their operation. In tumor cells resistance to lethal actions of glucocorticoids may emerge via the selection of cells with hardier membranes, that are better able to withstand the intracellular destructive events set in motion by high levels of glucocorticoids.

  8. Dual Role for Glucocorticoids in Cardiomyocyte Hypertrophy and Apoptosis

    Science.gov (United States)

    Ren, Rongqin; Oakley, Robert H.; Cruz-Topete, Diana

    2012-01-01

    Glucocorticoids and their synthetic derivatives are known to alter cardiac function in vivo; however, the nature of these effects and whether glucocorticoids act directly on cardiomyocytes are poorly understood. To explore the role of glucocorticoid signaling in the heart, we used rat embryonic H9C2 cardiomyocytes and primary cardiomyocytes as model systems. Dexamethasone (100 nm) treatment of cardiomyocytes caused a significant increase in cell size and up-regulated the expression of cardiac hypertrophic markers, including atrial natriuretic factor, β-myosin heavy chain, and skeletal muscle α-actin. In contrast, serum deprivation and TNFα exposure triggered cardiomyocyte apoptosis, and these apoptotic effects were inhibited by dexamethasone. Both the hypertrophic and anti-apoptotic actions of glucocorticoids were abolished by the glucocorticoid receptor (GR) antagonist RU486 and by short hairpin RNA-mediated GR depletion. Blocking the activity of the mineralocorticoid receptor had no effect on these glucocorticoid-dependent cardiomyocyte responses. Aldosterone (1 μm) activation of GR also promoted cardiomyocyte hypertrophy and cell survival. To elucidate the mechanism of the dual glucocorticoid actions, a genome-wide microarray was performed on H9C2 cardiomyocytes treated with vehicle or dexamethasone in the absence or presence of serum. Serum dramatically influenced the transcriptome regulated by GR, revealing potential glucocorticoid signaling mediators in both cardiomyocyte hypertrophy and apoptosis. These studies reveal a direct and dynamic role for glucocorticoids and GR signaling in the modulation of cardiomyocyte function. PMID:22989630

  9. Effect of perinatal glucocorticoids on vascular health and disease.

    Science.gov (United States)

    Millage, Aaron R; Latuga, Mariam S; Aschner, Judy L

    2017-01-01

    The benefits of antenatal glucocorticoids are now firmly established in the perinatal management of threatened preterm birth. Postnatal glucocorticoid therapy, however, remains controversial in neonatal medicine, with the need to balance short-term physiological benefits against the potential for long-term adverse consequences. This review focuses on the vascular effects of prenatal and postnatal glucocorticoids, synthesizing data from both experimental animal models and human infants with the goal of better appreciation of the short and long-term effects of these commonly used drugs. Due to their widespread and varied use, improved understanding of the cellular and molecular impact of glucocorticoids is important in guiding current practice and future research.

  10. Glucocorticoid-resistant asthma: more than meets the eye.

    Science.gov (United States)

    Reddy, Divya; Little, Frederic F

    2013-12-01

    For decades glucocorticoids have been considered as the gold standard for the treatment of asthma. We present a case report of typical glucocorticoid-resistant asthma and current consensus in definitions of "severe refractory", "difficult" and "glucocorticoid-resistant" asthma. Full-text papers and abstracts were identified on the basis of a comprehensive literature search primarily in MEDLINE (1966 to June 2012) but also in the Cochrane Central Register of Controlled Trials database. Glucocorticoid-resistant asthmatics are a small subset of patients who pose noteworthy diagnostic challenges while contributing disproportionately to health care costs. Recognition of various asthma phenotypes has aided in characterizing groups with severe asthma and given a better understanding of its pathophysiological process. The molecular mechanism of glucocorticoid action is complicated and several pathways have been identified to explain drug resistance, which in turn is crucial for drug development. Tobacco smoking appears to be the single most important contributor of glucocorticoid resistance. We present the emerging and promising concepts in the management of glucocorticoid-resistant asthma, which mainly include drugs targeting specific molecules, receptors, inflammatory cells or immune processes. The challenges in making a diagnosis of glucocorticoid-resistant asthma may contribute to underestimating its prevalence and impact on patient care. Considerable progress has been made in identifying distinct phenotypes and mechanisms of glucocorticoid resistance; therefore the future of new drug development in management of asthma is promising.

  11. Tissue-specific glucocorticoid action: a family affair.

    Science.gov (United States)

    Gross, Katherine L; Cidlowski, John A

    2008-11-01

    Glucocorticoids exert a wide variety of physiological and pathological responses, most of which are mediated by the ubiquitously expressed glucocorticoid receptor (GR). The glucocorticoid response varies among individuals, as well as within tissues from the same individual, and this phenomenon can be partially explained through understanding the process of generating bioavailable ligand and the molecular heterogeneity of GR. This review focuses on the recent advances in our understanding of prereceptor ligand metabolism, GR subtypes and GR polymorphisms. Furthermore, we evaluate the impact of tissue- and individual-specific diversity in the glucocorticoid pathway on human health and disease.

  12. Dibutyltin disrupts glucocorticoid receptor function and impairs glucocorticoid-induced suppression of cytokine production.

    Directory of Open Access Journals (Sweden)

    Christel Gumy

    Full Text Available BACKGROUND: Organotins are highly toxic and widely distributed environmental chemicals. Dibutyltin (DBT is used as stabilizer in the production of polyvinyl chloride plastics, and it is also the major metabolite formed from tributyltin (TBT in vivo. DBT is immunotoxic, however, the responsible targets remain to be defined. Due to the importance of glucocorticoids in immune-modulation, we investigated whether DBT could interfere with glucocorticoid receptor (GR function. METHODOLOGY: We used HEK-293 cells transiently transfected with human GR as well as rat H4IIE hepatoma cells and native human macrophages and human THP-1 macrophages expressing endogenous receptor to study organotin effects on GR function. Docking of organotins was used to investigate the binding mechanism. PRINCIPAL FINDINGS: We found that nanomolar concentrations of DBT, but not other organotins tested, inhibit ligand binding to GR and its transcriptional activity. Docking analysis indicated that DBT inhibits GR activation allosterically by inserting into a site close to the steroid-binding pocket, which disrupts a key interaction between the A-ring of the glucocorticoid and the GR. DBT inhibited glucocorticoid-induced expression of phosphoenolpyruvate carboxykinase (PEPCK and tyrosine-aminotransferase (TAT and abolished the glucocorticoid-mediated transrepression of TNF-alpha-induced NF-kappaB activity. Moreover, DBT abrogated the glucocorticoid-mediated suppression of interleukin-6 (IL-6 and TNF-alpha production in lipopolysaccharide (LPS-stimulated native human macrophages and human THP-1 macrophages. CONCLUSIONS: DBT inhibits ligand binding to GR and subsequent activation of the receptor. By blocking GR activation, DBT may disturb metabolic functions and modulation of the immune system, providing an explanation for some of the toxic effects of this organotin.

  13. Molecular mechanisms of glucocorticoid receptor signaling Mecanismos moleculares de señalización del receptor de glucocorticoides

    OpenAIRE

    Marta Labeur; Florian Holsboer

    2010-01-01

    This review highlights the most recent findings on the molecular mechanisms of the glucocorticoid receptor (GR). Most effects of glucocorticoids are mediated by the intracellular GR which is present in almost every tissue and controls transcriptional activation via direct and indirect mechanisms. Nevertheless the glucocorticoid responses are tissue -and gene- specific. GR associates selectively with corticosteroid ligands produced in the adrenal gland in response to changes of humoral homeost...

  14. Guide to Commensal Rodent Control

    Science.gov (United States)

    1991-12-01

    resulting from a rat bite may provide an entry point for the tetanus bacillus, Clostridium tetani. k. Rabies - Rats and mice are rarely infected with... rabies , and their bites do not normally require treatment for rabies . 1. Hemorrhagic fever with renal syndrome (Korean hemorrhagic fever...controlling rodent problems, and the risk of adversely affecting the environment is high. Organisms virulent enough to overcome natural resistance might also

  15. The Regulation of Muscle Mass by Endogenous Glucocorticoids

    Directory of Open Access Journals (Sweden)

    Daniel L Marks

    2015-02-01

    Full Text Available Glucocorticoids are highly conserved fundamental regulators of energy homeostasis. In response to stress in the form of perceived danger or acute inflammation, glucocorticoids are released from the adrenal gland, rapidly mobilizing energy from carbohydrate, fat and protein stores. In the case of inflammation, mobilized protein is critical for the rapid synthesis of acute phase reactants and an efficient immune response to infection. While adaptive in response to infection, chronic mobilization can lead to a p rofound depletion of energy stores. Skeletal muscle represents the major body store of protein, and can become substantially atrophied under conditions of chronic inflammation. Glucocorticoids elicit the atrophy of muscle by increasing the rate of protein degradation by the ubiquitin-proteasome system and autophagy lysosome system. Protein synthesis is also suppressed at the level of translational initiation, preventing the production of new myofibrillar protein. Glucocorticoids also antagonize the action of anabolic regulators such as insulin further exacerbating the loss of protein and muscle mass. The loss of muscle mass in the context of chronic disease is a key feature of cachexia and contributes substantially to morbidity and mortality. A growing body of evidence demonstrates that glucocorticoid signaling is a common mediator of wasting, irrespective of the underlying initiator or disease state. This review will highlight fundamental mechanisms of glucocorticoid signaling and detail the mechanisms of glucocorticoid-induced muscle atrophy. Additionally, the evidence for glucocorticoids as a driver of muscle wasting in numerous disease states will be discussed. Given the burden of wasting diseases and the nodal nature of glucocorticoid signaling, effective anti-glucocorticoid therapy would be a valuable clinical tool. Therefore, the progress and potential pitfalls in the development of glucocorticoid antagonists for muscle wasting will

  16. Exploring the molecular mechanisms of glucocorticoid receptor action from sensitivity to resistance.

    Science.gov (United States)

    Ramamoorthy, Sivapriya; Cidlowski, John A

    2013-01-01

    Glucocorticoids regulate a variety of physiological processes, and are commonly used to treat disorders of inflammation, autoimmune diseases, and cancer. Glucocorticoid action is predominantly mediated through the classic glucocorticoid receptor (GR), but sensitivity to glucocorticoids varies among individuals, and even within different tissues from the same individual. The molecular basis of this phenomenon can be partially explained through understanding the process of generating bioavailable ligand and the molecular heterogeneity of the GR. The molecular mechanisms that regulate glucocorticoid action highlight the dynamic nature of hormone signaling and provide novel insights into genomic glucocorticoid actions and glucocorticoid sensitivity. Although glucocorticoids are highly effective for therapeutic purposes, long-term and/or high-dose glucocorticoid administration often leads to reduced glucocorticoid sensitivity or resistance. Here, we summarize our current understanding of the mechanisms that modulate glucocorticoid sensitivity and resistance with a focus on GR-mediated signaling. Copyright © 2013 S. Karger AG, Basel.

  17. Two polymorphisms in the glucocorticoid receptor gene directly affect glucocorticoid-regulated gene expression.

    NARCIS (Netherlands)

    H. Russcher (Henk); P. Smit (Pauline); E.L.T. van den Akker (Erica); E.F.C. van Rossum (Liesbeth); A.O. Brinkmann (Albert); F.H. de Jong (Frank); S.W.J. Lamberts (Steven); J.W. Koper (Jan)

    2005-01-01

    textabstractCONTEXT: Interindividual variation in glucocorticoid (GC)-sensitivity can be partly explained by polymorphisms in the GC receptor (GR) gene. The ER22/23EK and N363S polymorphisms have been described to be associated with lower and higher GC sensitivity, respectively. OBJECTIVE AND

  18. Novel insights into mechanisms of glucocorticoid action and the development of new glucocorticoid receptor ligands

    NARCIS (Netherlands)

    Löwenberg, Mark; Stahn, Cindy; Hommes, Daniel W.; Buttgereit, Frank

    2008-01-01

    Glucocorticoids (GCs) are potent anti-inflammatory and immunosuppressant agents. Unfortunately, they also produce serious side effects that limit their usage. This discrepancy is the driving force for the intensive search for novel GC receptor ligands with a better benefit-risk ratio as compared to

  19. Specific and strain-independent effects of dexamethasone in the prevention and treatment of experimental autoimmune encephalomyelitis in rodents

    DEFF Research Database (Denmark)

    Donia, M; Mangano, K; Quattrocchi, C

    2010-01-01

    of inflammatory cells and the increased frequency of autoantigen-specific interferon-gamma-secreting lymph node mononuclear cells. The present data reproduced in rodent EAE models some of the beneficial effects observed with glucocorticoids in MS. This strengthens the validity of these five models as in vivo...... tested the effects of dexamethasone (Dex) and found that both prophylactic and early therapeutic regimens were effective in suppressing the development of monophasic EAE in myelin basic protein-immunized Lewis rats, the relapsing-remitting forms of EAE induced in SJL mice by proteolipid protein and in DA...

  20. Using fecal glucocorticoids for stress assessment in Mourning Doves

    Science.gov (United States)

    Washburn, Brian E.; Millspaugh, Joshua J.; Schulz, John H.; Jones, Susan B.; Mong, T.

    2003-01-01

    Fecal glucocorticoid assays provide a potentially useful, noninvasive means to study physiological responses of wildlife to various stressors. The objective of our study was to validate a method for measuring glucocorticoid metabolites in Mourning Dove (Zenaida macroura) feces. We validated the assay using standard procedures (e.g., parallelism, recovery of exogenous corticosterone) to demonstrate that the assay accurately and precisely measured glucocorticoid metabolites in Mourning Dove fecal extracts. We conducted adrenocorticotropin (ACTH) challenge experiments to validate the assay's ability to determine biologically important changes in fecal glucocorticoids. Fecal glucocorticoid levels increased significantly approximately 2-3 hr after administration of ACTH at 50 IU per kg body mass to wild Mourning Doves held in captivity. In contrast, fecal glucocorticoid metabolites did not increase in control birds, birds that received saline injections, or a lower dose of ACTH (1 IU per kg body mass). Variation in overall fecal glucocorticoid metabolite levels may have been influenced by season and the length of time birds were held in captivity. Non-invasive fecal glucocorticoid metabolite analyses, in combination with demographic information, may have considerable utility for monitoring the effects of natural and anthropogenic disturbances on Mourning Dove populations.

  1. Limiting glucocorticoid secretion increases the anorexigenic property of Exendin-4

    Directory of Open Access Journals (Sweden)

    Shin J. Lee

    2016-07-01

    Conclusions: Our findings demonstrate that limiting glucocorticoid secretion and actions with low dose dexamethasone or DSAP lesion increases Ex-4's ability to reduce food intake and body weight. Novel glucocorticoid receptor based mechanisms, therefore, may help enhance GLP-1-based obesity therapies.

  2. Glucocorticoids and hypothalamo-pituitary-adrenal function : prevention of suppression?

    NARCIS (Netherlands)

    E.N.W. Janssens (Emile )

    1984-01-01

    textabstractThe suppressive effects of prolonged administration of pharmacologic doses of glucocorticoids on the HPA function are wellknown and often represent a major problem in clinical practice: it is unknown after what duration of administration, and for what dosages of glucocorticoids precisely

  3. Primary hypoadrenocorticism in a dog receiving glucocorticoid supplementation

    Science.gov (United States)

    Harris, Paul

    1999-01-01

    A 5-year-old, spayed, female husky-Labrador retriever cross was diagnosed with primary hypoadrenocorticism, an uncommon endocrine disorder caused by a deficiency of glucocorticoid and mineralocorticoid hormones. Subtle clinical signs and previous treatment with exogenous glucocorticoid drugs required an adrenocorticotropic hormone stimulation test to confirm the diagnosis. PMID:10065324

  4. Glucocorticoid receptor antagonism reverts docetaxel resistance in human prostate cancer

    NARCIS (Netherlands)

    Kroon, Jan; Puhr, Martin; Buijs, Jeroen T.; Van Der Horst, Geertje; Lemhemmer, Daniël; Marijt, Koen A.; Hwang, Ming S.; Masood, Motasim; Grimm, Stefan; Storm, Gert; Metselaar, Josbert M.|info:eu-repo/dai/nl/244207690; Meijer, Onno C.; Culig, Zoran; Van Der Pluijm, Gabri

    2016-01-01

    Resistance to docetaxel is a major clinical problem in advanced prostate cancer (PCA). Although glucocorticoids (GCs) are frequently used in combination with docetaxel, it is unclear to what extent GCs and their receptor, the glucocorticoid receptor (GR), contribute to the chemotherapy resistance.

  5. Genomic and epigenomic mechanisms of glucocorticoids in the brain.

    Science.gov (United States)

    Gray, Jason D; Kogan, Joshua F; Marrocco, Jordan; McEwen, Bruce S

    2017-11-01

    Following the discovery of glucocorticoid receptors in the hippocampus and other brain regions, research has focused on understanding the effects of glucocorticoids in the brain and their role in regulating emotion and cognition. Glucocorticoids are essential for adaptation to stressors (allostasis) and in maladaptation resulting from allostatic load and overload. Allostatic overload, which can occur during chronic stress, can reshape the hypothalamic-pituitary-adrenal axis through epigenetic modification of genes in the hippocampus, hypothalamus and other stress-responsive brain regions. Glucocorticoids exert their effects on the brain through genomic mechanisms that involve both glucocorticoid receptors and mineralocorticoid receptors directly binding to DNA, as well as by non-genomic mechanisms. Furthermore, glucocorticoids synergize both genomically and non-genomically with neurotransmitters, neurotrophic factors, sex hormones and other stress mediators to shape an organism's present and future responses to a stressful environment. Here, we discuss the mechanisms of glucocorticoid action in the brain and review how glucocorticoids interact with stress mediators in the context of allostasis, allostatic load and stress-induced neuroplasticity.

  6. Roles of glucocorticoids in human parturition: a controversial fact?

    Science.gov (United States)

    Li, X Q; Zhu, P; Myatt, L; Sun, K

    2014-05-01

    The pivotal role of glucocorticoids in the initiation of parturition has been very well documented in several domestic mammalian animal species. However the role of glucocorticoids in human parturition remains controversial mainly because of the absence of effect of synthetic glucocorticoids, given to promote fetal organ maturation in pregnant women with threatened preterm delivery, on the length of gestation. This article will review studies of glucocorticoids in human parturition and provide evidence for an important role of glucocorticoids in human parturition as well but a simultaneous high concentration of estrogen within the intrauterine tissues may be necessary for GCs to initiate parturition. The synthetic GCs dexamethasone and betamethasone pass through the placenta intact resulting in potent negative feedback on the fetal HPA axis and diminished production of DHEA from fetal adrenal glands for estrogen synthesis by the placenta. This may negate the effect of systemic administration of GCs on the induction of labor, especially in cases where the myometrium is not yet fully primed by estrogen. Endogenous glucocorticoids are inactivated by the placental 11β-HSD2 thus limiting the negative feedback of maternal cortisol on the fetal HPA axis and allowing the simultaneous rise of cortisol and estrogen levels towards the end of gestation. Therefore, endogenous glucocorticoids, particularly glucocorticoids produced locally in the intrauterine tissues may play an important role in parturition in humans by enhancing prostaglandin production in the fetal membranes and stimulating estrogen and CRH production in the placenta. Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. Glucocorticoids decrease Treg cell numbers in lungs of allergic mice.

    Science.gov (United States)

    Olsen, P C; Kitoko, J Z; Ferreira, T P; de-Azevedo, C T; Arantes, A C; Martins, Μ A

    2015-01-15

    Glucocorticoids have been the hallmark anti-inflammatory drug used to treat asthma. It has been shown that glucocorticoids ameliorate asthma by increasing numbers and activity of Tregs, in contrast recent data show that glucocorticoid might have an opposite effect on Treg cells from normal mice. Since Tregs are target cells that act on the resolution of asthma, the aim of this study was to elucidate the effect of glucocorticoid treatment on lung Tregs in mouse models of asthma. Allergen challenged mice were treated with either oral dexamethasone or nebulized budesonide. Broncoalveolar lavage and airway hyperresponsiveness were evaluated after allergenic challenge. Lung, thymic and lymph node cells were phenotyped on Treg through flow cytometry. Lung cytokine secretion was detected by ELISA. Although dexamethasone inhibited airway inflammation and hyperresponsiveness, improving resolution, we have found that both dexamethasone and budesonide induce a reduction of Treg numbers on lungs and lymphoid organs of allergen challenged mice. The reduction of lung Treg levels was independent of mice strain or type of allergen challenge. Our study also indicates that both glucocorticoids do not increase Treg activity through production of IL-10. Glucocorticoid systemic or localized treatment induced thymic atrophy. Taken together, our results demonstrate that glucocorticoids decrease Treg numbers and activity in different asthma mouse models, probably by reducing thymic production of T cells. Therefore, it is possible that glucocorticoids do not have beneficial effects on lung populations of Treg cells from asthmatic patients. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. Profound postanesthetic hypoglycemia attributable to glucocorticoid deficiency in 2 dogs.

    OpenAIRE

    Lane, I F; Matwichuk, C L; Carpenter, L G; Behrend, E N

    1999-01-01

    Glucocorticoid deficiency was diagnosed as the cause of severe postanesthetic hypoglycemia in 2 dogs. Prior signs of systemic illness were not described in either dog; however, preoperative hematologic findings were consistent with glucocorticoid deficiency. Fasting hypoglycemia is a possible complication of chronic adrenal insufficiency primarily because of impaired gluconeogenesis.

  9. Glucocorticoids facilitate the retention of acquired immobility during forced swimming

    NARCIS (Netherlands)

    Veldhuis, H D; De Korte, C C; De Kloet, E R

    1985-01-01

    The adrenalectomy-induced decrease in the level of immobility during a 5 min retest period in the Porsolt swimming test could be reversed by glucocorticoids administered s.c. 15 min after the initial forced swimming exposure. The synthetic glucocorticoids dexamethasone and RU 28362 were active in

  10. Social memories in rodents: methods, mechanisms and modulation by stress.

    Science.gov (United States)

    van der Kooij, Michael A; Sandi, Carmen

    2012-08-01

    Intact social memory forms the basis of meaningful interactions between individuals. Many factors can modulate the quality of social memory, and these have been studied in detail in rodents. Social memory, however, cannot be considered a single entity. The term social memory reflects different processes, such as social recognition of a novel conspecific individual and social learning (or 'learning from others'). This review summarizes the findings obtained with behavioral paradigms that were developed for the study of memory formation by social recognition and social learning. In particular, we focus on studies that include tests for social habituation/discrimination paradigms, tests for memory of a previously established social hierarchy and the social transmission of the food preference test. The role of individual differences and the main neurobiological mechanisms (i.e., the brain regions and neurochemical systems involved) that have been implicated in each of these types of social-related memories are reviewed. In addition, we address the key modulatory influence of stress on the formation of these types of memories; discussing the contribution of central (corticotropin-releasing factor, CRF) and peripheral (glucocorticoids) stress systems and their interactions with the social neuropeptide systems. Overall, we present here a general overview of the current state of a thriving research area within the field of social neuroscience. Copyright © 2011 Elsevier Ltd. All rights reserved.

  11. Exogenous glucocorticoids and adverse cerebral effects in children

    DEFF Research Database (Denmark)

    Damsted, Sara K.; Born, A P; Paulson, Olaf B

    2011-01-01

    structures involved in axonal transport, long-term potentiation and neuronal plasticity. Significant maturation of the brain continues throughout childhood and we hypothesize that exposure to exogenous glucocorticoids during preschool and school age causes adverse cerebral effects. It is our opinion...... of the glucocorticoid receptor, which is associated with unfavorable cellular outcomes. Prenatal treatment with glucocorticoids can compromise brain growth and is associated with periventricular leukomalacia, attentions deficits and poorer cognitive performance. In the neonatal period exposure to glucocorticoids...... reduces neurogenesis and cerebral volume, impairs memory and increases the incidence of cerebral palsy. Cerebral effects of glucocorticoids in later childhood have been less thoroughly studied, but apparent brain atrophy, reduced size of limbic structures and neuropsychiatric symptoms have been reported...

  12. The effects of glucocorticoids on feeding behavior in rats.

    Science.gov (United States)

    la Fleur, Susanne E

    2006-08-30

    Glucocorticoids have major effects on food intake, however, the underlying mechanisms are poorly understood. This article highlights data on the changes that occur when glucocorticoids are removed by adrenalectomy, and the effects of central and systemic administered glucocorticoids on feeding behavior in rats. Next, animal data on the interaction of glucocorticoids with insulin on intake of comfort foods are addressed and the hypothesis that glucocorticoids modify feeding behavior, whereas insulin modifies the choice of food is discussed. Finally a view is presented that hormonal and vagal signals generated when (comfort) food is consumed will affect the corticotropin-releasing factor (CRF) brain network important for the response to stress and the regulation of feeding. With a society, where stress is experienced daily and comfort food is found at every street corner, it will be vital to understand the interactions between the systems that react to stress and regulate feeding behavior to fight the obesity epidemic.

  13. Chromatin Architecture Defines the Glucocorticoid Response

    Science.gov (United States)

    Burd, Craig J.; Archer, Trevor K.

    2013-01-01

    The glucocorticoid receptor (GR) functions to regulate a wide group of physiological processes through hormone inducible interaction with genomic loci and subsequent manipulation of the transcriptional output of target genes. Despite expression in a wide variety of tissues, the GR has diverse roles that are regulated tightly in a cell type specific manner. With the advent of whole genome approaches, the details of that diversity and the mechanisms regulating them are beginning to be elucidated. This review aims describe the recent advances detailing the role chromatin structure plays in dictating GR specificity. PMID:23545159

  14. The effect of chronic phenytoin administration on single prolonged stress induced extinction retention deficits and glucocorticoid upregulation in the rat medial prefrontal cortex.

    Science.gov (United States)

    George, Sophie A; Rodriguez-Santiago, Mariana; Riley, John; Rodriguez, Elizabeth; Liberzon, Israel

    2015-01-01

    Post-traumatic stress disorder (PTSD) is a chronic, debilitating disorder. Only two pharmacological agents are approved for PTSD treatment, and they often do not address the full range of symptoms nor are they equally effective in all cases. Animal models of PTSD are critical for understanding the neurobiology involved and for identification of novel therapeutic targets. Using the rodent PTSD model, single prolonged stress (SPS), we have implicated aberrant excitatory neural transmission and glucocorticoid receptor (GR) upregulation in the medial prefrontal cortex (mPFC) and hippocampus (HPC) in fear memory abnormalities associated with PTSD. The objective of this study is to examine the potential protective effect of antiepileptic phenytoin (PHE) administration on SPS-induced extinction retention deficits and GR expression. Forty-eight SPS-treated male Sprague Dawley rats or controls were administered PHE (40, 20 mg/kg, vehicle) for 7 days following SPS stressors; then, fear conditioning, extinction, and extinction retention were tested. Fear conditioning and extinction were unaffected by SPS or PHE, but SPS impaired extinction retention, and both doses of PHE rescued this impairment. Similarly, SPS increased GR expression in the mPFC and dorsal HPC, and PHE prevented SPS-induced GR upregulation in the mPFC. These data demonstrate that PHE administration can prevent the development of extinction retention deficits and upregulation of GR. PHE exerts inhibitory effects on voltage-gated sodium channels and decreases excitatory neural transmission via glutamate antagonism. If glutamate hyperactivity in the days following SPS contributes to SPS-induced deficits, then these data may suggest that the glutamatergic system constitutes a target for secondary prevention.

  15. Circadian and ultradian glucocorticoid rhythmicity: Implications for the effects of glucocorticoids on neural stem cells and adult hippocampal neurogenesis

    NARCIS (Netherlands)

    Fitzsimons, C.P.; Herbert, J.; Schouten, M.; Meijer, O.C.; Lucassen, P.J.; Lightman, S.

    2016-01-01

    Total glucocorticoid hormone levels in plasma of various species, including humans, follow a circadian rhythm that is made up from an underlying series of hormone pulses. In blood most of the glucocorticoid is bound to corticosteroid-binding globulin and albumin, resulting in low levels of free

  16. The fecal viral flora of wild rodents.

    OpenAIRE

    Tung G Phan; Beatrix Kapusinszky; Chunlin Wang; Robert K Rose; Howard L Lipton; Eric L Delwart

    2011-01-01

    The frequent interactions of rodents with humans make them a common source of zoonotic infections. To obtain an initial unbiased measure of the viral diversity in the enteric tract of wild rodents we sequenced partially purified, randomly amplified viral RNA and DNA in the feces of 105 wild rodents (mouse, vole, and rat) collected in California and Virginia. We identified in decreasing frequency sequences related to the mammalian viruses families Circoviridae, Picobirnaviridae, Picornaviridae...

  17. Skin and soft tissue artifacts due to postmortem damage caused by rodents.

    Science.gov (United States)

    Tsokos, M; Matschke, J; Gehl, A; Koops, E; Püschel, K

    1999-09-30

    Five cases of postmortem bite-injuries inflicted by rodents are presented (five males between 41 and 89 years; three cases caused by mice, one case by rats, one case of possible mixed rodent activity by rats and mice). The study presents a spectrum of phenomenological aspects of postmortem artifacts due to rodent activity to fresh skin and soft tissue: the majority of the injuries have a circular appearance. The wound margins are finely serrated with irregular edges and circumscribed 1-2 mm intervals within, partly showing protruding indentations up to 5 mm. Distinct parallel cutaneous lacerations deriving from the biting action of the upper and lower pairs of the rodents incisors are diagnostic for tooth marks of rodent origin but cannot always be found. No claw-induced damage can be found in the skin beyond the wound margins. Areas involved in the present study were: exposed and unprotected parts of the body, such as eyelids, nose and mouth (representing moist parts of the face); and the back of the hands. Postmortem rodent activity may occasionally be expected on clothed and therefore protected parts of the body. The phenomenon of postmortem rodent activity to human bodies can be found indoors especially under circumstances of low socioeconomic settings; outdoors this finding is particularly observed among fatalities among homeless people.

  18. Circadian and ultradian glucocorticoid rhythmicity: Implications for the effects of glucocorticoids on neural stem cells and adult hippocampal neurogenesis.

    Science.gov (United States)

    Fitzsimons, Carlos P; Herbert, Joe; Schouten, Marijn; Meijer, Onno C; Lucassen, Paul J; Lightman, Stafford

    2016-04-01

    Psychosocial stress, and within the neuroendocrine reaction to stress specifically the glucocorticoid hormones, are well-characterized inhibitors of neural stem/progenitor cell proliferation in the adult hippocampus, resulting in a marked reduction in the production of new neurons in this brain area relevant for learning and memory. However, the mechanisms by which stress, and particularly glucocorticoids, inhibit neural stem/progenitor cell proliferation remain unclear and under debate. Here we review the literature on the topic and discuss the evidence for direct and indirect effects of glucocorticoids on neural stem/progenitor cell proliferation and adult neurogenesis. Further, we discuss the hypothesis that glucocorticoid rhythmicity and oscillations originating from the activity of the hypothalamus-pituitary-adrenal axis, may be crucial for the regulation of neural stem/progenitor cells in the hippocampus, as well as the implications of this hypothesis for pathophysiological conditions in which glucocorticoid oscillations are affected. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Glucocorticoid-induced osteoporosis: 2013 update

    Directory of Open Access Journals (Sweden)

    M. Mazzantini

    2014-07-01

    Full Text Available Glucocorticoids are the most common cause of secondary osteoporosis leading to the so-called glucocorticoidinduced osteoporosis (GIO. A treatment with 10 mg/d of prednisone or equivalent for more than 3 months leads to a 7-fold increase in hip fractures and a 17-fold increase in vertebral fractures. The difference between bone quantity and quality in GIO makes bone mineral density measurements inadequate to detect patients at risk of fracture. The adverse effects of glucocorticoids on the skeleton derive from a direct impact on bone cells with a severe impairment of mechanical competence. Crucial to prevention of GIO is early timing of intervention. The World Health Organization has adopted a fracture prevention algorithm (FRAX intended to estimate fracture risk in GIO. The American College of Rhematology modified its prevention and treatment guidelines taking into account the individual risk of fracture calculated in GIO on the basis of the FRAX algorithm. Recently, also a joint Guideline Working Group of the International Osteoporosis Foundation (IOF and the European Calcified Tissue Society (ECTS published a framework for the development of national guidelines for the management of GIO. Bisphosphonates are the first-line drugs to treat GIO; teriparatide counteracts several fundamental pathophysiologic aspects of GIO; denosumab is useful in patients with renal failure and in potentially pregnant young women. Vertebroplasty and kyphoplasty may be less beneficial in GIO than in primary involutional osteoporosis.

  20. Exploring the Molecular Mechanisms of Glucocorticoid Receptor Action from Sensitivity to Resistance

    OpenAIRE

    Ramamoorthy, Sivapriya; Cidlowski, John A.

    2013-01-01

    Glucocorticoids regulate a variety of physiological processes, and are commonly used to treat disorders of inflammation, autoimmune diseases, and cancer. Glucocorticoid action is predominantly mediated through the classic glucocorticoid receptor (GR), but sensitivity to glucocorticoids varies among individuals, and even within different tissues from the same individual. The molecular basis of this phenomenon can be partially explained through understanding the process of generating bioavailab...

  1. The Metabolic Implications of Glucocorticoids in a High-Fat Diet Setting and the Counter-Effects of Exercise

    Directory of Open Access Journals (Sweden)

    Emily C. Dunford

    2016-12-01

    Full Text Available Glucocorticoids (GCs are steroid hormones, naturally produced by activation of the hypothalamic-pituitary-adrenal (HPA axis, that mediate the immune and metabolic systems. Synthetic GCs are used to treat a number of inflammatory conditions and diseases including lupus and rheumatoid arthritis. Generally, chronic or high dose GC administration is associated with side effects such as steroid-induced skeletal muscle loss, visceral adiposity, and diabetes development. Patients who are taking exogenous GCs could also be more susceptible to poor food choices, but the effect that increasing fat consumption in combination with elevated exogenous GCs has only recently been investigated. Overall, these studies show that the damaging metabolic effects initiated through exogenous GC treatment are significantly amplified when combined with a high fat diet (HFD. Rodent studies of a HFD and elevated GCs demonstrate more glucose intolerance, hyperinsulinemia, visceral adiposity, and skeletal muscle lipid deposition when compared to rodents subjected to either treatment on its own. Exercise has recently been shown to be a viable therapeutic option for GC-treated, high-fat fed rodents, with the potential mechanisms still being examined. Clinically, these mechanistic studies underscore the importance of a low fat diet and increased physical activity levels when individuals are given a course of GC treatment.

  2. Partial protection from organophosphate-induced cholinesterase inhibition by metyrapone treatment

    Directory of Open Access Journals (Sweden)

    Radosław Świercz

    2013-08-01

    Full Text Available Background: Organophosphates are cholinesterase (ChE inhibitors with worldwide use as insecticides. Stress response, evidenced by a dramatic and relatively long-lasting (several hours rise in the plasma glucocorticoid concentration is an integral element of the organophosphate (OP poisoning symptomatology. In rodents, corticosterone (CORT is the main glucocorticoid. There are several reports suggesting a relationship between the stressor-induced rise in CORT concentraion (the CORT response and the activity of the cerebral and peripheral ChE. Thus, it seems reasonable to presume that, in OP intoxication, the rise in plasma CORT concentration may somehow affect the magnitude of the OP-induced ChE inhibition. Metyrapone (MET [2-methyl-1,2-di(pyridin-3-ylpropan-1-one] blocks CORT synthesis by inhibiting steoid 11β-hydroxylase, thereby preventing the CORT response. Chlorfenvinphos (CVP [2-chloro-1-(2,4-dichlorophenyl ethenyl diethyl phosphate] is an organophosphate insecticide still in use in some countries. Material and Methods: The purose of the present work was to compare the CVP-induced effects - the rise of the plasma CORT concentration and the reduction in ChE activity - in MET-treated and MET-untreated rats. Chlorfenvinphos was administered once at 0.0, 0.5, 1.0 and 3.0 mg/kg i.p. Metyrapone, at 100 mg/kg i.p., was administered five times, at 24-h intervals. The first MET dose was given two hours before CVP. Conclusion: The following was observed in the MET-treated rats: i no rise in plasma CORT concentration after the CVP administration, ii a reduced inhibition and a faster restitution of blood and brain ChE activities. The results suggest that MET treatment may confer significant protection against at least some effects of OP poisoning. The likely mechanism of the protective MET action has been discussed.

  3. Treatment with Glucocorticoids or Calcineurin Inhibitors in Primary FSGS.

    Science.gov (United States)

    Laurin, Louis-Philippe; Gasim, Adil M; Poulton, Caroline J; Hogan, Susan L; Jennette, J Charles; Falk, Ronald J; Foster, Bethany J; Nachman, Patrick H

    2016-03-07

    In primary FSGS, calcineurin inhibitors have primarily been studied in patients deemed resistant to glucocorticoid therapy. Few data are available about their use early in the treatment of FSGS. We sought to estimate the association between choice of therapy and ESRD in primary FSGS. We used an inception cohort of patients diagnosed with primary FSGS by kidney biopsy between 1980 and 2012. Factors associated with initiation of therapy were identified using logistic regression. Time-dependent Cox models were performed to compare time to ESRD between different therapies. In total, 458 patients were studied (173 treated with glucocorticoids alone, 90 treated with calcineurin inhibitors with or without glucocorticoids, 12 treated with other agents, and 183 not treated with immunosuppressives). Tip lesion variant, absence of severe renal dysfunction (eGFR≥30 ml/min per 1.73 m(2)), and hypoalbuminemia were associated with a higher likelihood of exposure to any immunosuppressive therapy. Only tip lesion was associated with initiation of glucocorticoids alone over calcineurin inhibitors. With adjusted Cox regression, immunosuppressive therapy with glucocorticoids and/or calcineurin inhibitors was associated with better renal survival than no immunosuppression (hazard ratio, 0.49; 95% confidence interval, 0.28 to 0.86). Calcineurin inhibitors with or without glucocorticoids were not significantly associated with a lower likelihood of ESRD compared with glucocorticoids alone (hazard ratio, 0.42; 95% confidence interval, 0.15 to 1.18). The use of immunosuppressive therapy with calcineurin inhibitors and/or glucocorticoids as part of the early immunosuppressive regimen in primary FSGS was associated with improved renal outcome, but the superiority of calcineurin inhibitors over glucocorticoids alone remained unproven. Copyright © 2016 by the American Society of Nephrology.

  4. The Effect of Glucocorticoid and Glucocorticoid Receptor Interactions on Brain, Spinal Cord, and Glial Cell Plasticity

    Directory of Open Access Journals (Sweden)

    Kathryn M. Madalena

    2017-01-01

    Full Text Available Stress, injury, and disease trigger glucocorticoid (GC elevation. Elevated GCs bind to the ubiquitously expressed glucocorticoid receptor (GR. While GRs are in every cell in the nervous system, the expression level varies, suggesting that diverse cell types react differently to GR activation. Stress/GCs induce structural plasticity in neurons, Schwann cells, microglia, oligodendrocytes, and astrocytes as well as affect neurotransmission by changing the release and reuptake of glutamate. While general nervous system plasticity is essential for adaptation and learning and memory, stress-induced plasticity is often maladaptive and contributes to neuropsychiatric disorders and neuropathic pain. In this brief review, we describe the evidence that stress/GCs activate GR to promote cell type-specific changes in cellular plasticity throughout the nervous system.

  5. Neuropsychiatric findings in Cushing syndrome and exogenous glucocorticoid administration.

    Science.gov (United States)

    Starkman, Monica N

    2013-09-01

    This article reviews the neuropsychiatric presentations elicited by spontaneous hypercortisolism and exogenous supraphysiologic glucocorticoids. Patients with Cushing disease and syndrome develop a depressive syndrome: irritable and depressed mood, decreased libido, disrupted sleep and cognitive decrements. Exogenous short-term glucocorticoid administration may elicit a hypomanic syndrome with mood, sleep and cognitive disruptions. Treatment options are discussed. Brain imaging and neuropsychological studies indicate elevated cortisol and other glucocorticoids are especially deleterious to hippocampus and frontal lobe. The research findings also shed light on neuropsychiatric abnormalities in conditions that have substantial subgroups exhibiting elevated and dysregulated cortisol: aging, major depressive disorder and Alzheimer's disease. Copyright © 2013 Elsevier Inc. All rights reserved.

  6. Glucocorticoids and prostate cancer treatment: friend or foe?

    Science.gov (United States)

    Montgomery, Bruce; Cheng, Heather H; Drechsler, James; Mostaghel, Elahe A

    2014-01-01

    Glucocorticoids have been used in the treatment of prostate cancer to slow disease progression, improve pain control and offset side effects of chemo- and hormonal therapy. However, they may also have the potential to drive prostate cancer growth via mutated androgen receptors or glucocorticoid receptors (GRs). In this review we examine historical and contemporary use of glucocorticoids in the treatment of prostate cancer, review potential mechanisms by which they may inhibit or drive prostate cancer growth, and describe potential means of defining their contribution to the biology of prostate cancer. PMID:24625881

  7. Leptospira spp. in commensal rodents, Beijing, China.

    Science.gov (United States)

    Wang, Chengmin; He, Hongxuan

    2013-04-01

    Leptospirosis is a widely distributed zoonosis, and rats (Rattus spp.) are its most common source. We found antibodies to leptospires in 115 (30.2%) of 381 commensal rodents from Beijing, China. Commensal rodents might represent a potential source for human and pet leptospirosis in urban environments.

  8. Thermoregulation of the subterranean rodent genus Bathyergus ...

    African Journals Online (AJOL)

    The thermoregulation of the largest subterranean rodent, genus Bathyergus, comprising two species, B. suillus and B. janetta,occurring in mesic and semiarid habitats respectively, was investigated and compared with that of other subterranean rodents. Both species display low resting metabolic rates and low body ...

  9. Besnoitiosis in rodents from Colorado. [Parasitic infestations

    Energy Technology Data Exchange (ETDEWEB)

    Dagle, G E; Winsor, T F; Adee, R R

    1976-01-01

    Parasitic cysts of Besnoitia jellisoni (coccidia) were found in rodents (Peromyscus maniculatus and Spermophilus tridecemlineatus) trapped in Eastern Colorado. The parasite was associated with a granulomatous inflammatory reaction in the lungs of each rodent and was disseminated in several organs from one Peromyscus. The ultrastructural appearance of the merozoites and the cyst wall formed by the host cell were studied.

  10. Skin and glucocorticoids: effects of local skin glucocorticoid impairment on skin homeostasis.

    Science.gov (United States)

    Nikolakis, Georgios; Zouboulis, Christos C

    2014-11-01

    The role of skin as a de novo source of glucocorticoids and the importance of cutaneous glucocorticoidogenesis as a homeostatic mechanism in human skin is highlighted by Slominski et al. in a recently published issue. Impairment of glucocorticoidogenesis through noxious stimuli, such as UVB, can explain pathophysiology of skin diseases (e.g. rosacea). In addition to keratinocytes, melanocytes and fibroblasts, cutaneous adnexes also play a significant role as targets and sources of glucocorticoids, because they express most of the enzymes required for steroidogenesis. Glucocorticoids are also involved in the pathogenesis of acne lesions, affecting sebum production in vivo and in vitro. Certain steroidogenic enzymes, such as 11β-hydroxysteroid dehydrogenase, are upregulated in acne lesions. On this background, the paper by Slominski et al. provides further insights into dermatoendocrinology, with emphasis on the importance of an impairment of the skin's own hypothalamic-pituitary-adrenal-like axis in the pathophysiology of several skin diseases. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Opposite effects of serum- and glucocorticoid-regulated kinase-1 and glucocorticoids on POMC transcription and ACTH release.

    Science.gov (United States)

    Reiter, Marie Helene; Vila, Greisa; Knosp, Engelbert; Baumgartner-Parzer, Sabina M; Wagner, Ludwig; Stalla, Günter K; Luger, Anton

    2011-08-01

    Serum- and glucocorticoid-regulated kinase-1 (SGK1) is a glucocorticoid early-response gene; its function, however, has been elucidated mainly in the context of mineralocorticoid signaling. Here, we investigate the expression and function of SGK1 in the pituitary gland, one of the primary glucocorticoid targets. SGK1 is expressed in the human pituitary gland and colocalizes to ACTH. The AtT-20 murine corticotroph cell line was used for functional experiments. Glucocorticoids upregulated SGK1 mRNA and protein levels, parallel to decreasing proopiomelanocortin (POMC) transcription and ACTH release. Dexamethasone-induced changes in SGK1 protein were abolished by the steroid receptor antagonist RU-486 and reduced by the inhibition of PI 3-kinase with LY-294002. SGK1 overexpression increased CREB- and activator protein-1-dependent transcription, POMC transcription, and ACTH secretion but did not influence intracellular cAMP levels. SGK1 overexpression and corticotropin-releasing hormone had additive effects on POMC promoter activity but not on ACTH secretion. SGK1 knockdown by RNA interference decreased POMC promoter activity, demonstrating the importance of SGK1 for basal POMC signaling. In summary, SGK1 is strongly stimulated by glucocorticoids in pituitary corticotrophs; however, its effects on POMC transcription are antagonistic to the classical inhibitory glucocorticoid action, suggesting a cell-regulated counterregulatory mechanism to potentially detrimental glucocorticoid effects.

  12. Rodent Models for Metabolic Syndrome Research

    Directory of Open Access Journals (Sweden)

    Sunil K. Panchal

    2011-01-01

    Full Text Available Rodents are widely used to mimic human diseases to improve understanding of the causes and progression of disease symptoms and to test potential therapeutic interventions. Chronic diseases such as obesity, diabetes and hypertension, together known as the metabolic syndrome, are causing increasing morbidity and mortality. To control these diseases, research in rodent models that closely mimic the changes in humans is essential. This review will examine the adequacy of the many rodent models of metabolic syndrome to mimic the causes and progression of the disease in humans. The primary criterion will be whether a rodent model initiates all of the signs, especially obesity, diabetes, hypertension and dysfunction of the heart, blood vessels, liver and kidney, primarily by diet since these are the diet-induced signs in humans with metabolic syndrome. We conclude that the model that comes closest to fulfilling this criterion is the high carbohydrate, high fat-fed male rodent.

  13. Effect of Glucocorticoids on Ultrastructure of Myocardial Muscle in the Course of Experimentally Induced Acute Myocardial Ischemia

    Directory of Open Access Journals (Sweden)

    Piotr Kuropka

    2017-01-01

    Full Text Available The search for effective methods of myocardial cytoprotection against ischemia is the most significant issue in modern cardiology and cardiac surgery. Glucocorticoids are deemed very strong modulators of inflammatory response and thus can potentially protect heart muscle from postreperfusion injury and myocardial ischemia during cardiac surgery. Ultrastructural examination of the left ventricle heart samples revealed that the intravenous application of dexamethasone and hydrocortisone proved to exert cytoprotective effect on cardiomyocytes during experimentally induced acute ischemia in rats.

  14. Deposition of intranasal glucocorticoids--preliminary study.

    Science.gov (United States)

    Rapiejko, Piotr; Sosnowski, Tomasz R; Sova, Jarosław; Jurkiewicz, Dariusz

    2015-01-01

    Intranasal glucocorticoids are the treatment of choice in the therapy of rhinitis. The differences in efficiency of particular medications proven by therapeutic index may result from differences in composition of particular formulations as well as from diverse deposition in nasal cavities. Intranasal formulations of glucocorticoids differ in volume of a single dose in addition to variety in density, viscosity and dispenser nozzle structure. The aim of this report was to analyze the deposition of most often used intranasal glucocorticoids in the nasal cavity and assessment of the usefulness of a nose model from a 3D printer reflecting anatomical features of a concrete patient. Three newest and most often used in Poland intranasal glucocorticoids were chosen to analysis; mometasone furoate (MF), fluticasone propionate (FP) and fluticasone furoate (FF). Droplet size distribution obtained from the tested formulations was determined by use of a laser aerosol spectrometer Spraytec (Malvern Instruments, UK). The model of the nasal cavity was obtained using a 3D printer. The printout was based upon a tridimensional reconstruction of nasal cavity created on the basis of digital processing of computed tomography of paranasal sinuses. The deposition of examined medications was established by a method of visualization combined with image analysis using commercial substance which colored itself intensively under the influence of water being the dominant ingredient of all tested preparations. On the basis of obtained results regions of dominating deposition of droplets of intranasal medication on the wall and septum of the nasal cavity were compared. Droplet size of aerosol of tested intranasal medications typically lies within the range of 25-150 µm. All tested medications deposited mainly on the anterior part of inferior turbinate. FP preparation deposited also on the anterior part of the middle nasal turbinate, marginally embracing a fragment of the central part of this

  15. Lack of renal 11 beta-hydroxysteroid dehydrogenase type 2 at birth, a targeted temporal window for neonatal glucocorticoid action in human and mice.

    Science.gov (United States)

    Martinerie, Laetitia; Pussard, Eric; Meduri, Geri; Delezoide, Anne-Lise; Boileau, Pascal; Lombès, Marc

    2012-01-01

    Glucocorticoid hormones play a major role in fetal organ maturation. Yet, excessive glucocorticoid exposure in utero can result in a variety of detrimental effects, such as growth retardation and increased susceptibility to the development of hypertension. To protect the fetus, maternal glucocorticoids are metabolized into inactive compounds by placental 11beta-hydroxysteroid dehydrogenase type2 (11βHSD2). This enzyme is also expressed in the kidney, where it prevents illicit occupation of the mineralocorticoid receptor by glucocorticoids. We investigated the role of renal 11βHSD2 in the control of neonatal glucocorticoid metabolism in the human and mouse. Cortisol (F) and cortisone (E) concentrations were measured in maternal plasma, umbilical cord blood and human newborn urine using HPLC. 11βHSD2 activity was indirectly assessed by comparing the F/E ratio between maternal and neonatal plasma (placental activity) and between plasma and urine in newborns (renal activity). Direct measurement of renal 11βHSD2 activity was subsequently evaluated in mice at various developmental stages. Renal 11βHSD2 mRNA and protein expression were analyzed by quantitative RT-PCR and immunohistochemistry during the perinatal period in both species. We demonstrate that, at variance with placental 11βHSD2 activity, renal 11βHSD2 activity is weak in newborn human and mouse and correlates with low renal mRNA levels and absence of detectable 11βHSD2 protein. We provide evidence for a weak or absent expression of neonatal renal 11βHSD2 that is conserved among species. This temporal and tissue-specific 11βHSD2 expression could represent a physiological window for glucocorticoid action yet may constitute an important predictive factor for adverse outcomes of glucocorticoid excess through fetal programming.

  16. Lack of renal 11 beta-hydroxysteroid dehydrogenase type 2 at birth, a targeted temporal window for neonatal glucocorticoid action in human and mice.

    Directory of Open Access Journals (Sweden)

    Laetitia Martinerie

    Full Text Available BACKGROUND: Glucocorticoid hormones play a major role in fetal organ maturation. Yet, excessive glucocorticoid exposure in utero can result in a variety of detrimental effects, such as growth retardation and increased susceptibility to the development of hypertension. To protect the fetus, maternal glucocorticoids are metabolized into inactive compounds by placental 11beta-hydroxysteroid dehydrogenase type2 (11βHSD2. This enzyme is also expressed in the kidney, where it prevents illicit occupation of the mineralocorticoid receptor by glucocorticoids. We investigated the role of renal 11βHSD2 in the control of neonatal glucocorticoid metabolism in the human and mouse. METHODS: Cortisol (F and cortisone (E concentrations were measured in maternal plasma, umbilical cord blood and human newborn urine using HPLC. 11βHSD2 activity was indirectly assessed by comparing the F/E ratio between maternal and neonatal plasma (placental activity and between plasma and urine in newborns (renal activity. Direct measurement of renal 11βHSD2 activity was subsequently evaluated in mice at various developmental stages. Renal 11βHSD2 mRNA and protein expression were analyzed by quantitative RT-PCR and immunohistochemistry during the perinatal period in both species. RESULTS: We demonstrate that, at variance with placental 11βHSD2 activity, renal 11βHSD2 activity is weak in newborn human and mouse and correlates with low renal mRNA levels and absence of detectable 11βHSD2 protein. CONCLUSIONS: We provide evidence for a weak or absent expression of neonatal renal 11βHSD2 that is conserved among species. This temporal and tissue-specific 11βHSD2 expression could represent a physiological window for glucocorticoid action yet may constitute an important predictive factor for adverse outcomes of glucocorticoid excess through fetal programming.

  17. [Factors related to household rodent abundance in rodent-borne disease foci in western Yunnan].

    Science.gov (United States)

    Wang, Xiufang; Yin, Jiaxiang; Yang, Guangcan; Liu, Zhengxiang; Du, Chunhong; Shi, Liyuan; Su, Liqiong

    2015-02-01

    To analyze the factors related to the household abundance of rodents in rodent-borne disease foci in the western part of Yunnan province. From July 2011 to October 2012, 800 households (20 households in 1 village) were randomly selected in 40 natural villages of 10 counties in western Yunnan where rodent borne disease was endemic to conduct a study on relationship between rodent abundance and environmental factors. Five cages were placed in each household for 3 consecutive nights to capture rodents. The rodent species were identified based on their morphological characteristics. The data on potential factors related to rodent abundance were collected through questionnaires and field observation. A dataset was established by using EpiData software and the analysis was performed with hurdle regression model under R software. A total of 421 rodents were captured in 800 households, belonging to 9 species, 6 genera, 2 families, 2 orders. Rattus tanezumi was the predominant species (66.03%). The final hurdle regression model showed that the probability of capturing rodents in the households where family member had high education level and the garbage was placed outside declined by 50%-68% ;The probability of capturing rodents in the households of Dai and Yi ethnic groups increased by 2.16-2.87 times;The probability of capturing rodents in the households where rodents were observed or vegetables grown near houses increased by 1.54-1.59 times;In the households where many rodents were believed to exist, the probability of capturing rodents and the number of rodents captured increased by 1.59 and 1.84 times respectively. The number of rodents captured in the houses with cement or tile floor increased by 3.62 times. The household abundance of rodents in the area in western Yunnan, where the rodent-borne disease survey was conducted, seemed to be closely related to the social economy status, human intervention and ecological environment. To control the abundance of rodents

  18. Glucocorticoid programming of the mesopontine cholinergic system

    Directory of Open Access Journals (Sweden)

    Sónia eBorges

    2013-12-01

    Full Text Available Stress perception, response, adaptation and coping strategies are individually distinct, and the sequel of stress and/or glucocorticoids is also distinct between subjects. In the last years, it has become clear that early life stress is a powerful modulator of neuroendocrine stress-responsive circuits, programming intrinsic susceptibility to stress, and potentiating the appearance of stress-related disorders such as depression, anxiety and addiction. Herein we were interested in understanding how early life experiences reset the normal processing of negative stimuli, leading to emotional dysfunction. Animals prenatally exposed to glucocorticoids (iuGC present hyperanxiety, increased fear behaviour and hyper-reactivity to negative stimuli. In parallel, we found a remarkable increase in the number of aversive 22kHz ultrasonic vocalizations in response to an aversive cue. Considering the suggested role of the mesopontine tegmentum cholinergic pathway, arising from the laterodorsal tegmental nucleus (LDT and pedunculopontine tegmental nucleus (PPT, in the initiation of 22kHz vocalizations and hypothetically in the control of emotional arousal and tone, we decided to evaluate the condition of this circuit in iuGC animals. Notably, in a basal situation, iuGC animals present increased choline acetyltransferase (ChAT expression in the LDT and PPT, but not in other cholinergic nuclei, namely in the nucleus basalis of Meynert. In addition, and in accordance with the amplified response to an adverse stimulus of iuGC animals, we found marked changes in the cholinergic activation pattern of LDT and PPT regions. Altogether, our results suggest a specific cholinergic pathway programing by prenatal GC, and hint that this may be of relevance in setting individuals stress vulnerability threshold.

  19. Glucocorticoids in nephrology I: pharmacology and side effects

    Directory of Open Access Journals (Sweden)

    Jernej Pajek

    2015-05-01

    Full Text Available Glucocorticoids have been used in clinical medicine since 1940s. Despite the time-long use they are still a subject of active ongoing research. We describe the mode of action, pharmacology and side effects to enable proper prescription of these drugs. Glucocorticoids exert genomic and non-genomic effects, the latter become important at higher doses. The nomenclature of dosage ranges and the principles of dosage adjustments are given. Glucocortioid use is associated with frequent and important side effects in numerous organ systems. Prophylactic treatments for osteoporosis and infections are described. The suppression of hypothalamic-hypophyseal hormonal axis determines the need for gradual glucocorticoid withdrawal and supplementation after discontinuation. Finally, glucocorticoid withdrawal syndrome is described.

  20. Effects of suspension on tissue levels of glucocorticoid receptors

    Science.gov (United States)

    Steffen, J. M.

    1984-01-01

    Differential muscle responses can be simulated by hypokinetic/hypodynamic (H/H) suspension of rats with complete unloading of the hindlimb muscles. Since mechanism(s) underlying these atrophic effects were not clearly elucidated, experiments were initiated to investigate a possible role for glucocorticoids in the physiological and biochemical responses to H/H. The principal objective was to assess the potential for alterations in peripheral responsiveness to glucocorticoids in response to H/H. Studies have initially focused on the determination of tissue levels of glucocorticoid receptors as one index of hormonal sensitivity at the cellular level. Four hindlimb muscles (soleus, gastrocnemius, plantaris and EDL), previously demonstrated to exhibit differential responses to H/H, were investigated. Receptor levels in other glucocorticoid sensitive tissues (heart, liver, and kidney) were determined. Male rats (180-200g) were suspended for 7 or 14 days, sacrificed by cervical dislocation, and the tissues excised.

  1. Rapid immunosuppressive effects of glucocorticoids mediated through Lck and Fyn

    NARCIS (Netherlands)

    Lowenberg, M; Tuynman, J; Bilderbeek, J; Gaber, T; Buttgereit, F; van Deventer, S; Peppelenbosch, M; Hommes, D

    2005-01-01

    Glucocorticoids (GCs) are effective immunosuppressive agents and mediate well-defined transcriptional effects via GC receptors. There is increasing evidence that GCs also initiate rapid nongenomic signaling events. Using activated human CD4(+) lymphocytes and a peptide array containing 1176

  2. Glucocorticoids induce autophagy in rat bone marrow mesenchymal stem cells

    DEFF Research Database (Denmark)

    Wang, L.; Fan, J.; Lin, Y. S.

    2015-01-01

    and their responses to diverse stimuli, however, the role of autophagy in glucocorticoidinduced damage to bone marrow mesenchymal stem cells (BMSCs) remains unclear. The current study confirmed that glucocorticoid administration impaired the proliferation of BMSCs. Transmission electron microscopy...

  3. Comparison of two methods for glucocorticoid evaluation in maned wolves

    Directory of Open Access Journals (Sweden)

    Angélica S Vasconcellos

    2011-12-01

    Full Text Available Analysis of faecal glucocorticoid metabolites provides a powerful noninvasive tool for monitoring adrenocortical activity in wild animals. However, differences regarding the metabolism and excretion of these substances make a validation for each species and sex investigated obligatory. Although maned wolves (Chrysocyon brachyurus are the biggest canids in South America, their behaviour and physiology are poorly known and they are at risk in the wild. Two methods for measuring glucocorticoid metabolites in maned wolves were validated: a radio- and an enzyme immunoassay. An ACTH challenge was used to demonstrate that changes in adrenal function are reflected in faecal glucocorticoid metabolites. Our results suggest that both methods enable a reliable assessment of stress hormones in maned wolves avoiding short-term rises in glucocorticoid concentrations due to handling and restraint. These methods can be used as a valuable tool in studies of stress and conservation in this wild species.

  4. The emerging importance of ultradian glucocorticoid rhythms within metabolic pathology.

    Science.gov (United States)

    Flynn, Benjamin P; Conway-Campbell, Becky L; Lightman, Stafford L

    2018-04-04

    Glucocorticoid (GC) hormones play significant roles within homeostasis and the chrono-dynamics of their regulatory role has become increasingly recognised within dysregulated GC pathology, particularly with metabolic phenotypes. Within this article, we will discuss the relevance of the ultradian homeostatic rhythm, how its dysregulation effects glucocorticoid receptor and RNA polymeraseII recruitment and may play a significant role within aberrant metabolic action. Copyright © 2018 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

  5. The relevance of glucocorticoid receptor in early stress

    OpenAIRE

    Rodríguez Fernández, Jorge Mario; Hospital Universitario San Ignacio; García Acero, Mary; Hospital Universitario San Ignacio

    2010-01-01

    Previous studies have shown how Hypothalamic-Pituitary-adrenal Axis dysfunction is related to early life stress; several works show that Hypothalamic-Pituitary-adrenal Axishyperactivity increases production of ACTH and glucocorticoids, indicating a pathophysiological key factor in stress related diseases like depression.This review will discuss results of some epigenetical studies linking early life stress, decreased production of the glucocorticoid receptor and Hypothalamic-Pituitary-adrenal...

  6. Exogenous glucocorticoids and adverse cerebral effects in children

    DEFF Research Database (Denmark)

    Damsted, Sara K.; Born, A P; Paulson, Olaf B

    2011-01-01

    reduces neurogenesis and cerebral volume, impairs memory and increases the incidence of cerebral palsy. Cerebral effects of glucocorticoids in later childhood have been less thoroughly studied, but apparent brain atrophy, reduced size of limbic structures and neuropsychiatric symptoms have been reported....... Glucocortioids affect several cellular structures and functions, which may explain the observed adverse effects. Glucocorticoids can impair neuronal glucose uptake, decrease excitability, cause atrophy of dendrites, compromise development of myelin-producing oligodendrocytes and disturb important cellular...

  7. Rodents: food or pests in Neolithic Orkney

    Science.gov (United States)

    Romaniuk, Andrzej A.; Shepherd, Alexandra N.; Clarke, David V.; Sheridan, Alison J.; Fraser, Sheena; Bartosiewicz, László

    2016-01-01

    Rodents have important effects on contemporary human societies, sometimes providing a source of food but more often as agricultural pests, or as vectors and reservoirs of disease. Skeletal remains of rodents are commonly found in archaeological assemblages from around the world, highlighting their potential importance to ancient human populations. However, there are few studies of the interactions between people and rodents at such sites and most of these are confined to locations where rodents have formed a part of the recent diet. Here we compare the accumulation pattern of rodent remains from four locations within and adjacent to the renowned Neolithic site of Skara Brae, Orkney, showing that those within the settlement itself were the result of deliberate human activity. The accumulation and nature of burnt bones, incorporated over an extended period within deposits of household waste, indicate that rodents were used as a nutritional resource and may have been the subject of early pest control. We, therefore, provide the first evidence for the exploitation or control of rodents by the Neolithic inhabitants of Europe. PMID:27853568

  8. Glucocorticoid-Induced Avascular Bone Necrosis: Diagnosis and Management

    Science.gov (United States)

    Chan, KL; Mok, CC

    2012-01-01

    Glucocorticoid use is one of the most important causes of avascular bone necrosis (AVN). The pathogenesis of glucocorticoid-induced AVN is not fully understood but postulated mechanisms include fat hypertrophy, fat emboli and intravascular coagulation that cause impedance of blood supply to the bones. Data regarding the relationship between AVN and dosage, route of administration and treatment duration of glucocorticoids are conflicting, with some studies demonstrating the cumulative dose of glucocorticoid being the most important determining factor. Early recognition of this complication is essential as the prognosis is affected by the stage of the disease. Currently, there is no consensus on whether universal screening of asymptomatic AVN should be performed for long-term glucocorticoid users. A high index of suspicion should be exhibited for bone and joint pain at typical sites. Magnetic resonance imaging (MRI) or bone scintigraphy is more sensitive than plain radiograph for diagnosing early-stage AVN. Conservative management of AVN includes rest and reduction of weight bearing. Minimization of glucocorticoid dose or a complete withdrawal of the drug should be considered if the underlying conditions allow. The efficacy of bisphosphonates in reducing the rate of collapse of femoral head in AVN is controversial. Surgical therapy of AVN includes core decompression, osteotomy, bone grafting and joint replacement. Recent advances in the treatment of AVN include the use of tantalum rod and the development of more wear resistant bearing surface in hip arthroplasty. PMID:23115605

  9. Antenatal glucocorticoids: where are we after forty years?

    Science.gov (United States)

    McKinlay, C J D; Dalziel, S R; Harding, J E

    2015-04-01

    Since their introduction more than forty years ago, antenatal glucocorticoids have become a cornerstone in the management of preterm birth and have been responsible for substantial reductions in neonatal mortality and morbidity. Clinical trials conducted over the past decade have shown that these benefits may be increased further through administration of repeat doses of antenatal glucocorticoids in women at ongoing risk of preterm and in those undergoing elective cesarean at term. At the same time, a growing body of experimental animal evidence and observational data in humans has linked fetal overexposure to maternal glucocorticoids with increased risk of cardiovascular, metabolic and other disorders in later life. Despite these concerns, and somewhat surprisingly, there has been little evidence to date from randomized trials of longer-term harm from clinical doses of synthetic glucocorticoids. However, with wider clinical application of antenatal glucocorticoid therapy there has been greater need to consider the potential for later adverse effects. This paper reviews current evidence for the short- and long-term health effects of antenatal glucocorticoids and discusses the apparent discrepancy between data from randomized clinical trials and other studies.

  10. Molecular mechanisms of glucocorticoid action in mast cells.

    Science.gov (United States)

    Oppong, Emmanuel; Flink, Nesrin; Cato, Andrew C B

    2013-11-05

    Glucocorticoids are compounds that have successfully been used over the years in the treatment of inflammatory disorders. They are known to exhibit their effects through the glucocorticoid receptor (GR) that acts to downregulate the action of proinflammatory transcription factors such as AP-1 and NF-κB. The GR also exerts anti-inflammatory effects through activation of distinct genes. In addition to their anti-inflammatory actions, glucocorticoids are also potent antiallergic compounds that are widely used in conditions such as asthma and anaphylaxis. Nevertheless the mechanism of action of this hormone in these disorders is not known. In this article, we have reviewed reports on the effects of glucocorticoids in mast cells, one of the important immune cells in allergy. Building on the knowledge of the molecular action of glucocorticoids and the GR in the treatment of inflammation in other cell types, we have made suggestions as to the likely mechanisms of action of glucocorticoids in mast cells. We have further identified some important questions and research directions that need to be addressed in future studies to improve the treatment of allergic disorders. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  11. Mechanisms of Brain Glucocorticoid Resistance in Stress-Induced Psychopathologies.

    Science.gov (United States)

    Merkulov, V M; Merkulova, T I; Bondar, N P

    2017-03-01

    Exposure to stress activates the hypothalamic-pituitary-adrenal axis and leads to increased levels of glucocorticoid (GC) hormones. Prolonged elevation of GC levels causes neuronal dysfunction, decreases the density of synapses, and impairs neuronal plasticity. Decreased sensitivity to glucocorticoids (glucocorticoid resistance) that develops as a result of chronic stress is one of the characteristic features of stress-induced psychopathologies. In this article, we reviewed the published data on proposed molecular mechanisms that contribute to the development of glucocorticoid resistance in brain, including changes in the expression of the glucocorticoid receptor (GR) gene, biosynthesis of GR isoforms, and GR posttranslational modifications. We also present data on alterations in the expression of the FKBP5 gene encoding the main component of cell ultra-short negative feedback loop of GC signaling regulation. Recent discoveries on stress- and GR-induced changes in epigenetic modification patterns as well as normalizing action of antidepressants are discussed. GR and FKBP5 gene polymorphisms associated with stress-induced psychopathologies are described, and their role in glucocorticoid resistance is discussed.

  12. Endogenous Glucocorticoid Deficiency in Psoriasis Promotes Inflammation and Abnormal Differentiation.

    Science.gov (United States)

    Sarkar, Mrinal K; Kaplan, Nihal; Tsoi, Lam C; Xing, Xianying; Liang, Yun; Swindell, William R; Hoover, Paul; Aravind, Maya; Baida, Gleb; Clark, Matthew; Voorhees, John J; Nair, Rajan P; Elder, James T; Budunova, Irina; Getsios, Spiro; Gudjonsson, Johann E

    2017-07-01

    The factors involved in maintaining a localized inflammatory state in psoriatic skin remain poorly understood. Here, we demonstrate through metabolomic and transcriptomic profiling marked suppression of glucocorticoid biosynthesis in the epidermis of psoriatic skin leading to localized deficiency of cortisol. Utilizing a 3D human epidermis model, we demonstrate that glucocorticoid biosynthesis is suppressed by proinflammatory cytokines and that glucocorticoid deficiency promotes inflammatory responses in keratinocytes. Finally, we show in vitro and in vivo that treatment with topical glucocorticoids leads to rapid restoration of glucocorticoid biosynthesis gene expression coincident with normalization of epidermal differentiation and suppression of inflammatory responses. Taken together, our data suggest that localized glucocorticoid deficiency in psoriatic skin interferes with epidermal differentiation and promotes a sustained and localized inflammatory response. This may shed new light on the mechanism of action of topical steroids, and demonstrates the critical role of endogenous steroid in maintaining both inflammatory and differentiation homeostasis in the epidermis. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  13. Glucocorticoid inhibition of cellular proliferation in rat hepatoma cell lines

    International Nuclear Information System (INIS)

    Cook, P.W.

    1987-01-01

    Glucocorticoids were shown to inhibit the growth rate of Fu5 rat hepatoma cells cultured in the presence or absence of serum and thus, induced a more stringent dependence on serum for growth in this cell line. Fu5 cells, made quiescent at low cell density by continuous exposure to glucocorticoid in the absence of serum, were induced with serum and insulin, which subsequently caused a rapid reinitiation of cellular proliferation. Analysis of total RNA isolated from hormone treated Fu5 cells undergoing serum/insulin induction of DNA synthesis revealed a sequential expression of cellular proto-oncogene products in the absence of any immediate changes in intracellular Ca ++ levels. Introduction of functional glucocorticoid receptor genes into both classes of dexamethasone resistant variants restored glucocorticoid responsiveness and suppression of cell growth. The BDS1 rat hepatoma cell line, an Fu5 derived subclone hypersensitive to the antiprofliferation effects of glucocorticoid, was observed to externalize a glucocorticoid suppressible mitogen (GSM) activity capable of mimicking EGF and insulin induced stimulation of [ 3 H]thymidine incorporation into serum starved, competant Balb/c 3T3 cells

  14. [Glucocorticoid and Bone. The effect of glucocorticoid and PTH in osteoblast apoptosis and differentiation via interleukin 11 expression].

    Science.gov (United States)

    Endo, Itsuro

    2014-09-01

    Intermittent PTH administration stimulates bone formation and counteracts the inhibition of bone formation by glucocorticoid excess. We have previously demonstrated that PTH enhances interleukin (IL) -11 gene transcription by a rapid induction of delta-fosB expression and Smad1/5 phosphorylation. On the other hand, glucocorticoid can suppress osteoblast differentiation and enhance apoptosis of osteoblast cells via down-regulation of IL-11 expression. PTH could reverse glucocorticoid-induced these damage of osteoblast via stimulation of IL-11 expression. Our data also suggested that IL-11 mediates stimulatory and inhibitory signals of osteoblast differentiation by affecting Wnt signaling. These data demonstrates that PTH and glucocorticoid may regulate osteoblast differentiation and apoptosis via their effect on IL-11 expression.

  15. Development of glucocorticoid receptor regulation in the rat forebrain: Implications for adverse effects of glucocorticoids in preterm infants

    Science.gov (United States)

    Glucocorticoids are the consensus treatment to avoid respiratory distress in preterm infants but there is accumulating evidence that these agents evoke long-term neurobehavioral deficits. Earlier, we showed that the developing rat forebrain is far more sensitive to glucocorticoi...

  16. Glucocorticoid stress responses of lions in relationship to group composition, human land use, and proximity to people.

    Science.gov (United States)

    Creel, Scott; Christianson, David; Schuette, Paul

    2013-01-01

    Large carnivore populations are in global decline, and conflicts between large carnivores and humans or their livestock contribute to low tolerance of large carnivores outside of protected areas. African lions (Panthera leo) are a conflict-prone species, and their continental range has declined by 75% in the face of human pressures. Nonetheless, large carnivore populations persist (or even grow) in some areas that are occupied by humans. Lions attain locally high density in the Olkiramatian and Shompole Group Ranches of Kenya's South Rift region, despite residence by pastoralist Maasai people and their sheep, goats, and cattle. We have previously found that these lions respond to seasonal movements of people by moving away from occupied settlements, shifting into denser habitats when people are nearby, and moving into a protected conservation area when people move into the adjacent buffer zone. Here, we examined lion stress responses to anthropogenic activities, using enzyme-linked immunoassay to measure the concentration of faecal glucocorticoid metabolites in 136 samples collected from five lion groups over 2 years. Faecal glucocorticoid metabolite concentrations were significantly lower for lions in the conservation area than for lions in the human-settled buffer zone, and decreased significantly with increasing distance to the nearest occupied human settlement. Faecal glucocorticoid metabolite concentrations were not detectably related to fine-scaled variation in prey or livestock density, and surprisingly, faecal glucocorticoid metabolite concentrations were higher in the wet season, when regional prey abundance was high. Lions coexist with people and livestock on this landscape by adjusting their movements, but they nonetheless mount an appreciable stress response when conditions do not allow them to maintain adequate separation. Thus, physiological data confirm inferences from prior data on lion movements and habitat use, showing that access to undisturbed

  17. Stress-induced enhancement of mouse amygdalar synaptic plasticity depends on glucocorticoid and ß-adrenergic activity.

    Directory of Open Access Journals (Sweden)

    Ratna Angela Sarabdjitsingh

    Full Text Available BACKGROUND: Glucocorticoid hormones, in interaction with noradrenaline, enable the consolidation of emotionally arousing and stressful experiences in rodents and humans. Such interaction is thought to occur at least partly in the basolateral nucleus of the amygdala (BLA which is crucially involved in emotional memory formation. Extensive evidence points to long-term synaptic potentiation (LTP as a mechanism contributing to memory formation. Here we determined in adolescent C57/Bl6 mice the effects of stress on LTP in the LA-BLA pathway and the specific roles of corticosteroid and β-adrenergic receptor activation in this process. PRINCIPAL FINDINGS: Exposure to 20 min of restraint stress (compared to control treatment prior to slice preparation enhanced subsequent LTP induction in vitro, without affecting baseline fEPSP responses. The role of glucocorticoid receptors, mineralocorticoid receptors and β2-adrenoceptors in the effects of stress was studied by treating mice with the antagonists mifepristone, spironolactone or propranolol respectively (or the corresponding vehicles prior to stress or control treatment. In undisturbed controls, mifepristone and propranolol administration in vivo did not influence LTP induced in vitro. By contrast, spironolactone caused a gradually attenuating form of LTP, both in unstressed and stressed mice. Mifepristone treatment prior to stress strongly reduced the ability to induce LTP in vitro. Propranolol normalized the stress-induced enhancement of LTP to control levels during the first 10 min after high frequency stimulation, after which synaptic responses further declined. CONCLUSIONS: Acute stress changes BLA electrical properties such that subsequent LTP induction is facilitated. Both β-adrenergic and glucocorticoid receptors are involved in the development of these changes. Mineralocorticoid receptors are important for the maintenance of LTP in the BLA, irrespective of stress-induced changes in the

  18. Glucocorticoid effects on the programming of AT1b angiotensin receptor gene methylation and expression in the rat.

    Directory of Open Access Journals (Sweden)

    Irina Bogdarina

    2010-02-01

    Full Text Available Adverse events in pregnancy may 'programme' offspring for the later development of cardiovascular disease and hypertension. Previously, using a rodent model of programmed hypertension we have demonstrated the role of the renin-angiotensin system in this process. More recently we showed that a maternal low protein diet resulted in undermethylation of the At1b angiotensin receptor promoter and the early overexpression of this gene in the adrenal of offspring. Here, we investigate the hypothesis that maternal glucocorticoid modulates this effect on fetal DNA methylation and gene expression. We investigated whether treatment of rat dams with the 11beta-hydroxylase inhibitor metyrapone, could prevent the epigenetic and gene expression changes we observed. Offspring of mothers subjected to a low protein diet in pregnancy showed reduced adrenal Agtr1b methylation and increased adrenal gene expression as we observed previously. Treatment of mothers with metyrapone for the first 14 days of pregnancy reversed these changes and prevented the appearance of hypertension in the offspring at 4 weeks of age. As a control for non-specific effects of programmed hypertension we studied offspring of mothers treated with dexamethasone from day 15 of pregnancy and showed that, whilst they had raised blood pressure, they failed to show any evidence of Agtr1b methylation or increase in gene expression. We conclude that maternal glucocorticoid in early pregnancy may induce changes in methylation and expression of the Agtr1b gene as these are clearly reversed by an 11 beta-hydroxylase inhibitor. However in later pregnancy a converse effect with dexamethasone could not be demonstrated and this may reflect either an alternative mechanism of this glucocorticoid or a stage-specific influence.

  19. Tactile learning in rodents: Neurobiology and neuropharmacology.

    Science.gov (United States)

    Roohbakhsh, Ali; Shamsizadeh, Ali; Arababadi, Mohammad Kazemi; Ayoobi, Fateme; Fatemi, Iman; Allahtavakoli, Mohammad; Mohammad-Zadeh, Mohammad

    2016-02-15

    Animal models of learning and memory have been the subject of considerable research. Rodents such as mice and rats are nocturnal animals with poor vision, and their survival depends on their sense of touch. Recent reports have shown that whisker somatosensation is the main channel through which rodents collect and process environmental information. This review describes tactile learning in rodents from a neurobiological and neuropharmacological perspective, and how this is involved in memory-related processes. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Systematic review of the clinical effect of glucocorticoids on nonhematologic malignancy

    Directory of Open Access Journals (Sweden)

    Keith Bruce D

    2008-03-01

    Full Text Available Abstract Background Glucocorticoids are often used in the treatment of nonhematologic malignancy. This review summarizes the clinical evidence of the effect of glucocorticoid therapy on nonhematologic malignancy. Methods A systematic review of clinical studies of glucocorticoid therapy in patients with nonhematologic malignancy was undertaken. Only studies having endpoints of tumor response or tumor control or survival were included. PubMed, EMBASE, the Cochrane Register/Databases, conference proceedings (ASCO, AACR, ASTRO/ASTR, ESMO, ECCO and other resources were used. Data was extracted using a standard form. There was quality assessment of each study. There was a narrative synthesis of information, with presentation of results in tables. Where appropriate, meta-analyses were performed using data from published reports and a fixed effect model. Results Fifty four randomized controlled trials (RCTs, one meta-analysis, four phase l/ll trials and four case series met the eligibility criteria. Clinical trials of glucocorticoid monotherapy in breast and prostate cancer showed modest response rates. In advanced breast cancer meta-analyses, the addition of glucocorticoids to either chemotherapy or other endocrine therapy resulted in increased response rate, but not increased survival. In GI cancer, there was one RCT each of glucocorticoids vs. supportive care and chemotherapy +/- glucocorticoids; glucocorticoid effect was neutral. The only RCT found of chemotherapy +/- glucocorticoids, in which the glucocorticoid arm did worse, was in lung cancer. In glucocorticoid monotherapy, meta-analysis found that continuous high dose glucocorticoids had a detrimental effect on survival. The only other evidence, for a detrimental effect of glucocorticoid monotherapy, was in one of the two trials in lung cancer. Conclusion Glucocorticoid monotherapy has some benefit in breast and prostate cancer. In advanced breast cancer, the addition of glucocorticoids to other

  1. Plasma-Glucocorticoids and ACTH Levels During Different Periods of Activity in the European Beaver (Castor fiber L.).

    Science.gov (United States)

    Czerwińska, Joanna; Chojnowska, Katarzyna; Kamiński, Tadeusz; Bogacka, Iwona; Panasiewicz, Grzegorz; Smolińska, Nina; Kamińska, Barbara

    2015-01-01

    Glucocorticoids (GCs) and adrenocorticotropic hormone (ACTH) are major components of the classic endocrine stress response. Free-living vertebrates are characterized by circannual changes in the baseline and/or stress-induced secretion of GCs and ACTH. In mammalian species, GC and ACTH levels vary seasonally but there is no consensus to the season in which animals have elevated GC and ACTH levels. The aim of our study was to determine, for the first time, the type and amount of glucocorticoids produced in free-living beaver (Castor fiber L.)--the largest rodent in Eurasia, and to find out whether stress-induced plasma GC and ACTH levels show seasonal variations. Blood samples were obtained from animals under general anesthesia in April (pregnancy in females), July (offspring rearing) and November (preparing for the winter). The adrenals of beavers produce both cortisol and corticosterone, and plasma cortisol levels were higher than corticosterone. In the current experiment, plasma cortisol concentrations in beavers were affected by the season. The highest stress-associated cortisol levels were noted in males in July during offspring rearing. Corticosterone and ACTH concentrations in beavers remained generally constant, regardless of the season and sex. In conclusion, seasonal changes were observed only in relation to stress-induced plasma cortisol levels in the beaver.

  2. Levels of central oxytocin and glucocorticoid receptor and serum adrenocorticotropic hormone and corticosterone in mandarin voles with different levels of sociability.

    Science.gov (United States)

    Qiao, Xufeng; Yan, Yating; Tai, Fadao; Wu, Ruiyong; Hao, Ping; Fang, Qianqian; Zhang, Shuwei

    2014-11-01

    Sociability is the prerequisite to social living. Oxytocin and the hypothalamo-pituitary-adrenocortical axis mediate various social behaviors across different social contexts in different rodents. We hypothesized that they also mediate levels of non-reproductive social behavior. Here we explored naturally occurring variation in sociability through a social preference test and compared central oxytocin, glucocorticoid receptors, serum adrenocorticotropic hormone and corticosterone in mandarin voles with different levels of sociability. We found that low-social voles showed higher levels of anxiety-like behavior in open field tests, and had more serum adrenocorticotropic hormone and corticosterone than high-social voles. High-social individuals had more glucocorticoid receptor positive neurons in the hippocampus and more oxytocin positive neurons in the paraventricular nuclei and supraoptic nuclei of the hypothalamus than low-social individuals. Within the same level of sociability, females had more oxytocin positive neurons in the paraventricular nuclei and supraoptic nuclei of the hypothalamus than males. These results indicate that naturally occurring social preferences are associated with higher levels of central oxytocin and hippocampus glucocorticoid receptor and lower levels of anxiety and serum adrenocorticotropic hormone and corticosterone. Copyright © 2014 Elsevier B.V. All rights reserved.

  3. A structural explanation of the effects of dissociated glucocorticoids on glucocorticoid receptor transactivation.

    Science.gov (United States)

    Dezitter, Xavier; Fagart, Jérôme; Taront, Solenne; Fay, Michel; Masselot, Bernadette; Hétuin, Dominique; Formstecher, Pierre; Rafestin-Oblin, Marie-Edith; Idziorek, Thierry

    2014-02-01

    There is a therapeutic need for glucocorticoid receptor (GR) ligands that distinguish between the transrepression and transactivation activity of the GR, the later thought to be responsible for side effects. These ligands are known as "dissociated glucocorticoids" (dGCs). The first published dGCs, RU24782 (9α-fluoro-11β-hydroxy-16α-methylpregna-21-thiomethyl-1,4-diene-3,20-dione) and RU24858 (9α-fluoro-11β-hydroxy-16α-methylpregna-21-cyanide-1,4-diene-3,20-dione), do not have the 17α-hydroxyl group that characterizes dexamethasone (Dex; 9α-fluoro-11β,17α,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione), and they differ from one another by having C21-thiomethyl and C21-cyanide moieties, respectively. Our aim was therefore to establish the structural basis of their activity. Both RU24782 and RU24858 induced a transactivation activity highly dependent on the GR expression level but always lower than dexamethasone. They also display less ability than dexamethasone to trigger steroid receptor coactivator 1 (SRC-1) recruitment and histone H3 acetylation. Docking studies, validated by mutagenesis experiments, revealed that dGCs are not anchored by Gln642, in contrast to Dex, which is hydrogen bonded to this residue via its 17α-hydroxyl group. This contact is essential for SRC-1 recruitment and subsequent dexamethasone-induced GR transactivation, but not transrepression. The ability of dGCs to make contacts with Ile747, for both RU24858 and RU24782 and with Asn564 for RU24858 are not strong enough to maintain GR in a conformation able to efficiently recruit SRC-1, unless SRC-1 is overexpressed. Overall, our findings provide some structural guidelines for the synthesis of potential new dissociated glucocorticoids with a better therapeutic ratio.

  4. Modelling hemoglobin and hemoglobin:haptoglobin complex clearance in a non-rodent species– pharmacokinetic and therapeutic implications

    Directory of Open Access Journals (Sweden)

    Felicitas S Boretti

    2014-10-01

    Full Text Available Preclinical studies suggest that haptoglobin (Hp supplementation could be an effective therapeutic modality during acute or chronic hemolytic diseases. Hp prevents Hb extravasation and neutralizes Hb’s oxidative and NO scavenging activity in the vasculature. Small animal models such as mouse, rat and guinea pig appear to be valuable to provide proof-of-concept for Hb neutralization by Hp in diverse pre-clinical conditions. However, these species differ significantly from human in the clearance of Hb:Hp complexes, which leads to long persistence of circulating Hb:Hp complexes after administration of human plasma derived Hp. Alternative animal models must therefore be explored to guide pre-clinical development of these potential therapeutics. In contrast to rodents, dogs have high Hp plasma concentrations comparable to human. In this study we show that like human macrophages, dog peripheral blood monocyte derived macrophages express a glucocorticoid inducible endocytic clearance pathways with a high specificity for the Hb:Hp complex. Evaluating the Beagle dog as a non-rodent model species we provide the first pharmacokinetic parameter estimates of free Hb and Hb:Hp phenotype complexes. The data reflect a drastically reduced volume of distribution (Vc of the complex compared to free Hb, increased exposures (Cmax and AUC and significantly reduced total body clearance (CL with a terminal half-life (t1/2 of approximately 12 hours. Distribution and clearance was identical for dog and human Hb (± glucocorticoid stimulation and for dimeric and multimeric Hp preparations bound to Hb. Collectively, our study supports the dog as a non-rodent animal model to study pharmacological and pharmacokinetic aspects of Hb clearance systems and apply the model to studying Hp therapeutics.

  5. Role of glucocorticoid-induced leucine zipper (GILZ in inflammatory bone loss.

    Directory of Open Access Journals (Sweden)

    Nianlan Yang

    Full Text Available TNF-α plays a key role in the development of rheumatoid arthritis (RA and inflammatory bone loss. Unfortunately, treatment of RA with anti-inflammatory glucocorticoids (GCs also causes bone loss resulting in osteoporosis. Our previous studies showed that overexpression of glucocorticoid-induced leucine zipper (GILZ, a mediator of GC's anti-inflammatory effect, can enhance osteogenic differentiation in vitro and bone acquisition in vivo. To investigate whether GILZ could antagonize TNF-α-induced arthritic inflammation and protect bone in mice, we generated a TNF-α-GILZ double transgenic mouse line (TNF-GILZ Tg by crossbreeding a TNF-α Tg mouse, which ubiquitously expresses human TNF-α, with a GILZ Tg mouse, which expresses mouse GILZ under the control of a 3.6kb rat type I collagen promoter fragment. Results showed that overexpression of GILZ in bone marrow mesenchymal stem/progenitor cells protected mice from TNF-α-induced inflammatory bone loss and improved bone integrity (TNF-GILZ double Tg vs. TNF-αTg, n = 12-15. However, mesenchymal cell lineage restricted GILZ expression had limited effects on TNF-α-induced arthritic inflammation as indicated by clinical scores and serum levels of inflammatory cytokines and chemokines.

  6. Corticoterapia: minimizando efeitos colaterais Glucocorticoid therapy: minimizing side effects

    Directory of Open Access Journals (Sweden)

    Carlos Alberto Longui

    2007-11-01

    Full Text Available OBJETIVO: Ressaltar os principais efeitos indesejáveis durante a corticoterapia, o mecanismo de seu desencadeamento e as medidas necessárias para minimizar os efeitos colaterais. FONTES DOS DADOS: Experiência do autor, complementada com trabalhos publicados no MEDLINE. SÍNTESE DOS DADOS: Os princípios para que se minimizem os efeitos indesejáveis da corticoterapia incluem: a indicação rígida em que o uso do glicocorticóide seja essencial; b evitar o uso de glicocorticóides de ação prolongada, preferindo glicocorticóide de ação curta ou intermediária; c reduzir ao m��nimo necessário a duração do tratamento, visto que tratamentos com duração entre 5 e 7 dias apresentam poucos efeitos colaterais e rápida recuperação do eixo hipotalâmico-hipofisário; d preferir glicocorticóides de ação local, como glicocorticóides inalatórios; e associação com outros fármacos, em especial outros antiinflamatórios ou imunossupressores mais específicos, buscando efeitos sinérgicos que permitam evitar o uso de glicocorticóides ou reduzir a dose e o tempo da corticoterapia; f oferecer a menor dose necessária para o efeito desejado, respeitando a sensibilidade de cada indivíduo aos glicocorticóides. CONCLUSÕES: o conhecimento das características farmacológicas e ações biológicas dos glicocorticóides permite a melhor opção terapêutica quanto à indicação, dose, via de administração e duração da corticoterapia.OBJECTIVE:To describe the main undesirable side effects of glucocorticoid therapy, mechanisms of action and the necessary measures to minimize side effects. SOURCES: Author's experience, supplemented with papers published in MEDLINE. SUMMARY OF THE FINDINGS: The principles for minimizing undesirable side effects of glucocorticoid therapy include: a only use glucocorticoids if they are essential; b avoid the use of long-acting glucocorticoids, using short- and intermediate-acting glucocorticoids instead; c

  7. Recent advances in the molecular mechanisms determining tissue sensitivity to glucocorticoids: novel mutations, circadian rhythm and ligand-induced repression of the human glucocorticoid receptor

    Science.gov (United States)

    2014-01-01

    Glucocorticoids are pleiotropic hormones, which are involved in almost every cellular, molecular and physiologic network of the organism, and regulate a broad spectrum of physiologic functions essential for life. The cellular response to glucocorticoids displays profound variability both in magnitude and in specificity of action. Tissue sensitivity to glucocorticoids differs among individuals, within tissues of the same individual and within the same cell. The actions of glucocorticoids are mediated by the glucocorticoid receptor, a ubiquitously expressed intracellular, ligand-dependent transcription factor. Multiple mechanisms, such as pre-receptor ligand metabolism, receptor isoform expression, and receptor-, tissue-, and cell type-specific factors, exist to generate diversity as well as specificity in the response to glucocorticoids. Alterations in the molecular mechanisms of glucocorticoid receptor action impair glucocorticoid signal transduction and alter tissue sensitivity to glucocorticoids. This review summarizes the recent advances in our understanding of the molecular mechanisms determining tissue sensitivity to glucocorticoids with particular emphasis on novel mutations and new information on the circadian rhythm and ligand-induced repression of the glucocorticoid receptor. PMID:25155432

  8. Recent advances in the molecular mechanisms determining tissue sensitivity to glucocorticoids: novel mutations, circadian rhythm and ligand-induced repression of the human glucocorticoid receptor.

    Science.gov (United States)

    Nicolaides, Nicolas C; Charmandari, Evangelia; Chrousos, George P; Kino, Tomoshige

    2014-08-25

    Glucocorticoids are pleiotropic hormones, which are involved in almost every cellular, molecular and physiologic network of the organism, and regulate a broad spectrum of physiologic functions essential for life. The cellular response to glucocorticoids displays profound variability both in magnitude and in specificity of action. Tissue sensitivity to glucocorticoids differs among individuals, within tissues of the same individual and within the same cell. The actions of glucocorticoids are mediated by the glucocorticoid receptor, a ubiquitously expressed intracellular, ligand-dependent transcription factor. Multiple mechanisms, such as pre-receptor ligand metabolism, receptor isoform expression, and receptor-, tissue-, and cell type-specific factors, exist to generate diversity as well as specificity in the response to glucocorticoids. Alterations in the molecular mechanisms of glucocorticoid receptor action impair glucocorticoid signal transduction and alter tissue sensitivity to glucocorticoids. This review summarizes the recent advances in our understanding of the molecular mechanisms determining tissue sensitivity to glucocorticoids with particular emphasis on novel mutations and new information on the circadian rhythm and ligand-induced repression of the glucocorticoid receptor.

  9. Antiosteoporotic effect of Petroselinum crispum, Ocimum basilicum and Cichorium intybus L. in glucocorticoid-induced osteoporosis in rats.

    Science.gov (United States)

    Hozayen, Walaa G; El-Desouky, Mohamed A; Soliman, Hanan A; Ahmed, Rasha R; Khaliefa, Amal K

    2016-06-02

    Glucocorticoid-induced osteoporosis (GIO) is one of the serious side effects which have become the most common secondary osteoporosis. The purpose of this study is to evaluate the effect of aqueous extract of parsley, basil and chicory on glucocorticoid-induced osteoporosis in rats. Fifty Female rats were divided into five groups and treated for 8 weeks as follow: group 1 served as control; group (2) subcutaneously injected with 0.1 mg/kg b. wt. dexamethasone dissolved in saline; group 3 received similar dose of dexamethasone together with aqueous parsley extract in a dose of 2 g/kg b. wt.; group 4 received similar dose of dexamethasone together with 400 mg/kg b. wt. aqueous basil extract and group 5 received similar dose of dexamethasone together with 100 mg/kg b. wt. aqueous chicory extract. The dexamethasone group showed a significant decrease in serum E2, Ca, P levels and significant decrease in total BMD, BMC and a significant increase in serum PTH, ALP and ACP. Bone TBARs was significantly increased while GSH, antioxidant enzymes were significantly decreased. These changes were attenuated by parsley, basil and chicory extracts in the group 3, 4 and 5 respectively. Aqueous extracts of parsley, basil and chicory showed bone protection against glucocorticoid-induced in rats. From our results, we concluded that chicory has a potent protective effect more than parsley and basil due to containing flavonoids and inulin.

  10. Rodent phylogeny revised: analysis of six nuclear genes from all major rodent clades

    Directory of Open Access Journals (Sweden)

    Pupko Tal

    2009-04-01

    Full Text Available Abstract Background Rodentia is the most diverse order of placental mammals, with extant rodent species representing about half of all placental diversity. In spite of many morphological and molecular studies, the family-level relationships among rodents and the location of the rodent root are still debated. Although various datasets have already been analyzed to solve rodent phylogeny at the family level, these are difficult to combine because they involve different taxa and genes. Results We present here the largest protein-coding dataset used to study rodent relationships. It comprises six nuclear genes, 41 rodent species, and eight outgroups. Our phylogenetic reconstructions strongly support the division of Rodentia into three clades: (1 a "squirrel-related clade", (2 a "mouse-related clade", and (3 Ctenohystrica. Almost all evolutionary relationships within these clades are also highly supported. The primary remaining uncertainty is the position of the root. The application of various models and techniques aimed to remove non-phylogenetic signal was unable to solve the basal rodent trifurcation. Conclusion Sequencing and analyzing a large sequence dataset enabled us to resolve most of the evolutionary relationships among Rodentia. Our findings suggest that the uncertainty regarding the position of the rodent root reflects the rapid rodent radiation that occurred in the Paleocene rather than the presence of conflicting phylogenetic and non-phylogenetic signals in the dataset.

  11. Fructose consumption enhances glucocorticoid action in rat visceral adipose tissue.

    Science.gov (United States)

    Bursać, Biljana N; Djordjevic, Ana D; Vasiljević, Ana D; Milutinović, Danijela D Vojnović; Veličković, Nataša A; Nestorović, Nataša M; Matić, Gordana M

    2013-06-01

    The rise in consumption of refined sugars high in fructose appears to be an important factor for the development of obesity and metabolic syndrome. Fructose has been shown to be involved in genesis and progression of the syndrome through deregulation of metabolic pathways in adipose tissue. There is evidence that enhanced glucocorticoid regeneration within adipose tissue, mediated by the enzyme 11beta-hydroxysteroid dehydrogenase Type 1 (11βHSD1), may contribute to adiposity and metabolic disease. 11βHSD1 reductase activity is dependent on NADPH, a cofactor generated by hexose-6-phosphate dehydrogenase (H6PDH). We hypothesized that harmful effects of long-term high fructose consumption could be mediated by alterations in prereceptor glucocorticoid metabolism and glucocorticoid signaling in the adipose tissue of male Wistar rats. We analyzed the effects of 9-week drinking of 10% fructose solution on dyslipidemia, adipose tissue histology and both plasma and tissue corticosterone level. Prereceptor metabolism of glucocorticoids was characterized by determining 11βHSD1 and H6PDH mRNA and protein levels. Glucocorticoid signaling was examined at the level of glucocorticoid receptor (GR) expression and compartmental redistribution, as well as at the level of expression of its target genes (GR, phosphoenolpyruvate carboxyl kinase and hormone-sensitive lipase). Fructose diet led to increased 11βHSD1 and H6PDH expression and elevated corticosterone level within the adipose tissue, which was paralleled with enhanced GR nuclear accumulation. Although the animals did not develop obesity, nonesterified fatty acid and plasma triglyceride levels were elevated, indicating that fructose, through enhanced prereceptor metabolism of glucocorticoids, could set the environment for possible later onset of obesity. Copyright © 2013 Elsevier Inc. All rights reserved.

  12. Unintentional wildlife poisoning and proposals for sustainable management of rodents.

    Science.gov (United States)

    Coeurdassier, Michael; Riols, Romain; Decors, Anouk; Mionnet, Aymeric; David, Fabienne; Quintaine, Thomas; Truchetet, Denis; Scheifler, Renaud; Giraudoux, Patrick

    2014-04-01

    In Europe, bromadiolone, an anticoagulant rodenticide authorized for plant protection, may be applied intensively in fields to control rodents. The high level of poisoning of wildlife that follows such treatments over large areas has been frequently reported. In France, bromadiolone has been used to control water voles (Arvicola terrestris) since the 1980s. Both regulation and practices of rodent control have evolved during the last 15 years to restrict the quantity of poisoned bait used by farmers. This has led to a drastic reduction of the number of cases of poisoned wildlife reported by the French surveillance network SAGIR. During the autumn and winter 2011, favorable weather conditions and high vole densities led to the staging of several hundreds of Red Kites (Milvus milvus) in the Puy-de-Dôme department (central France). At the same time, intensive treatments with bromadiolone were performed in this area. Although no misuse has been mentioned by the authorities following controls, 28 Red Kites and 16 Common Buzzards (Buteo buteo) were found dead during surveys in November and December 2011. For all these birds, poisoning by bromadiolone as the main cause of death was either confirmed or highly suspected. Other observations suggest a possible impact of bromadiolone on the breeding population of Red Kites in this area during the spring 2011. French regulation of vole control for plant protection is currently under revision, and we believe this event calls for more sustainable management of rodent outbreaks. Based on large-scale experiments undertaken in eastern France, we propose that direct control of voles at low density (with trapping or limited chemical treatments) and mechanical destruction of vole tunnels, mole control, landscape management, and predator fostering be included in future regulation because such practices could help resolve conservation and agricultural issues. © 2014 Society for Conservation Biology.

  13. Effects of glucocorticoids on human brown adipocytes.

    Science.gov (United States)

    Barclay, Johanna L; Agada, Hadiya; Jang, Christina; Ward, Micheal; Wetzig, Neil; Ho, Ken K Y

    2015-02-01

    Clinical cases of glucocorticoid (GC) excess are characterized by increased fat mass and obesity through the accumulation of white adipocytes. The effects of GCs on growth and function of brown adipose tissue are unknown and may contribute to the negative energy balance observed clinically. This study aims to evaluate the effect of GCs on proliferation, differentiation, and metabolic function of brown adipocytes. Human brown adipocytes sourced from supraclavicular fat biopsies were grown in culture and differentiated to mature adipocytes. Human white adipocytes sourced from subcutaneous abdominal fat biopsies were cultured as controls. Effects of dexamethasone on growth, differentiation (UCP1, CIDEA, and PPARGC1A expression), and function (oxygen consumption rate (OCR)) of brown adipocytes were quantified. Dexamethasone (1 μM) significantly stimulated the proliferation of brown preadipocytes and reduced that of white preadipocytes. During differentiation, dexamethasone (at 0.1, 1, and 10 μM) stimulated the expression of UCP1, CIDEA, and PPARGC1A in a concentration-dependent manner and enhanced by fourfold to sixfold the OCR of brown adipocytes. Isoprenaline (100 nM) significantly increased (Peffects were significantly reduced (Peffects on development and function of brown adipocytes. These findings provide strong evidence for an effect of GCs on the biology of human brown adipose tissue (BAT) and for the involvement of the BAT system in the metabolic manifestation of Cushing's syndrome. © 2015 Society for Endocrinology.

  14. Glucocorticoid regulation of astrocytic fate and function.

    Directory of Open Access Journals (Sweden)

    Shuang Yu

    Full Text Available Glial loss in the hippocampus has been suggested as a factor in the pathogenesis of stress-related brain disorders that are characterized by dysregulated glucocorticoid (GC secretion. However, little is known about the regulation of astrocytic fate by GC. Here, we show that astrocytes derived from the rat hippocampus undergo growth inhibition and display moderate activation of caspase 3 after exposure to GC. Importantly, the latter event, observed both in situ and in primary astrocytic cultures is not followed by either early- or late-stage apoptosis, as monitored by stage I or stage II DNA fragmentation. Thus, unlike hippocampal granule neurons, astrocytes are resistant to GC-induced apoptosis; this resistance is due to lower production of reactive oxygen species (ROS and a greater buffering capacity against the cytotoxic actions of ROS. We also show that GC influence hippocampal cell fate by inducing the expression of astrocyte-derived growth factors implicated in the control of neural precursor cell proliferation. Together, our results suggest that GC instigate a hitherto unknown dialog between astrocytes and neural progenitors, adding a new facet to understanding how GC influence the cytoarchitecture of the hippocampus.

  15. Treatment of frozen shoulder with subcutaneous TNF-alpha blockade compared with local glucocorticoid injection

    DEFF Research Database (Denmark)

    Schydlowsky, Pierre; Szkudlarek, Marcin; Madsen, Ole Rintek

    2012-01-01

    We compared the effect of subcutaneous adalimumab injections with intraarticular glucocorticoid injections on frozen shoulder of 18 patients with unilateral joint involvement. Ten patients were randomised to subcutaneous injections with adalimumab and eight to intraarticular glucocorticoid inject...

  16. ROLE OF THE ENDOCANNABINOID SYSTEM IN REGULATING GLUCOCORTICOID EFFECTS ON MEMORY FOR EMOTIONAL EXPERIENCES

    NARCIS (Netherlands)

    Atsak, P.; Roozendaal, B.; Campolongo, P.

    2012-01-01

    Glucocorticoids, stress hormones released from the adrenal cortex, have potent modulatory effects on emotional memory. Whereas early studies focused mostly on the detrimental effects of chronic stress and glucocorticoid exposure on cognitive performance and the classic genomic pathways that mediate

  17. Role of the endocannabinoid system in regulating glucocorticoid effects on memory for emotional experiences

    NARCIS (Netherlands)

    Atsak, P.; Roozendaal, B.; Campolongo, P.

    2012-01-01

    Glucocorticoids, stress hormones released from the adrenal cortex, have potent modulatory effects on emotional memory. Whereas early studies focused mostly on the detrimental effects of chronic stress and glucocorticoid exposure on cognitive performance and the classic genomic pathways that mediate

  18. Minireview: glucocorticoids--food intake, abdominal obesity, and wealthy nations in 2004

    NARCIS (Netherlands)

    Dallman, Mary F.; la Fleur, Susanne E.; Pecoraro, Norman C.; Gomez, Francisca; Houshyar, Hani; Akana, Susan F.

    2004-01-01

    Glucocorticoids have a major effect on food intake that is underappreciated, although the effects of glucocorticoids on metabolism and abdominal obesity are quite well understood. Physiologically appropriate concentrations of naturally secreted corticosteroids (cortisol in humans, corticosterone in

  19. Glucocorticoids interact with the hippocampal endocannabinoid system in impairing retrieval of contextual fear memory

    NARCIS (Netherlands)

    Atsak, P.; Hauer, D.; Campolongo, P.; Schelling, G.; McGaugh, J.L.; Roozendaal, B.

    2012-01-01

    There is extensive evidence that glucocorticoid hormones impair the retrieval of memory of emotionally arousing experiences. Although it is known that glucocorticoid effects on memory retrieval impairment depend on rapid interactions with arousal-induced noradrenergic activity, the exact mechanism

  20. Glomerular Glucocorticoid Receptors Expression and Clinicopathological Types of Childhood Nephrotic Syndrome.

    Science.gov (United States)

    Gamal, Yasser; Badawy, Ahlam; Swelam, Salwa; Tawfeek, Mostafa S K; Gad, Eman Fathalla

    2017-02-01

    Glucocorticoids are primary therapy of idiopathic nephrotic syndrome (INS). However, not all children respond to steroid therapy. We assessed glomerular glucocorticoid receptor expression in fifty-one children with INS and its relation to response to steroid therapy and to histopathological type. Clinical, laboratory and glomerular expression of glucocorticoid receptors were compared between groups with different steroid response. Glomerular glucocorticoid expression was slightly higher in controls than in minimal change early responders, which in turn was significantly higher than in minimal change late responders. There was significantly lower glomerular glucocorticoid receptor expression in steroid-resistance compared to early responders, late responders and controls. Glomerular glucocorticoid expression was significantly higher in all minimal change disease (MCD) compared to focal segmental glomerulosclerosis. In INS, response to glucocorticoid is dependent on glomerular expression of receptors and peripheral expression. Evaluation of glomerular glucocorticoid receptor expression at time of diagnosis of NS can predict response to steroid therapy.

  1. Control of cell proliferation in human glioma by glucocorticoids.

    Science.gov (United States)

    Freshney, R I; Sherry, A; Hassanzadah, M; Freshney, M; Crilly, P; Morgan, D

    1980-06-01

    Survival and proliferation of cell cultures from human anaplastic astrocytomas were shown to be enhanced by glucocorticoids with an optimal concentration of approximately 2.5 x 10(-5)M (10 micrograms/ml). The stimulation of proliferation was only observed in a clonal growth assay and was reversed as the size of individual colonies reached approximately 50 cells. Above this size, and in regular monolayer cultures, glucocorticoids were found to inhibit cell proliferation as measured by direct cell counting and incorporation of [3H] thymidine. Cultures grown to maximum cell densities in non-limiting medium conditions reached a lower terminal cell density, and had a reduced labelling index with [3H] thymidine in the presence of glucocorticoids. Although there was little difference between the actions of beta-methasone, dexamethasone and ethyl prednisolone, methyl prednisolone was found to be more effective, both in terms of stimulation of clonal growth and inhibition of growth at high cell densities. There was no evidence of cytotoxicity with glucocorticoids up to 5 x 10(-5)M (20 micrograms/ml) and it is suggested that glucocorticoids act via a normal regulatory process, perhaps enhancing cell-cell recognition.

  2. Glucocorticoid hyper- and hypofunction: stress effects on cognition and aggression.

    Science.gov (United States)

    Kim, Jeansok J; Haller, József

    2007-10-01

    It is now well documented that both increased and decreased stress responses can profoundly affect cognition and behavior. This mini review presents possible neural mechanisms subserving stress effects on memory and aggression, particularly focusing on glucocorticoid (GC) hyper- and hypofunction. First, uncontrollable stress impedes hippocampal memory and long-term potentiation (LTP). Because the hippocampus is important for the stability of long-term memory and because LTP has qualities desirable of an information storage mechanism, it has been hypothesized that stress-induced alterations in LTP contribute to memory impairments. Recent evidence suggests a neural-endocrine network comprising amygdala, prefrontal cortex (PFC), and glucocorticoids may be involved in regulating stress effects on hippocampal mnemonic functioning. Second, antisocial aggressiveness correlates with chronically decreased glucocorticoid production, and this condition leads in rats to behavioral-autonomic deficits reminiscent of the human disorder. Glucocorticoid deficiency-induced antisocial aggressiveness results from functional changes in the PFC, medial and central amygdala, and altered serotonin and substance P neurotransmissions. Accordingly, a neurobiological understanding of how stress and glucocorticoid deficiency alter brain, cognition, and behavior is an important challenge facing modern neuroscience with broad implications for individual and social well-being.

  3. Presumed Pseudotumor Cerebri Syndrome After Withdrawal of Inhaled Glucocorticoids.

    Science.gov (United States)

    Kwon, Young Joon; Allen, Julian L; Liu, Grant T; McCormack, Shana E

    2016-06-01

    Pseudotumor cerebri syndrome (PTCS) is characterized by increased intracranial pressure with normal brain parenchyma and cerebrospinal fluid constituents. PTCS after withdrawal of systemic corticosteroids also has been described in children. In contrast, to our knowledge, PTCS after withdrawal of inhaled glucocorticoids has not previously been described. Here we report the case of an 8-year and 6-month-old girl who developed signs and symptoms consistent with PTCS after withdrawal of inhaled glucocorticoids. The patient had excellent adherence to inhaled glucocorticoid therapy for ∼1 year before presentation, after which the therapy was stopped for concern related to poor growth. The withdrawal of inhaled glucocorticoids was associated with the development of severe headaches and diplopia, and further clinical examination led to the patient's diagnosis of likely PTCS. Although its occurrence is likely rare, clinicians caring for the many children receiving inhaled glucocorticoid therapy should be aware of the potential for PTCS after abrupt withdrawal of such treatment, and consider ophthalmology evaluation if patients report suggestive symptoms, such as headaches or vision changes in this context. Copyright © 2016 by the American Academy of Pediatrics.

  4. [Treatment of iatrogenic Cushing syndrome: questions of glucocorticoid withdrawal].

    Science.gov (United States)

    Igaz, Péter; Rácz, Károly; Tóth, Miklós; Gláz, Edit; Tulassay, Zsolt

    2007-02-04

    Iatrogenic Cushing's syndrome is the most common form of hypercortisolism. Glucocorticoids are widely used for the treatment of various diseases, often in high doses that may lead to the development of severe hypercortisolism. Iatrogenic hypercortisolism is unique, as the application of exogenous glucocorticoids leads to the simultaneous presence of symptoms specific for hypercortisolism and the suppression of the endogenous hypothalamic-pituitary-adrenal axis. The principal question of its therapy is related to the problem of glucocorticoid withdrawal. There is considerable interindividual variability in the suppression and recovery of the hypothalamic-pituitary-adrenal axis, therefore, glucocorticoid withdrawal and substitution can only be conducted in a stepwise manner with careful clinical follow-up and regular laboratory examinations regarding endogenous hypothalamic-pituitary-adrenal axis activity. Three major complications which can be associated with glucocorticoid withdrawal are: i. reactivation of the underlying disease, ii. secondary adrenal insufficiency, iii. steroid withdrawal syndrome. Here, the authors summarize the most important aspects of this area based on their clinical experience and the available literature data.

  5. Glucocorticoid influence on prognosis of idiopathic sudden sensorineural hearing loss

    Directory of Open Access Journals (Sweden)

    Eduardo Amaro Bogaz

    2014-06-01

    Full Text Available INTRODUCTION: Idiopathic Sudden Sensorineural Hearing Loss (ISSHL is defined when a loss of at least 30 dB occurs in over 3 continuous frequencies, in up to 72 hours, of which etiology is not established, despite adequate investigation. Different types of treatment regimens have been proposed, but only glucocorticoids have shown some evidence of benefit in the literature. OBJECTIVE: To analyze whether the type of treatment or time of treatment with glucocorticoids have any influence on hearing recovery in ISSHL. METHODS: Observational retrospective cohort study. One hundred twenty-seven patients with ISSHL, treated at outpatient clinics between the years 2000 and 2010, were studied. We evaluated the prognostic correlation of the type of treatment and time to treatment with glucocorticoids and ISSHL. RESULTS: The absolute hearing gain and the relative hearing gain was as follows: 23.6 dB and 37.2%. Complete recovery was observed in 15.7% of patients, significant recovery in 27.6% and recovery in 57.5%. CONCLUSION: In this study, there was no difference between the use and nonuse of glucocorticoids in hearing improvement. However, when started within seven days after onset, the use of glucocorticoids was a factor of better prognosis.

  6. Maternal gestational cortisol and testosterone are associated with trade-offs in offspring sex and number in a free-living rodent (Urocitellus richardsonii.

    Directory of Open Access Journals (Sweden)

    Calen P Ryan

    Full Text Available The adaptive manipulation of offspring sex and number has been of considerable interest to ecologists and evolutionary biologists. The physiological mechanisms that translate maternal condition and environmental cues into adaptive responses in offspring sex and number, however, remain obscure. In mammals, research into the mechanisms responsible for adaptive sex allocation has focused on two major endocrine axes: the hypothalamic pituitary adrenal (HPA axis and glucocorticoids, and the hypothalamic pituitary gonadal (HPG axis and sex steroids, particularly testosterone. While stress-induced activation of the HPA axis provides an intuitive model for sex ratio and litter size adjustment, plasma glucocorticoids exist in both bound and free fractions, and may be acting indirectly, for example by affecting plasma glucose levels. Furthermore, in female mammals, activation of the HPA axis stimulates the secretion of adrenal testosterone in addition to glucocorticoids (GCs. To begin to untangle these physiological mechanisms influencing offspring sex and number, we simultaneously examined fecal glucocorticoid metabolites, free and bound plasma cortisol, free testosterone, and plasma glucose concentration during both gestation and lactation in a free-living rodent (Urocitellus richardsonii. We also collected data on offspring sex and litter size from focal females and from a larger study population. Consistent with previous work in this population, we found evidence for a trade-off between offspring sex and number, as well as positive and negative correlations between glucocorticoids and sex ratio and litter size, respectively, during gestation (but not lactation. We also observed a negative relationship between testosterone and litter size during gestation (but not lactation, but no effect of glucose on either sex ratio or litter size. Our findings highlight the importance of binding proteins, cross-talk between endocrine systems, and temporal windows

  7. Distribution and protection of endemic or threatened rodents ...

    African Journals Online (AJOL)

    tions. They occur in all zoogeographic regions except the. Antarctic and some oceanic islands (De Graaff 1981). The order Macroscelidea comprises the elephant shrews, ..... Stafford's Hill Bird Sanctuary, LA, 25 ha. 31198D. Akkerdam Nature Reserve, LA, 2301 ha. 3219AC. Cederberg Wildemess Area, WCe, 64400 ha. RR.

  8. Distribution and protection of endemic or threatened rodents ...

    African Journals Online (AJOL)

    An analysis of biome specificity of all species revealed that Myomyscus verreauxii is endemic to the fynbos, Bathyergus janetta to the Succulent Karoo, Zelotomys woosnami to the arid savanna, and Steatomys parvus to the savanna woodlands. No species are endemic to the Nama-Karoo or grasslands, although several ...

  9. Rapid central corticosteroid effects: evidence for membrane glucocorticoid receptors in the brain

    OpenAIRE

    Tasker, Jeffrey G.; Shi Di; Malcher-Lopes, Renato

    2005-01-01

    Glucocorticoid secretion occurs in a circadian pattern and in response to stress. Among the broad array of glucocorticoid actions are multiple effects in the brain, including negative feedback regulation of hypothalamic hormone secretion. The negative feedback of glucocorticoids occurs on both rapid and delayed time scales, reflecting different regulatory mechanisms. While the slow glucocorticoid effects are widely held to involve regulation of gene transcription, the rapid effects are too fa...

  10. The fecal viral flora of wild rodents.

    Directory of Open Access Journals (Sweden)

    Tung G Phan

    2011-09-01

    Full Text Available The frequent interactions of rodents with humans make them a common source of zoonotic infections. To obtain an initial unbiased measure of the viral diversity in the enteric tract of wild rodents we sequenced partially purified, randomly amplified viral RNA and DNA in the feces of 105 wild rodents (mouse, vole, and rat collected in California and Virginia. We identified in decreasing frequency sequences related to the mammalian viruses families Circoviridae, Picobirnaviridae, Picornaviridae, Astroviridae, Parvoviridae, Papillomaviridae, Adenoviridae, and Coronaviridae. Seventeen small circular DNA genomes containing one or two replicase genes distantly related to the Circoviridae representing several potentially new viral families were characterized. In the Picornaviridae family two new candidate genera as well as a close genetic relative of the human pathogen Aichi virus were characterized. Fragments of the first mouse sapelovirus and picobirnaviruses were identified and the first murine astrovirus genome was characterized. A mouse papillomavirus genome and fragments of a novel adenovirus and adenovirus-associated virus were also sequenced. The next largest fraction of the rodent fecal virome was related to insect viruses of the Densoviridae, Iridoviridae, Polydnaviridae, Dicistroviriade, Bromoviridae, and Virgaviridae families followed by plant virus-related sequences in the Nanoviridae, Geminiviridae, Phycodnaviridae, Secoviridae, Partitiviridae, Tymoviridae, Alphaflexiviridae, and Tombusviridae families reflecting the largely insect and plant rodent diet. Phylogenetic analyses of full and partial viral genomes therefore revealed many previously unreported viral species, genera, and families. The close genetic similarities noted between some rodent and human viruses might reflect past zoonoses. This study increases our understanding of the viral diversity in wild rodents and highlights the large number of still uncharacterized viruses in

  11. Adrenal Insufficiency Caused by Locally Applied Glucocorticoids-Myth or Fact?

    Science.gov (United States)

    Borresen, Stina Willemoes; Klose, Marianne; Rasmussen, Ase Krogh; Feldt-Rasmussen, Ulla

    2015-01-01

    Case-reports have made it evident that both inhaled, percutaneous, intranasal, intraarticular and ophthalmic administered glucocorticoids have the potential to cause life threatening adrenal insufficiency. With few and sometimes conflicting data and study methodology the prevalence of adrenal insufficiency secondary to locally applied glucocorticoids is not clear. Adrenal insufficiency can only be correctly evaluated by a stimulation test, and has by this procedure been reported in up to 40-50% of patients treated with high-dose inhaled glucocorticoids. Medium- to low-dose inhaled glucocorticoids have been shown to cause adrenal suppression in 0-16% of patients. Glucocorticoid creams and nasal glucocorticoids can cause adrenal insufficiency, also when used within prescribed doses, but the frequency seems to be less than with inhaled glucocorticoids. Intraarticularly administered glucocorticoids can cause adrenal suppression after a single injection. The systemic effect of locally applied glucocorticoids depends on pharmacokinetic and -dynamic properties of the particular glucocorticoid as well as individual factors. Many of the symptoms in iatrogen adrenal insufficiency are unspecific and often difficult to differentiate from symptoms of underlying disease activity. The condition might therefore be more common than widely believed and underdiagnosed in clinical practice. Potential adrenal insufficiency must therefore always be kept in mind in patients treated with all forms of glucocorticoids. Clinically important points and patient management are discussed on the basis of a case report and review of the literature. More work assessing the prevalence of adrenal insufficiency secondary to locally applied glucocorticoids is urgently needed.

  12. Glucocorticoids exert context-dependent effects on cells of the joint in vitro

    DEFF Research Database (Denmark)

    Madsen, Suzi H; Andreassen, Kim V; Christensen, Søren T

    2011-01-01

    Glucocorticoids are known to attenuate bone formation in vivo leading to decreased bone volume and increased risk of fractures, whereas effects on the joint tissue are less characterized. However, glucocorticoids appear to have a reducing effect on inflammation and pain in osteoarthritis....... This study aimed at characterizing the effect of glucocorticoids on chondrocytes, osteoclasts, and osteoblasts....

  13. Glucocorticoid receptor polymorphism in obesity and glucose homeostasis.

    Science.gov (United States)

    Majer-Łobodzińska, Agnieszka; Adamiec-Mroczek, Joanna

    2017-01-01

    Glucocorticoid receptor (GR) activity plays a significant role in the etiology of obesity and is essential for glucose homeostasis, the development of hyperinsulinaemia and subsequent increased fat deposition. Several polymorphisms in the GR gene have been described, and at least three of them seem to be associated with altered glucocorticoid sensitivity and changes in glucose homeostasis, and other metabolic parameters. The N363S polymorphism has been associated with increased sensitivity to glucocorticoides, increased insulin response to dexamethasone and increased plasma glucose level. BclI polymorphism is associated with increased abdominal obesity, hyperinsulinaemia and increased insulin resistance. Another polymorphism, ER22/23EK, in contrast to the others, is associated with relative resistance to glucocoricides actions and more beneficial metabolic profile-lower insulin resistance level, decreased lower cardiovascular risk and subseuent prolongation of life time. More research is still needed to understand the mechanisms behind these associations at the molecular level.

  14. [Steroids: The physiologic and pharmacologic effects of glucocorticoids].

    Science.gov (United States)

    Zelena, Dóra; Makara, B Gábor

    2015-08-30

    Glucocorticoids are widely used in medical practice mainly for suppression of the immune system. According to Selye - who named them - the endogenous molecules are very important for the adaptation to challenges, stress. They were synthesized in the 1940s. Since then numerous data have been published about their production (also locally in several organs), transportation (primarily cortisol-binding globulin) and receptors (nuclear and non-genomic effects). Although glucocorticoids are primarily under the control of the hypothalamo-pituitary-adrenocortical axis, several other molecules (especially catecholamines) may also increase their secretion. Their permissive influences are dominant, thereby they are indispensable for the effect of numerous other molecules. Thus, glucocorticoids have very diverse influence from metabolism through cardiovascular effect to bone-metabolism, affecting even the central nervous system. They are also important in metabolic syndrome. Their extensive therapeutic usage are limited by side-effects, which could be diminished - among others - with concomitant usage of the anabolic dehydroepiandrosterone.

  15. [Toward an explanation for the mnemonic effects of glucocorticoids?].

    Science.gov (United States)

    Jeanneteau, Freddy

    2015-04-01

    If the engram of long-term memory is encoded by structural changes of neuronal circuits, they are expected to be present at distant time points after learning, to be specific of circuits activated by learning, and sensitive to behavioral contingencies. In this review we present new concepts that emerged from in vivo imaging studies that tracked the structural bases of the memory trace. A fine balance of spine formation and spine elimination needed for behavioral adaptation to new experience is regulated by glucocorticoids, which are secreted in synchrony with circadian rhythms and in response to stress. Disruption of glucocorticoid oscillations frequently observed in psychiatric disorders like depression and post-traumatic stress produces spine turnover defects and learning disabilities. These new findings provide a new framework for explaining the potent but complex mnemonic effects of glucocorticoids. © 2015 médecine/sciences – Inserm.

  16. Canonical and Noncanonical Mechanisms of Glucocorticoid Stress Hormones Action.

    Science.gov (United States)

    2016-01-01

    Hormones of stress, glucocorticoids, regulate numerous physiological processes and functions. These hormonal effects involve diverse mechanisms of action. Glucocorticoid receptors (GRs) are transcription factors which regulate gene expression by canonical mechanism of the hormone action through interaction with specific nucleotide sequence (GRE) in the regulatory region of the gene. The effects of the canonical mechanism develop for several hours. Non-genomic rapid effects of the hormone emerged in seconds- minuets and supposed to be associated with yet not identified receptor in the plasma membrane. In addition to these slow and rapid hormonal actions, one more slow non-canonical mechanism of glucocorticoid action become increasingly evident. This mechanism is based on protein-protein interactions of GRs with other transcription factors. The main modern concepts of canonical, non-canonical and membrane mechanisms of hormone action are discussed in the review.

  17. Prescription duration and treatment episodes in oral glucocorticoid users

    DEFF Research Database (Denmark)

    Laugesen, Kristina; Støvring, Henrik; Hallas, Jesper

    2017-01-01

    Purpose: Glucocorticoids are widely used medications. In many pharmacoepidemiological studies, duration of individual prescriptions and definition of treatment episodes are important issues. However, many data sources lack this information. We aimed to estimate duration of individual prescriptions...... for oral glucocorticoids and to describe continuous treatment episodes using the parametric waiting time distribution. Methods: We used Danish nationwide registries to identify all prescriptions for oral glucocorticoids during 1996-2014. We applied the parametric waiting time distribution to estimate...... duration of individual prescriptions each year by estimating the 80th, 90th, 95th and 99th percentiles for the interarrival distribution. These corresponded to the time since last prescription during which 80%, 90%, 95% and 99% of users presented a new prescription for redemption. We used the Kaplan...

  18. Osteoporosis secundaria y Osteoporosis inducida por glucocorticoides (OIG

    Directory of Open Access Journals (Sweden)

    Elías Forero Illera

    2006-01-01

    Full Text Available La osteoporosis es un problema de salud pública importante a nivel mundial, y su prevalencia está aumentando. La osteoporosis secundaria se puede producir por varias patologías y el uso de ciertos medicamentos. Los glucocorticoides son un grupo de fármacos usados extensamente en la práctica médica debido a su indiscutible utilidad. La osteoporosis inducida por glucocorticoides es un problema de salud pública. Aunque la patogénesis de la pérdida producida por los glucocorticoides en el hueso no se conoce totalmente, investigaciones recientes han proporcionado nuevas conocimientos en los mecanismos de estos fármacos a nivel celular y molecular. Diversas guías han sido propuestas por diversos grupos para el tratamiento de la OIG; desafortunadamente, las guías del tratamiento no se utilizan adecuadamente en los pacientes.

  19. Glucocorticoid receptors in monocytes in type 1 diabetes mellitus

    DEFF Research Database (Denmark)

    Damm, P; Binder, C

    1989-01-01

    Glucocorticoid receptor binding characteristics were investigated in 8 males with poorly controlled Type 1 diabetes mellitus and 14 healthy males. The cell type studied was monocytes, and a method for correction for heterogeneity in glucocorticoid binding in a mononuclear leucocyte population...... was introduced. The number of receptors and the dissociation constant KD were, respectively, 13,699 and 2.93 X 10(-8) mol/l for the control group and 15,788 and 2.75 X 10(-8) mol/l for diabetics (p greater than 0.05). In diabetics, KD correlated negatively with blood glucose (r = 0.762, p less than 0.......05) indicating an increased sensitivity to cortisol at high blood glucose levels. In 6 of the diabetics and 7 of the control group, a simultaneous insulin receptor study was carried out. However, glucocorticoid receptor binding characteristics did not correlate with insulin receptor binding characteristics...

  20. Glucocorticoids, master modulators of the thymic catecholaminergic system?

    Directory of Open Access Journals (Sweden)

    I. Pilipović

    Full Text Available There is evidence that the major mediators of stress, i.e., catecholamines and glucocorticoids, play an important role in modulating thymopoiesis and consequently immune responses. Furthermore, there are data suggesting that glucocorticoids influence catecholamine action. Therefore, to assess the putative relevance of glucocorticoid-catecholamine interplay in the modulation of thymopoiesis we analyzed thymocyte differentiation/maturation in non-adrenalectomized and andrenalectomized rats subjected to treatment with propranolol (0.4 mg·100 g body weight-1·day-1 for 4 days. The effects of β-adrenoceptor blockade on thymopoiesis in non-adrenalectomized rats differed not only quantitatively but also qualitatively from those in adrenalectomized rats. In adrenalectomized rats, besides a more efficient thymopoiesis [judged by a more pronounced increase in the relative proportion of the most mature single-positive TCRαβhigh thymocytes as revealed by two-way ANOVA; for CD4+CD8- F (1,20 = 10.92, P < 0.01; for CD4-CD8+ F (1,20 = 7.47, P < 0.05], a skewed thymocyte maturation towards the CD4-CD8+ phenotype, and consequently a diminished CD4+CD8-/CD4-CD8+ mature TCRαβhigh thymocyte ratio (3.41 ± 0.21 in non-adrenalectomized rats vs 2.90 ± 0.31 in adrenalectomized rats, P < 0.05 were found. Therefore, we assumed that catecholaminergic modulation of thymopoiesis exhibits a substantial degree of glucocorticoid-dependent plasticity. Given that glucocorticoids, apart from catecholamine synthesis, influence adrenoceptor expression, we also hypothesized that the lack of adrenal glucocorticoids affected not only β-adrenoceptor- but also α-adrenoceptor-mediated modulation of thymopoiesis.

  1. Dose-related patterns of glucocorticoid-induced side effects.

    Science.gov (United States)

    Huscher, D; Thiele, K; Gromnica-Ihle, E; Hein, G; Demary, W; Dreher, R; Zink, A; Buttgereit, F

    2009-07-01

    To identify patterns of self-reported health problems relating to dose and duration of glucocorticoid intake in unselected patients with rheumatoid arthritis from routine practice. Data from 1066 patients were analysed. The clinical status and drug treatment were reported by the physician, health problems during the past 6 months by the patient using a comprehensive list of symptoms. Patients with ongoing glucocorticoid treatment for more than 6 months and current doses of less than 5, 5-7.5 and over 7.5 mg/day prednisone equivalent were compared with a group without any glucocorticoid treatment for at least 12 months. The frequency of self-reported health problems was lowest in the group without glucocorticoid exposition and increased with dosage. Two distinct dose-related patterns of adverse events were observed. A "linear" rising with increasing dose was found for cushingoid phenotype, ecchymosis, leg oedema, mycosis, parchment-like skin, shortness of breath and sleep disturbance. A "threshold pattern" describing an elevated frequency of events beyond a certain threshold value was observed at dosages of over 7.5 mg/day for glaucoma, depression/listlessness and increase in blood pressure. Dosages of 5 mg/day or more were associated with epistaxis and weight gain. A very low threshold was seen for eye cataract (<5 mg/day). The associations found are in agreement with biological mechanisms and clinical observations. As there is a paucity of real-life data on adverse effects of glucocorticoids prescribed to unselected groups of patients, these data may help the clinician to adapt therapy with glucocorticoids accordingly and improve the benefit-risk ratio.

  2. Quintupling Inhaled Glucocorticoids to Prevent Childhood Asthma Exacerbations.

    Science.gov (United States)

    Jackson, Daniel J; Bacharier, Leonard B; Mauger, David T; Boehmer, Susan; Beigelman, Avraham; Chmiel, James F; Fitzpatrick, Anne M; Gaffin, Jonathan M; Morgan, Wayne J; Peters, Stephen P; Phipatanakul, Wanda; Sheehan, William J; Cabana, Michael D; Holguin, Fernando; Martinez, Fernando D; Pongracic, Jacqueline A; Baxi, Sachin N; Benson, Mindy; Blake, Kathryn; Covar, Ronina; Gentile, Deborah A; Israel, Elliot; Krishnan, Jerry A; Kumar, Harsha V; Lang, Jason E; Lazarus, Stephen C; Lima, John J; Long, Dayna; Ly, Ngoc; Marbin, Jyothi; Moy, James N; Myers, Ross E; Olin, J Tod; Raissy, Hengameh H; Robison, Rachel G; Ross, Kristie; Sorkness, Christine A; Lemanske, Robert F

    2018-03-08

    Asthma exacerbations occur frequently despite the regular use of asthma-controller therapies, such as inhaled glucocorticoids. Clinicians commonly increase the doses of inhaled glucocorticoids at early signs of loss of asthma control. However, data on the safety and efficacy of this strategy in children are limited. We studied 254 children, 5 to 11 years of age, who had mild-to-moderate persistent asthma and had had at least one asthma exacerbation treated with systemic glucocorticoids in the previous year. Children were treated for 48 weeks with maintenance low-dose inhaled glucocorticoids (fluticasone propionate at a dose of 44 μg per inhalation, two inhalations twice daily) and were randomly assigned to either continue the same dose (low-dose group) or use a quintupled dose (high-dose group; fluticasone at a dose of 220 μg per inhalation, two inhalations twice daily) for 7 days at the early signs of loss of asthma control ("yellow zone"). Treatment was provided in a double-blind fashion. The primary outcome was the rate of severe asthma exacerbations treated with systemic glucocorticoids. The rate of severe asthma exacerbations treated with systemic glucocorticoids did not differ significantly between groups (0.48 exacerbations per year in the high-dose group and 0.37 exacerbations per year in the low-dose group; relative rate, 1.3; 95% confidence interval, 0.8 to 2.1; P=0.30). The time to the first exacerbation, the rate of treatment failure, symptom scores, and albuterol use during yellow-zone episodes did not differ significantly between groups. The total glucocorticoid exposure was 16% higher in the high-dose group than in the low-dose group. The difference in linear growth between the high-dose group and the low-dose group was -0.23 cm per year (P=0.06). In children with mild-to-moderate persistent asthma treated with daily inhaled glucocorticoids, quintupling the dose at the early signs of loss of asthma control did not reduce the rate of severe asthma

  3. Glucocorticoid-induced myopathy in the intensive care unit

    DEFF Research Database (Denmark)

    Eddelien, Heidi Shil; Hoffmeyer, Henrik Westy; Lund, Eva Charlotte Løbner

    2015-01-01

    Glucocorticoids (GC) are used for intensive care unit (ICU) patients on several indications. We present a patient who was admitted to the ICU due to severe respiratory failure caused by bronchospasm requiring mechanical ventilation and treated with methylprednisolone 240 mg/day in addition...... to antibiotics and bronchiolytics. When the sedation was lifted on day 10, the patient was awake but quadriplegic. Blood samples revealed elevated muscle enzymes, electromyography showed myopathy, and a muscle biopsy was performed. Glucocorticoid-induced myopathy was suspected, GC treatment was tapered...

  4. Type 1 plaminogen activator inhibitor gene: Functional analysis and glucocorticoid regulation of its promoter

    Energy Technology Data Exchange (ETDEWEB)

    Van Zonneveld, A.J.; Curriden, S.A.; Loskutoff, D.J. (Scripps Clinic and Research Foundation, La Jolla, CA (USA))

    1988-08-01

    Plasminogen activator inhibitor type 1 is an important component of the fibrinolytic system and its biosynthesis is subject to complex regulation. To study this regulation at the level of transcription, the authors have identified and sequenced the promoter of the human plasminogen activator inhibitor type 1 gene. Nuclease protection experiments were performed by using endothelial cell mRNA and the transcription initiation (cap) site was established. Sequence analysis of the 5{prime} flanking region of the gene revealed a perfect TATA box at position {minus}28 to position {minus}23, the conserved distance from the cap site. Comparative functional studies with the firefly luciferase gene as a reporter gene showed that fragments derived from this 5{prime} flanking region exhibited high promoter activity when transfected into bovine aortic endothelial cells and mouse Ltk{sup {minus}} fibroblasts but were inactive when introduced into HeLa cells. These studies indicate that the fragments contain the plasminogen activator inhibitor type 1 promoter and that it is expressed in a tissue-specific manner. Although the fragments were also silent in rat FTO2B hepatoma cells, their promoter activity could be induced up to 40-fold with the synthetic glucocorticoid dexamethasone. Promoter deletion mapping experiments and studies involving the fusion of promoter fragments to a heterologous gene indicated that dexamethasone induction is mediated by a glucocorticoid responsive element with enhancer-like properties located within the region between nucleotides {minus}305 and +75 of the plasminogen activator inhibitor type 1 gene.

  5. Differential response of risedronate on tibial and mandibular bone quality in glucocorticoid-treated growing rats

    International Nuclear Information System (INIS)

    Fujita, Yuko

    2008-01-01

    Glucocorticoids induce bone loss and retard bone growth in children. In this study we investigated the effect of treatment with risedronate on glucocorticoid -prednisolone-induced decreases in bone density, quality, strength and growth of the tibia and mandible in growing rats. Trabecular and cortical bone structure was measured by peripheral quantitative computed tomography (pQCT) and three-dimensional (3D) micro-computed tomography (micro-CT). Indicators of bone strength were calculated from cortical bone density and the modulus of sections obtained from pQCT analysis. Tibial and mandibular bone sizes were also measured. Prednisolone decreased the bone growth of both tibia and mandible. It also caused deterioration of trabecular and cortical bone structure and strength in the mandible, and in cortical bone in the tibia, but had no effect on trabecular bone in the tibia. Risedronate inhibited the prednisolone-induced decreases in tibial width and mandibular length and height but did not improve the retardation of longitudinal bone growth. Risedronate prevented prednisolone-induced deterioration of trabecular and cortical bone architecture. In the mandible, this protective effect of risedronate was accompanied by an increase in cortical bone density and in bone strength. These findings show that risedronate inhibits prednisolone-induced loss of bone density, structure, decrease in bone strength, and retardation of bone growth in the mandible in young growing rats. (author)

  6. Heterogeneity in mechanisms influencing glucocorticoid sensitivity: the need for a systems biology approach to treatment of glucocorticoid-resistant inflammation.

    Science.gov (United States)

    Keenan, Christine R; Radojicic, Danica; Li, Meina; Radwan, Asmaa; Stewart, Alastair G

    2015-06-01

    Glucocorticoids (GCs) have impressive anti-inflammatory and immunosuppressive effects and show a diversity of actions across a variety of cell phenotypes. Implicit in efforts to optimize GCs as anti-inflammatory agents for any or all indications is the notion that the relevant mechanism(s) of action of GCs are fully elucidated. However, recent advances in understanding GC signalling mechanisms have revealed remarkable complexity and contextual dependence, calling into question whether the mechanisms of action are sufficiently well-described to embark on optimization. In the current review, we address evidence for differences in the mechanism of action in different cell types and contexts, and discuss contrasts in mechanisms of glucocorticoid insensitivity, with a focus on asthma and Chronic Obstructive Pulmonary Disease (COPD). Given this complexity, we consider the potential breadth of impact and selectivity of strategies directed to reversing the glucocorticoid insensitivity. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Low-dose glucocorticoids in hyperandrogenism Efecto de bajas dosis de glucocorticoides en el hiperandrogenismo

    Directory of Open Access Journals (Sweden)

    Leonardo Rizzo

    2007-06-01

    Full Text Available To investigate the effect of low-doses of glucocorticoids on androgen and cortisol secretion during the course of the day, we evaluated clinical signs of hyperandrogenism and total, free and bioavailable testosterone, SHBG, and cortisol following two different protocols: A fourteen patients received betamethasone 0.6 mg/day (n=8 or methylprednisolone 4 mg/day (n=6, as single daily oral dose at 11.00 PM, during 30 days, B fourteen patients were evaluated under betamethasone 0.3 mg in a single daily dose at 11.00 PM during six months, 11 out of whom were re-evaluated six months later. Twenty eight women with hyperandrogenism were included and seven normal females were used as control. Blood samples were taken in follicular phase at 8 AM and 7 PM to determine SHBG, cortisol, total, free and bioavailable testosterone. In both protocols, a significant morning and evening decrease in cortisol and testosterone (pCon el objetivo de investigar el efecto de bajas dosis de glucocorticoides sobre la secreción de andrógenos y cortisol en el curso del día, evaluamos signos de hiperandrogenismo, testosterona total, libre y biodisponible y cortisol según dos protocolos diferentes: A catorce pacientes recibieron betametasona 0.6 mg/día (n= 8 o metilprednisolona 4 mg/día (n= 6 en dosis única cotidiana, a las 23 h, durante 30 días, B catorce pacientes fueron evaluadas bajo betametasona 0.3 mg en dosis única cotidiana a la 23 h, administrada durante 6 meses; de ellas, 11 pacientes fueron re-evaluadas 6 meses más tarde. Se incluyeron 28 mujeres con hiperandrogenismo y 7 controles normales. Se obtuvieron muestras de sangre en fase folicular a las 08:00 y 9:00 h para determinar SHBG, cortisol, testosterona total, libre y biodisponible. En ambos protocolos se observó una disminución significativa de cortisol y testosterona (p<0.05 a <0.01, más importante con betametasona (p<0.05. En el protocolo B, los niveles matutinos de SHBG aumentaron

  8. The MAM rodent model of schizophrenia.

    Science.gov (United States)

    Lodge, Daniel J

    2013-01-01

    Rodent models of human disease are essential to obtain a better understanding of disease pathology, the mechanism of action underlying conventional treatments, as well as for the generation of novel therapeutic approaches. There are a number of rodent models of schizophrenia based on either genetic manipulations, acute or sub-chronic drug administration, or developmental disturbances. The prenatal methylazoxymethanol acetate (MAM) rodent model is a developmental disruption model gaining increased attention because it displays a number of histological, neurophysiological, and behavioral deficits analogous to those observed in schizophrenia patients. This unit describes the procedures required to safely induce the MAM phenotype in rats. In addition, we describe a simple behavioral procedure, amphetamine-induced hyperlocomotion, which can be utilized to verify the MAM phenotype.

  9. Behavioral and mechanistic insight into rodent empathy.

    Science.gov (United States)

    Sivaselvachandran, Sivaani; Acland, Erinn L; Abdallah, Salsabil; Martin, Loren J

    2016-06-14

    Empathy is a psychological construct that allows individuals to understand and share the emotions of others. The ability to share emotional states relies on basic social mechanisms, such as mimicry and emotional contagion, which are considered building blocks for empathy. Mimicking another's emotional or physical state is essential for successful social interactions and is found in a number of animal species. For the current review we focus on emotional state sharing in rodents, a core feature of empathy that is often measured using pain and fear as proxies; we also discuss prosociality in rodents. The evidence for empathy in rodents shows that rats and mice consistently imitate arousal states and behaviors of conspecifics and will even sacrifice personal gain to relieve the distress of a conspecific. These behaviors support basic processes that are crucial for the survival of individual animals and give us insight into the neural mechanisms that govern empathy-related behaviors. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. Structural variants of glucocorticoid receptor binding sites and different versions of positive glucocorticoid responsive elements: Analysis of GR-TRRD database.

    Science.gov (United States)

    Merkulov, Vasily M; Merkulova, Tatyana I

    2009-05-01

    The GR-TRRD section of the TRRD database contains the presently largest sample of published nucleotide sequences with experimentally confirmed binding to the glucocorticoid hormone receptor (GR). This sample comprises 160 glucocorticoid receptor binding sites (GRbs) from 77 vertebrate glucocorticoid-regulated genes. Analysis of this sample has demonstrated that the structure of only half GRbs (54%) corresponds to the generally accepted organization of glucocorticoid response element (GRE) as an inverted repeat of the TGTTCT hexanucleotide. As many as 40% of GRbs contain only the hexanucleotide, and the majority of such "half-sites" belong to the glucocorticoid-inducible genes. An expansion of the sample allowed the consensus of GRbs organized as an inverted repeat to be determined more precisely. Several possible mechanisms underlying the role of the noncanonical receptor binding sites (hexanucleotide half-sites) in the glucocorticoid induction are proposed based on analysis of the literature data.

  11. Molecular mechanisms of glucocorticoids action: implications for treatment of rhinosinusitis and nasal polyposis.

    Science.gov (United States)

    Grzanka, Alicja; Misiołek, Maciej; Golusiński, Wojciech; Jarząb, Jerzy

    2011-02-01

    Intra-nasal glucocorticoids are the most effective drugs available for rhinosinusitis and nasal polyposis treatment. Their effectiveness depends on many factors and not all of them have been well recognized so far. The authors present the basic information on molecular mechanisms of glucocorticoid action, direct and indirect effects of glucocorticoids on transcription of genes encoding inflammatory mediators. They focus on recently proved nongenomic mechanisms which appear quickly, from several seconds to minutes after glucocorticoid administration and discuss clinical implications resulting from this knowledge. Discovery of nongenomic glucocorticoid actions allows for better use of these drugs in clinical practice.

  12. Understanding arid environments using fossil rodent middens

    Science.gov (United States)

    Pearson, S.; Betancourt, J.L.

    2002-01-01

    American rodent middens have made a more dramatic contribution to understanding past environments and the development of ecological theory than Australian rodent middens. This relates to differences in the natural environment, the landscape histories, the scale and scientific approaches of the researchers. The comparison demonstrates: the power of synoptic perspectives; the value of thorough macrofossil identification in midden analysis and its potential advance in Australia where pollen has dominated analyses, the value of herbaria and reference collections; the potential of environmental databases; the importance of scientific history and 'critical research mass' and; finally, the opportunistic nature of palaeoecological research. ?? 2002 Elsevier Science Ltd.

  13. Neurogenic inflammation in human and rodent skin

    DEFF Research Database (Denmark)

    Schmelz, M; Petersen, Lars Jelstrup

    2001-01-01

    The combination of vasodilation and protein extravasation following activation of nociceptors has been termed "neurogenic inflammation." In contrast to rodents, no neurogenic protein extravasation can be elicited in healthy human skin. Dermal microdialysis has considerably increased our knowledge...... about neurogenic inflammation in human skin, including the involvement of mast cells.......The combination of vasodilation and protein extravasation following activation of nociceptors has been termed "neurogenic inflammation." In contrast to rodents, no neurogenic protein extravasation can be elicited in healthy human skin. Dermal microdialysis has considerably increased our knowledge...

  14. Molecular mechanisms of glucocorticoid receptor signaling Mecanismos moleculares de señalización del receptor de glucocorticoides

    Directory of Open Access Journals (Sweden)

    Marta Labeur

    2010-10-01

    Full Text Available This review highlights the most recent findings on the molecular mechanisms of the glucocorticoid receptor (GR. Most effects of glucocorticoids are mediated by the intracellular GR which is present in almost every tissue and controls transcriptional activation via direct and indirect mechanisms. Nevertheless the glucocorticoid responses are tissue -and gene- specific. GR associates selectively with corticosteroid ligands produced in the adrenal gland in response to changes of humoral homeostasis. Ligand interaction with GR promotes either GR binding to genomic glucocorticoid response elements, in turn modulating gene transcription, or interaction of GR monomers with other transcription factors activated by other signalling pathways leading to transrepression. The GR regulates a broad spectrum of physiological functions, including cell differentiation, metabolism and inflammatory responses. Thus, disruption or dysregulation of GR function will result in severe impairments in the maintenance of homeostasis and the control of adaptation to stress.Esta revisión destaca los más recientes hallazgos sobre los mecanismos moleculares del receptor de glucocorticoides (GR. La mayoría de los efectos de los glucocorticoides son mediados por los GR intracelulares presentes en casi todos los tejidos y controlan la activación transcripcional por mecanismos directos e indirectos. Las respuestas a los glucocorticoides son específicas para cada gen y tejido. Los GR se asocian en forma selectiva con ligandos producidos en la glándula adrenal, corticosteroides, en respuesta a cambios neuroendocrinos. La interacción del ligando con el GR promueve: a la unión del GR a elementos genómicos de respuesta a glucocorticoides, modulando la transcripción; b la interacción de monómeros del GR con otros factores de transcripción activados por otras vías, llevando a la transrepresión. El GR regula un amplio espectro de funciones fisiológicas, incluyendo la

  15. X-ray Crystal Structure of the Novel Enhanced-Affinity Glucocorticoid Agonist Fluticasone Furoate in the Glucocorticoid Receptor−Ligand Binding Domain

    Energy Technology Data Exchange (ETDEWEB)

    Biggadike, Keith; Bledsoe, Randy K.; Hassell, Anne M.; Kirk, Barrie E.; McLay, Iain M.; Shewchuk, Lisa M.; Stewart, Eugene L. (GSKNC); (GSK)

    2008-07-08

    An X-ray crystal structure is reported for the novel enhanced-affinity glucocorticoid agonist fluticasone furoate (FF) in the ligand binding domain of the glucocorticoid receptor. Comparison of this structure with those of dexamethasone and fluticasone propionate shows the 17{alpha} furoate ester to occupy more fully the lipophilic 17{alpha} pocket on the receptor, which may account for the enhanced glucocorticoid receptor binding of FF.

  16. Glucocorticoids: Dose-related effects on osteoclast formation and function via reactive oxygen species and autophagy.

    Science.gov (United States)

    Shi, Jun; Wang, Long; Zhang, Hongyang; Jie, Qiang; Li, Xiaojie; Shi, Qiyue; Huang, Qiang; Gao, Bo; Han, Yuehu; Guo, Kai; Liu, Jian; Yang, Liu; Luo, Zhuojing

    2015-10-01

    Whether glucocorticoids directly enhance or interrupt osteoclastogenesis is still a controversial subject. In this study, we ascertained the dose-dependent positive effects of glucocorticoids on osteoclastogenesis in vivo and in vitro as well as investigated the mechanism in vitro. As the dose of glucocorticoids increased, osteoclastogenesis was stimulated at 0.1 μM, a peak was achieved at 1 μM and a corresponding decrease occurred at 10 μM. Reactive oxygen species (ROS), which play a crucial role in osteoclastogenesis, and autophagy flux activity, a cellular recycling process, were consistently up-regulated along with the dose-dependent effects of the glucocorticoids on osteoclast formation and function. N-acetyl-cysteine (NAC), a ROS scavenger, abrogated the effects of the glucocorticoids on autophagy and osteoclastogenesis. Moreover, 3-methyladenine (3-MA), an autophagy inhibitor, interrupted osteoclastogenesis stimulation by the glucocorticoids. These results implied that with glucocorticoid administration, ROS and autophagy, as a downstream factor of ROS, played vital roles in osteoclast formation and function. 3-MA administration did not enhance ROS accumulation, so that autophagy had no effect on ROS induced by glucocorticoids. Our investigation demonstrated that glucocorticoids had dose-dependent positive effects on osteoclast formation and function via ROS and autophagy. These results provide support for ROS and autophagy as therapeutic targets in glucocorticoid-related bone loss diseases such as glucocorticoid-induced osteoporosis. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Pioglitazone Enhances the Beneficial Effects of Glucocorticoids in Experimental Nephrotic Syndrome.

    Science.gov (United States)

    Agrawal, S; Chanley, M A; Westbrook, D; Nie, X; Kitao, T; Guess, A J; Benndorf, R; Hidalgo, G; Smoyer, W E

    2016-05-04

    Glucocorticoids are the primary therapy for nephrotic syndrome (NS), but have serious side effects and are ineffective in ~20-50% of patients. Thiazolidinediones have recently been suggested to be renoprotective, and to modulate podocyte glucocorticoid-mediated nuclear receptor signaling. We hypothesized that thiazolidinediones could enhance glucocorticoid efficacy in NS. We found that puromycin aminonucleoside-induced proteinuria in rats was significantly reduced by both high-dose glucocorticoids (79%) and pioglitazone (61%), but not low-dose glucocorticoids (25%). Remarkably, pioglitazone + low-dose glucocorticoids also reduced proteinuria (63%) comparably to high-dose glucocorticoids, whereas pioglitazone + high-dose glucocorticoids reduced proteinuria to almost control levels (97%). Molecular analysis revealed that both glucocorticoids and pioglitazone enhanced glomerular synaptopodin and nephrin expression, and reduced COX-2 expression, after injury. Furthermore, the glomerular phosphorylation of glucocorticoid receptor and Akt, but not PPARγ, correlated with treatment-induced reductions in proteinuria. Notably, clinical translation of these findings to a child with refractory NS by the addition of pioglitazone to the treatment correlated with marked reductions in both proteinuria (80%) and overall immunosuppression (64%). These findings together suggest that repurposing pioglitazone could potentially enhance the proteinuria-reducing effects of glucocorticoids during NS treatment.

  18. Cardiac outcome prevention effectiveness of glucocorticoids in acute decompensated heart failure: COPE-ADHF study.

    Science.gov (United States)

    Liu, Chao; Liu, Kunshen

    2014-04-01

    Newly emerging evidence showed that glucocorticoids could potentiate natriuretic peptides' action by increasing the density of natriuretic peptide receptor A, leading to a potent diuresis and a renal function improvement in patients with acute decompensated heart failure (ADHF). Therefore, glucocorticoid therapy may be used in patients with ADHF. One hundred two patients with ADHF were randomized to receive glucocorticoids or standard treatment. Change from baseline in serum creatinine (SCr) at day 7 and cardiovascular death within 30 days were recorded. The study was terminated early because of slow site initiation and patient enrolment. Glucocorticoid therapy seemed to be well tolerated. There was a remarkable SCr reduction after 7 days treatment. The change from baseline in SCr is -0.14 mg/dL in glucocorticoid group versus -0.02 mg/dL in standard treatment group (P glucocorticoid group with odds ratio of 0.26 (3 deaths in glucocorticoid vs. 10 deaths in standard treatment group, P glucocorticoid therapy persisted during the follow-up. Patient-assessed dyspnea and physician-assessed global clinical status were also improved in glucocorticoid group. Limited data indicate that glucocorticoid therapy may be used safely in patients with ADHF in short term. Glucocorticoid therapy did not cause heart failure deterioration. Further investigations are warranted.

  19. Glucocorticoids Sensitize the Innate Immune System through Regulation of the NLRP3 Inflammasome*

    Science.gov (United States)

    Busillo, John M.; Azzam, Kathleen M.; Cidlowski, John A.

    2011-01-01

    Glucocorticoids have long been recognized as powerful anti-inflammatory compounds that are one of the most widely prescribed classes of drugs in the world. However, their role in the regulation of innate immunity is not well understood. We sought to examine the effects of glucocorticoids on the NOD-like receptors (NLRs), a central component of the inflammasome and innate immunity. Surprisingly, we show that glucocorticoids induce both NLRP3 messenger RNA and protein, which is a critical component of the inflammasome. The glucocorticoid-dependent induction of NLRP3 sensitizes the cells to extracellular ATP and significantly enhances the ATP-mediated release of proinflammatory molecules, including mature IL-1β, TNF-α, and IL-6. This effect was specific for glucocorticoids and dependent on the glucocorticoid receptor. These studies demonstrate a novel role for glucocorticoids in sensitizing the initial inflammatory response by the innate immune system. PMID:21940629

  20. Why glucocorticoid withdrawal may sometimes be as dangerous as the treatment itself

    DEFF Research Database (Denmark)

    Dinsen, Stina; Baslund, Bo; Klose, Marianne

    2013-01-01

    Glucocorticoid therapy is widely used, but withdrawal from glucocorticoids comes with a potential life-threatening risk of adrenal insufficiency. Recent case reports document that adrenal crisis after glucocorticoid withdrawal remains a serious problem in clinical practice. Partly due...... to difficulties in inter-study comparison the true prevalence of glucocorticoid-induced adrenal insufficiency is unknown, but it might be somewhere between 46 and 100% 24h after glucocorticoid withdrawal, 26-49% after approximately one week, and some patients show prolonged suppression lasting months to years....... Adrenal insufficiency might therefore be underdiagnosed in clinical practice. Clinical data do not permit accurate estimates of a lower limit of glucocorticoid dose and duration of treatment, where adrenal insufficiency will not occur. Due to individual variation, neither the glucocorticoid dose nor...

  1. Glucocorticoid actions on synapses, circuits, and behavior: Implications for the energetics of stress

    Science.gov (United States)

    Herman, James P.

    2015-01-01

    Environmental stimuli that signal real or potential threats to homeostasis lead to glucocorticoid secretion by the hypothalamic-pituitary-adrenocortical (HPA) axis. Glucocorticoids promote energy redistribution and are critical for survival and adaptation. This adaptation requires the integration of multiple systems and engages key limbic-neuroendocrine circuits. Consequently, glucocorticoids have profound effects on synaptic physiology, circuit regulation of stress responsiveness, and, ultimately, behavior. While glucocorticoids initiate adaptive processes that generate energy for coping, prolonged or inappropriate glucocorticoid secretion becomes deleterious. Inappropriate processing of stressful information may lead to energetic drive that does not match environmental demand, resulting in risk factors for pathology. Thus, dysregulation of the HPA axis may promote stress-related illnesses (e.g. depression, PTSD). This review summarizes the latest developments in central glucocorticoid actions on synaptic, neuroendocrine, and behavioral regulation. Additionally, these findings will be discussed in terms of the energetic integration of stress and the importance of context-specific regulation of glucocorticoids. PMID:24361584

  2. Glucocorticoid-induced osteoporosis – a disorder of mesenchymal stromal cells?

    Directory of Open Access Journals (Sweden)

    Mark Stuart Cooper

    2011-08-01

    Full Text Available Glucocorticoids are a class of steroid hormones that are essential to life but cause serious harm in excess. The main clinical features of glucocorticoid excess are due to adverse effects on cells and tissues that arise from a common developmental precursor – the mesenchymal stromal cell (MSC; sometimes referred to as the mesenchymal stem cell. Interestingly glucocorticoids appear essential for the differentiation of cells and tissues that arise from MSCs. High levels of glucocorticoids are used in tissue engineering strategies to enhance the formation of tissues such as bone, cartilage and muscle. This article discusses the paradox that glucocorticoids both enhance and impair MSC development and function. It will describe how endogenous glucocorticoids are likely to be important in these processes in vivo and will discuss the implications for therapies aimed at reducing the damage associated with the use of therapeutic glucocorticoids.

  3. Glucocorticoid management in rheumatoid arthritis: morning or night low dose?

    Science.gov (United States)

    Paolino, Sabrina; Cutolo, Maurizio; Pizzorni, Carmen

    2017-01-01

    Morning symptoms of rheumatoid arthritis (RA) are linked to circadian increase of night inflammation, supported by inadequate cortisol secretion in active disease. Therefore, exogenous glucocorticoid administration in RA is recommended by EULAR and ACR from the beginning of the diagnosis, since may partially act like a "replacement therapy". In addition, the prevention/treatment of the night up-regulation of the immune/inflammatory reaction has been shown more effective when exogenous glucocorticoid administration is managed with a night-time-release formulation. Despite a considerably higher cost than conventional prednisone (immediate release), chronotherapy with night-time-release prednisone has been recognized a cost-effective option for RA patients not on glucocorticoids who are eligible for therapy with biologic disease-modifying antirheumatic drugs (DMARDs). Interestingly, since different cell populations involved in the inflammatory process are particularly activated during the night (i.e. monocytes, macrophages), other therapeutical approaches used in RA, such as conventional DMARDs and non-steroidal anti-inflammatory drugs (NSAIDs) should follow the same concepts of glucocorticoid chronotherapy. Therefore, bedtime methotrexate chronotherapy was found to better manage RA symptoms, and several available NSAIDs (i.e. indomethacin, aceclofenac, ketoprofen, flurbiprofen, lornoxicam) have been recently modified in their formulation, in order to obtain more focused night action.

  4. the effect of early administration of glucocorticoids on learning and ...

    African Journals Online (AJOL)

    Daniel Owu

    was observed that the animals in the treatment group preferred to return to the start arm or explore the other arm. This is indicative of impaired spatial memory. Steroids administered postnatally may have transient retarding effect on learning and memory functions. Keywords: Glucocorticoids, learning, memory, brain, rat.

  5. Calycosin regulates glucocorticoid-induced apoptosis via Nrf2/ARE ...

    African Journals Online (AJOL)

    Calycosin regulates glucocorticoid-induced apoptosis via Nrf2/ARE signaling in MC3T3-E1 cells. ... If you would like more information about how to print, save, and work with PDFs, Highwire Press provides a helpful Frequently Asked Questions about PDFs. Alternatively, you can download the PDF file directly to your ...

  6. Uso de glucocorticoides en enfermedades alérgicas

    Directory of Open Access Journals (Sweden)

    M Rodríguez-González

    2017-01-01

    Full Text Available Los glucocorticoides son análogos sintéticos de las hormonas adrenocorticales, de uso común, de gran utilidad en la práctica clínica del pediatra y se consideran la piedra angular del tratamiento farmacológico de enfermedades alérgicas.

  7. Glucocorticoids, the etiology of obesity and the metabolic syndrome

    NARCIS (Netherlands)

    Dallman, Mary F.; Akana, Susan F.; Pecoraro, Norman C.; Warne, James P.; la Fleur, Susanne E.; Foster, Michelle T.

    2007-01-01

    In mammals, glucocorticoid actions appear to have evolved to maintain and enhance energy stores to be used for life-saving gluconeogenesis. They act on the brain to stimulate search behaviors, palatable feeding and emotionally relevant memories, and they act on the body to mobilize stored peripheral

  8. Brief report: Glucocorticoid receptor polymorphism affects transrepression but not transactivation

    NARCIS (Netherlands)

    E.L.T. van den Akker (Erica); H. Russcher (Henk); E.F.C. van Rossum (Liesbeth); A.O. Brinkmann (Albert); F.H. de Jong (Frank); A.C.S. Hokken-Koelega (Anita); H.A.P. Pols (Huib); J.W. Koper (Jan); S.W.J. Lamberts (Steven)

    2006-01-01

    textabstractContext: Glucocorticoids (GCs) are extensively used in the treatment of inflammatory and autoimmune diseases. Their beneficial effects are thought to be mediated by GC transrepression on gene expression. However, their use is limited by serious adverse effects, presumably mediated by GC

  9. Glucocorticoid management in rheumatoid arthritis: morning or night low dose?

    Directory of Open Access Journals (Sweden)

    Sabrina Paolino

    2017-08-01

    Full Text Available Morning symptoms of rheumatoid arthritis (RA are linked to circadian increase of night inflammation, supported by inadequate cortisol secretion in active disease. Therefore, exogenous glucocorticoid administration in RA is recommended by EULAR and ACR from the beginning of the diagnosis, since may partially act like a “replacement therapy”. In addition, the prevention/treatment of the night up-regulation of the immune/inflammatory reaction has been shown more effective when exogenous glucocorticoid administration is managed with a night-time-release formulation. Despite a considerably higher cost than conventional prednisone (immediate release, chronotherapy with night-time-release prednisone has been recognized a cost-effective option for RA patients not on glucocorticoids who are eligible for therapy with biologic disease-modifying antirheumatic drugs (DMARDs. Interestingly, since different cell populations involved in the inflammatory process are particularly activated during the night (i.e. monocytes, macrophages, other therapeutical approaches used in RA, such as conventional DMARDs and non-steroidal anti-inflammatory drugs (NSAIDs should follow the same concepts of glucocorticoid chronotherapy. Therefore, bedtime methotrexate chronotherapy was found to better manage RA symptoms, and several available NSAIDs (i.e. indomethacin, aceclofenac, ketoprofen, flurbiprofen, lornoxicam have been recently modified in their formulation, in order to obtain more focused night action.

  10. Liposomal targeting of glucocorticoids to inhibit tumor angiogenesis

    NARCIS (Netherlands)

    Banciu, M.

    2007-01-01

    Glucocorticoids (GC) have inhibitory actions on solid tumor growth due to suppressive effects on tumor angiogenesis and inflammation. When evaluating the preclinical studies on solid tumor growth inhibition, it appears that GC-induced antitumor effects are achieved by using substantially higher

  11. Optimized glucocorticoid therapy: teaching old drugs new tricks.

    Science.gov (United States)

    Strehl, Cindy; Buttgereit, Frank

    2013-11-05

    Glucocorticoids (GCs) are commonly used in the treatment of a wide range of rheumatic and other inflammatory diseases. They exert their potent anti-inflammatory and immunosuppressive effects primarily via so called genomic mechanisms, mediated by the cytosolic glucocorticoid receptor (cGR). This mechanism of GC action can be divided into the transactivation and the transrepression processes. However, also rapid effects of GCs exist which are mediated by specific and unspecific non-genomic mechanisms. A clinical relevance of this mode of GC action is assumed for effects mediated by membrane-bound glucocorticoid receptors, but detailed knowledge on the underlying mechanisms is still missing. Great efforts have been made in the past to diminish GC-induced adverse effects, thus improving the benefit/risk ratio of the drugs. Besides approaches to improve the treatment with conventional glucocorticoids currently available to clinicians, new innovative GCs or GC receptor ligands are also being developed. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  12. Glucocorticoid Receptor Variants Modulate the Sensitivity to Cortisol

    NARCIS (Netherlands)

    H. Russcher (Henk)

    2006-01-01

    textabstractSynthetic glucocorticoids are used therapeutically for numerous indications. However, due to their broad physiological effects across many systems, side effects of GC therapy can be extensive and limit the clinical utility of GCs as a drug. One of the main urgent questions at this

  13. The effect of early administration of glucocorticoids on learning and ...

    African Journals Online (AJOL)

    It has been observed that steroids administered postnatally may have transient retarding effect on learning and memory functions, and that animal age and sex may modify such effects. This study aims to illustrate the effect of early administration of glucocorticoids on learning and spatial memory. Wistar rat pups were ...

  14. Impact of Preterm Birth on Glucocorticoid Variability in Human Milk.

    Science.gov (United States)

    Pundir, Shikha; Mitchell, Cameron J; Thorstensen, Eric B; Wall, Clare R; Perrella, Sharon L; Geddes, Donna T; Cameron-Smith, David

    2018-02-01

    Preterm birth is a stressful event for both the mother and infant. Whereas the initiation of breastfeeding is important for preterm infant health, little is known of the glucocorticoid hormones (cortisol and cortisone) in human milk following preterm birth. Research aim: The aim of this study was to investigate the relationship between human milk glucocorticoid concentrations and preterm birth. Human milk was sampled weekly for up to 6 weeks from 22 women who delivered a preterm infant at 28 to 32 weeks' gestation. Human milk was analyzed for total and free cortisol and cortisone concentrations using liquid chromatography-tandem mass spectrometry. Milk sampled from mothers of preterm infants had more cortisone than cortisol ( p hormones ( p = .001, r = .85). The cortisone was significantly higher in the milk of mothers who delivered infants after 30 weeks compared with those who delivered before 30 weeks of gestation ( p = .02). Glucocorticoid concentrations did not change over the sampling time (weeks 1 to 6 postpartum) and did not differ by infant gender. Glucocorticoids were present in all milk samples following preterm birth. Cortisone concentration tended to be higher in those who delivered after 30 weeks' gestation but did not increase further over the weeks following birth.

  15. Glucocorticoids and inhibition of bone formation induced by skeletal unloading

    Energy Technology Data Exchange (ETDEWEB)

    Halloran, B.P.; Bikle, D.D.; Cone, C.M.; Morey-Holton, E. (Univ. of California, San Francisco (USA) Veterans Administration Medical Center, San Francisco, CA (USA) NASA-Ames Research Center, Moffett Field, CA (USA))

    1988-12-01

    Skeletal unloading or loss of normal weight bearing in the growing animal inhibits bone formation and reduces bone calcium. To determine whether the inhibition of bone formation induced by skeletal unloading is a consequence of an increase in plasma glucocorticoids and/or an increase in bone sensitivity to glucocorticoids, the authors measured plasma corticosterone throughout the day in unloaded and normally loaded rats (hindlimb elevation model) and examined the effect of adrenalectomy on the response of bone to skeletal unloading. Plasma corticosterone levels were similar in normally loaded and unloaded rats at all times. Skeletal unloading in sham-adrenalectomized animals reduced tibial and vertebral calcium by 11.5 and 11.1%, respectively, and in adrenalectomized animals by 15.3 and 20.3%, respectively. Uptake of {sup 45}Ca and ({sup 3}H)proline in the tibia was reduced by 8 and 14%, respectively, in the sham-adrenalectomized animals and by 13 and 19% in the adrenalectomized animals. Bone formation and apposition rates were reduced to the same level in sham- and adrenalectomized animals. These results suggest that the inhibition of bone formation induced by skeletal unloading is not a consequence of increased plasma glucocorticoids or an increase in bone sensitivity to the glucocorticoids but, rather, point to a local mediator in bone that senses mechanical load and transmits that information to the bone-forming cells directly.

  16. Glucocorticoid Treatment in Childhood Nephrotic Syndrome : weighting the cornerstone

    NARCIS (Netherlands)

    N. Teeninga (Nynke)

    2013-01-01

    textabstractUnderstanding which factors influence relapse patterns in childhood nephrotic syndrome is clinically very relevant and could aid in developing new treatment strategies. Clinicians are continuously challenged to reduce relapse rates and at the same time to avoid glucocorticoid toxicity.

  17. Adrenocorticotropic Hormone Secreting Pheochromocytoma Underlying Glucocorticoid Induced Pheochromocytoma Crisis

    Directory of Open Access Journals (Sweden)

    Gil A. Geva

    2018-01-01

    Full Text Available Context. Pheochromocytomas are hormone secreting tumors of the medulla of the adrenal glands found in 0.1–0.5% of patients with hypertension. The vast majority of pheochromocytomas secrete catecholamines, but they have been occasionally shown to also secrete interleukins, calcitonin, testosterone, and in rare cases adrenocorticotropic hormone. Pheochromocytoma crisis is a life threatening event in which high levels of catecholamines cause a systemic reaction leading to organ failure. Case Description. A 70-year-old man was admitted with acute myocardial ischemia following glucocorticoid administration as part of an endocrine workup for an adrenal mass. Cardiac catheterization disclosed patent coronary arteries and he was discharged. A year later he returned with similar angina-like chest pain. During hospitalization, he suffered additional events of chest pain, shortness of breath, and palpitations following administration of glucocorticoids as preparation for intravenous contrast administration. Throughout his admission, the patient demonstrated both signs of Cushing’s syndrome and high catecholamine levels. Following stabilization of vital parameters and serum electrolytes, the adrenal mass was resected surgically and was found to harbor an adrenocorticotropic hormone secreting pheochromocytoma. This is the first documented case of adrenocorticotropic hormone secreting pheochromocytoma complicated by glucocorticoid induced pheochromocytoma crisis. Conclusion. Care should be taken when administering high doses of glucocorticoids to patients with suspected pheochromocytoma, even in a patient with concomitant Cushing’s syndrome.

  18. The Glucocorticoid Receptor Controls Hepatic Dyslipidemia through Hes1

    NARCIS (Netherlands)

    Lemke, U.; Krones-Herzig, A.; Berriel Diaz, M.; Narvekar, P.; Ziegler, A.; Vegiopoulos, A.; Cato, A.C.B.; Bohl, S.; Klingmüller, U.; Screaton, R.A.; Müller-Decker, K.; Kersten, A.H.; Herzig, S.

    2008-01-01

    Aberrant accumulation of lipids in the liver (¿fatty liver¿ or hepatic steatosis) represents a hallmark of the metabolic syndrome and is tightly associated with obesity, type II diabetes, starvation, or glucocorticoid (GC) therapy. While fatty liver has been connected with numerous abnormalities of

  19. Glucocorticoid receptor effects on the immune system and infl ammation

    NARCIS (Netherlands)

    E.L.T. van den Akker (Erica)

    2008-01-01

    textabstractThomas Addison’s discovery in the mid-1800s that the adrenal cortex was essential for survival preceded by nearly a century the demonstration that this gland produced at least two distinct hormones, each essential for normal life. How glucocorticoids sustained life remained a mystery for

  20. Methods for measuring populations of arboreal rodents.

    Science.gov (United States)

    Andrew B. Carey; Brian L. Biswell; Joseph W. Witt

    1991-01-01

    Three arboreal rodents are sensitive indicators of forest ecosystem function in the Pacific Northwest. The northern flying squirrel (Glaucomys sabrinus) is mycophagous, cavity-nesting, and a major prey of the spotted owl (Strix occidentalis). The red tree vole (Phenacomys longicaudus) is restricted to trees...

  1. Estimating body mass of fossil rodents

    NARCIS (Netherlands)

    Freudenthal, M.; Martín-Suárez, E.

    2013-01-01

    Reconstructing the body mass of a fossil animal is an essential step toward understanding its palaeoecological role. Length × width (L×W) of the first lower molar (m1) is frequently used as a proxy for body mass in fossil mammals. However, among rodents, Muroidea have no premolar and an elongated

  2. Evaluating Glucocorticoid Administration on Biomechanical Properties of Rats’ Tibial Diaphysis

    Science.gov (United States)

    Freidouni, Mohammadjavad; Nejati, Hossein; Salimi, Maryam; Bayat, Mohammad; Amini, Abdollah; Noruzian, Mohsen; Asgharie, Mohammad Ali; Rezaian, Milad

    2015-01-01

    Background: Osteoporosis is a disease, which causes bone loss and fractures. Although glucocorticoids effectively suppress inflammation, their chronic use is accompanied by bone loss with a tendency toward secondary osteoporosis. Objectives: This study took into consideration the importance of cortical bone in the entire bone's mechanical competence. Hence, the aim of this study was to assess the effects of different protocols of glucocorticoid administration on the biomechanical properties of tibial bone diaphysis in rats compared to control and low-level laser-treated rats. Materials and Methods: This experimental study was conducted at Shahid Beheshti University of Medical Sciences, Tehran, Iran. We used systematic random sampling to divide 40 adult male rats into 8 groups with 5 rats in each group. Groups were as follows: 1) control, 2) dexamethasone (7 mg/week), 3) dexamethasone (0.7 mg/week), 4) methylprednisolone (7 mg/kg/week), 5) methylprednisolone (5 mg/kg twice weekly), 6) dexamethasone (7 mg/kg three times per week), 7) dexamethasone (0.7 mg/kg thrice per week), and 8) low-level laser-treated rats. The study periods were 4-7 weeks. At the end of the treatment periods, we examined the mechanical properties of tibial bone diaphysis. Data were analyzed by statistical analyses. Results: Glucocorticoid-treated rats showed weight loss and considerable mortality (21%). The biomechanical properties (maximum force) of glucocorticoid-treated rats in groups 4 (62 ± 2.9), 6 (63 ± 5.1), and 7 (60 ± 5.3) were comparable with the control (46 ± 1.5) and low-level laser-treated (57 ± 3.2) rats. Conclusions: In contrast to the findings in humans and certain other species, glucocorticoid administration caused anabolic effect on the cortical bone of tibia diaphysis bone in rats. PMID:26019900

  3. Preadmission Use of Glucocorticoids and 30-Day Mortality After Stroke.

    Science.gov (United States)

    Sundbøll, Jens; Horváth-Puhó, Erzsébet; Schmidt, Morten; Dekkers, Olaf M; Christiansen, Christian F; Pedersen, Lars; Bøtker, Hans Erik; Sørensen, Henrik T

    2016-03-01

    The prognostic impact of glucocorticoids on stroke mortality remains uncertain. We, therefore, examined whether preadmission use of glucocorticoids is associated with short-term mortality after ischemic stroke, intracerebral hemorrhage (ICH), or subarachnoid hemorrhage (SAH). We conducted a nationwide population-based cohort study using medical registries in Denmark. We identified all patients with a first-time inpatient diagnosis of stroke between 2004 and 2012. We categorized glucocorticoid use as current use (last prescription redemption ≤90 days before admission), former use, and nonuse. Current use was further classified as new or long-term use. We used Cox regression to compute 30-day mortality rate ratios with 95% confidence intervals (CIs), controlling for confounders. We identified 100 042 patients with a first-time stroke. Of these, 83 735 patients had ischemic stroke, 11 779 had ICH, and 4528 had SAH. Absolute mortality risk was higher for current users compared with nonusers for ischemic stroke (19.5% versus 10.2%), ICH (46.5% versus 34.4%), and SAH (35.0% versus 23.2%). For ischemic stroke, the adjusted 30-day mortality rate ratio was increased among current users compared with nonusers (1.58, 95% CI: 1.46-1.71), driven by the effect of glucocorticoids among new users (1.80, 95% CI: 1.62-1.99). Current users had a more modest increase in the adjusted 30-day mortality rate ratio for hemorrhagic stroke (1.26, 95% CI: 1.09-1.45 for ICH and 1.40, 95% CI: 1.01-1.93 for SAH) compared with nonusers. Former use was not substantially associated with mortality. Preadmission use of glucocorticoids was associated with increased 30-day mortality among patients with ischemic stroke, ICH, and SAH. © 2016 American Heart Association, Inc.

  4. FBXW7 regulates glucocorticoid response in T-cell acute lymphoblastic leukaemia by targeting the glucocorticoid receptor for degradation.

    Science.gov (United States)

    Malyukova, A; Brown, S; Papa, R; O'Brien, R; Giles, J; Trahair, T N; Dalla Pozza, L; Sutton, R; Liu, T; Haber, M; Norris, M D; Lock, R B; Sangfelt, O; Marshall, G M

    2013-04-01

    Loss of function mutation in FBXW7, an E3 ubiquitin ligase, is associated with good prognosis and early glucocorticoid treatment response in childhood T-cell acute lymphoblastic leukemia (T-ALL) by unknown mechanisms. Here, we show that FBXW7 targets the glucocorticoid receptor α (GRα) for ubiquitylation and proteasomal degradation in a manner dependent on glycogen synthase kinase 3 β-mediated phsophorylation. FBXW7 inactivation caused elevated GRα levels, and enhanced the transcriptional response to glucocorticoids. There was significant enhancement of GR transcriptional responses in FBXW7-deficient cell lines and primary T-ALL samples, in particular, for those pro-apoptotic regulatory proteins, BIM and PUMA. Reduced FBXW7 expression or function promoted glucocorticoid sensitivity, but not sensitivity to other chemotherapeutic agents used in T-ALL. Moreover, this was a general feature of different cancer cell types. Taken together, our work defines GRα as a novel FBXW7 substrate and demonstrates that favorable patient prognosis in T-ALL is associated with FBXW7 mutations due to enhanced GRα levels and steroid sensitivity. These findings suggest that inactivation of FBXW7, a putative tumor suppressor protein, may create a synthetic lethal state in the presence of specific anticancer therapies.

  5. Dietary patterns of two herbivorous rodents: and Parotomys brantsii ...

    African Journals Online (AJOL)

    Frequency of occurrence of plant species in the diets were compared with availability of the plants in the rodents' habitats. Both rodents are generalist herbivores, eating plants species in proportion to the availability in their habitats. Dietary patterns, diversity of diet and degree of overlap between rodent's diets are a function ...

  6. 20 CFR 654.415 - Insect and rodent control.

    Science.gov (United States)

    2010-04-01

    ... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false Insect and rodent control. 654.415 Section 654.415 Employees' Benefits EMPLOYMENT AND TRAINING ADMINISTRATION, DEPARTMENT OF LABOR SPECIAL... Insect and rodent control. Housing and facilities shall be free of insects, rodents, and other vermin. ...

  7. Landform and surface attributes for prediction of rodent burrows in ...

    African Journals Online (AJOL)

    Previous studies suggest that rodent burrows, a proxy for rodent population are important for predicting plague risk areas. However, studies that link landform, surface attributes and rodent burrows in the Western Usambara Mountains in Tanzania are scanty. Therefore, this study was conducted in plague endemic area of ...

  8. 7 CFR 58.247 - Insect and rodent control program.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 3 2010-01-01 2010-01-01 false Insect and rodent control program. 58.247 Section 58... Service 1 Operations and Operating Procedures § 58.247 Insect and rodent control program. In addition to... made responsible for the performance of a regularly scheduled insect and rodent control program as...

  9. Glucocorticoids induce mitochondrial gene transcription in HepG2 cells: role of the mitochondrial glucocorticoid receptor.

    Science.gov (United States)

    Psarra, Anna-Maria G; Sekeris, Constantine E

    2011-10-01

    Glucocorticoids are major regulators of a plethora of cellular functions, acting on target cells through glucocorticoid receptors (GR) and modulation of gene transcription, among other mechanisms. One main site of action of glucocorticoids is the hepatocyte, which responds to the hormonal stimulus with induction of several proteins among them enzymes of oxidative phosphorylation (OXPHOS), both nuclearly and mitochondrially encoded. The induction of OXPHOS is regarded as a result of a nuclear action of the receptor on the respective nuclear genes and on genes encoding mitochondrial transcription factors. The presence of GR in mitochondria and of sequences in the mitochondrial genome similar to glucocorticoid responsive elements, suggested a direct action of GR on mitochondrial transcription. We demonstrate in HepG2 hepatocarcinoma cells specific binding of GR to the regulatory D-loop region of the mitochondrial genome and show that dexamethasone induces the mitochondrial transcription factors A, B1, and B2, the mitochondrial ribosomal RNA, and several mitochondrially encoded OXPHOS genes. Applying α-amanitin, the specific inhibitor of DNA-dependent RNA polymerase II, the dexamethasone-induced transcription of the mitochondrial genes can still proceeds, whereas the DEX effect on transcription of the mitochondrial transcription factors is suppressed. Moreover, HepG2 cells overexpressing mitochondrial targeted GR showed increased RNA synthesis, cytrochrome oxidase subunit I protein expression, and mitochondrial ATP production. We conclude that glucocorticoids can stimulate directly mitochondrial transcription by the mitochondrially localized GR, affecting OXPHOS enzyme biosynthesis. This takes place in addition to their action on mitochondrial genes by way of induction of the nuclearly encoded mitochondrial transcription factors. Copyright © 2011 Elsevier B.V. All rights reserved.

  10. Rapid Nongenomic Glucocorticoid Actions in Male Mouse Hypothalamic Neuroendocrine Cells Are Dependent on the Nuclear Glucocorticoid Receptor

    Science.gov (United States)

    Nahar, Jebun; Haam, Juhee; Chen, Chun; Jiang, Zhiying; Glatzer, Nicholas R.; Muglia, Louis J.; Dohanich, Gary P.; Herman, James P.

    2015-01-01

    Corticosteroids act classically via cognate nuclear receptors to regulate gene transcription; however, increasing evidence supports rapid, nontranscriptional corticosteroid actions via activation of membrane receptors. Using whole-cell patch clamp recordings in hypothalamic slices from male mouse genetic models, we tested for nongenomic glucocorticoid actions at glutamate and gamma aminobutyric acid (GABA) synapses in hypothalamic neuroendocrine cells, and for their dependence on the nuclear glucocorticoid receptor (GR). In enhanced green fluorescent protein-expressing CRH neurons of the paraventricular nucleus (PVN) and in magnocellular neurons of the PVN and supraoptic nucleus (SON), dexamethasone activated postsynaptic membrane-associated receptors and G protein signaling to elicit a rapid suppression of excitatory postsynaptic inputs, which was blocked by genetic deletion of type I cannabinoid receptors and a type I cannabinoid receptor antagonist. In magnocellular neurons, dexamethasone also elicited a rapid nitric oxide-dependent increase in inhibitory postsynaptic inputs. These data indicate a rapid, synapse-specific glucocorticoid-induced retrograde endocannabinoid signaling at glutamate synapses and nitric oxide signaling at GABA synapses. Unexpectedly, the rapid glucocorticoid effects on both excitatory and inhibitory synaptic transmission were lost with conditional deletion of GR in the PVN and SON in slices from a single minded-1-cre-directed conditional GR knockout mouse. Thus, the nongenomic glucocorticoid actions at glutamate and GABA synapses on PVN and SON neuroendocrine cells are dependent on the nuclear GR. The nuclear GR, therefore, is responsible for transducing the rapid steroid response at the membrane, or is either a critical component in the signaling cascade or regulates a critical component of the signaling cascade of a distinct membrane GR. PMID:26061727

  11. REDD1/DDIT4-independent mTORC1 inhibition and apoptosis by glucocorticoids in thymocytes.

    Science.gov (United States)

    Wolff, Nicholas C; McKay, Renée M; Brugarolas, James

    2014-06-01

    Glucocorticoids induce apoptosis in lymphocytes and are commonly used to treat hematologic malignancies. However, they are also associated with significant adverse effects and their molecular mechanism of action is not fully understood. Glucocorticoid treatment induces expression of the mTORC1 inhibitor Regulated in Development and DNA Damage Response 1 (REDD1), also known as DNA-Damage Inducible Transcript 4 (DDIT4), and mTORC1 inhibition may distinguish glucocorticoid-sensitive from glucocorticoid-resistant acute lymphoblastic leukemia (ALL). Interestingly, REDD1 induction was impaired in glucocorticoid-resistant ALL cells and inhibition of mTORC1 using rapamycin restored glucocorticoid sensitivity. These data suggest that REDD1 may be essential for the response of ALL cells to glucocorticoids. To further investigate the role of REDD1, we evaluated the effects of glucocorticoids on primary thymocytes from wild-type and REDD1-deficient mice. Glucocorticoid-mediated apoptosis was blocked by a glucocorticoid receptor antagonist and by an inhibitor of transcription, which interfered with REDD1 induction and mTORC1 inhibition. However, REDD1 ablation had no effect on glucocorticoid-induced mTORC1 inhibition and apoptosis in thymocytes ex vivo. Overall, these data not only demonstrate the contextual differences of downstream signaling following glucocorticoid treatment but also provide a better mechanistic understanding of the role of REDD1. These molecular findings underlying glucocorticoid action and the role of REDD1 are fundamental for the design of novel, more efficacious, and less toxic analogs. Mol Cancer Res; 12(6); 867-77. ©2014 AACR. ©2014 American Association for Cancer Research.

  12. Glucocorticoids inhibit glucose transport and glutamate uptake in hippocampal astrocytes: implications for glucocorticoid neurotoxicity.

    Science.gov (United States)

    Virgin, C E; Ha, T P; Packan, D R; Tombaugh, G C; Yang, S H; Horner, H C; Sapolsky, R M

    1991-10-01

    Glucocorticoids (GCs), the adrenal steroid hormones secreted during stress, can damage the hippocampus and impair its capacity to survive coincident neurological insults. This GC endangerment of the hippocampus is energetic in nature, as it can be prevented when neurons are supplemented with additional energy substrates. This energetic endangerment might arise from the ability of GCs to inhibit glucose transport into both hippocampal neurons and astrocytes. The present study explores the GC inhibition in astrocytes. (1) GCs inhibited glucose transport approximately 15-30% in both primary and secondary hippocampal astrocyte cultures. (2) The parameters of inhibition agreed with the mechanisms of GC inhibition of glucose transport in peripheral tissues: A minimum of 4 h of GC exposure were required, and the effect was steroid specific (i.e., it was not triggered by estrogen, progesterone, or testosterone) and tissue specific (i.e., it was not triggered by GCs in cerebellar or cortical cultures). (3) Similar GC treatment caused a decrease in astrocyte survival during hypoglycemia and a decrease in the affinity of glutamate uptake. This latter observation suggests that GCs might impair the ability of astrocytes to aid neurons during times of neurologic crisis (i.e., by impairing their ability to remove damaging glutamate from the synapse).

  13. Food neophobia and food preference in rodents (Rodentia) and its interaction with social learning.

    OpenAIRE

    Rudolfová, Veronika

    2015-01-01

    Neophobia (fear of novelty) is first protection from ingesting potentially dangerous food in rodents. After overcoming the fear an animal begins to sample the food (take small parts). The animal then forms an aversion to dangerous food and preference for safe and nutritionally favourable food on the grounds of its experience with its ingestion. These mechanisms of behaviour towards food can be learned individually but an individual's behaviour is also influenced by other animals, especially i...

  14. Among rodents and rhinos: interplay between small mammals and large herbivores in a South African savanna

    OpenAIRE

    Hagenah, N.

    2006-01-01

    Keywords:African savanna, biodiversity, Dichrostachys cinerea , different-sized herbivores, fire, herbivore interactions, murid rodents, spatial heterogeneityMankind has caused species extinction of many groups of organisms through the transformation and fragmentation of once continuous natural habitats. In order to protect and restore natural biodiversity hotspots such as the African savannas we need to understand the determinants of their community structure and species diversity. Evidence ...

  15. Association between allelic variants of the human glucocorticoid receptor gene and autoimmune diseases: A systematic review and meta-analysis.

    Science.gov (United States)

    Herrera, Cristian; Marcos, Miguel; Carbonell, Cristina; Mirón-Canelo, José Antonio; Espinosa, Gerard; Cervera, Ricard; Chamorro, Antonio-Javier

    2018-03-08

    The human glucocorticoid receptor gene (NR3C1) is considered to play a role in the differences and sensitivities of the glucocorticoid response in individuals with autoimmune diseases. The objective of this study was to examine by means of a systematic review previous findings regarding allelic variants of NR3C1 in relation to the risk of developing systemic autoimmune diseases. Studies that analysed the genotype distribution of NR3C1 allelic variants among patients with systemic autoimmune diseases were retrieved. A meta-analysis was conducted with a random effects model. Odds ratios (ORs) and their confidence intervals (CIs) were calculated. In addition, sub-analysis by ethnicity, sensitivity analysis and tests for heterogeneity of the results were performed. Eleven studies met the inclusion criteria for meta-analysis. We found no evidence that the analysed NR3C1 polymorphisms, rs6198, rs56149945, and rs6189/rs6190, modulate the risk of developing a systemic autoimmune disease. Nonetheless, a protective role for the minor allele of rs41423247 was found among Caucasians (OR = 0.78; 95% CI: 0.65, 0.92; P = 0.004). A subgroup analysis according to underlying diseases revealed no significant association either for Behçet's disease or rheumatoid arthritis, while correlations between NR3C1 polymorphisms and disease activity or response to glucocorticoids could not be evaluated due to insufficient data. There is no clear evidence that the analysed NR3C1 allelic variants confer a risk for developing systemic autoimmune diseases although the minor G allele of rs41423247 may be protective among Caucasians. Copyright © 2018. Published by Elsevier B.V.

  16. REVIEW: GENETIC MANIPULATION OF THE RODENT PLACENTA

    Science.gov (United States)

    Renaud, Stephen J.; Rumi, M.A. Karim; Soares, Michael J.

    2011-01-01

    The principal role of the placenta is the maintenance of pregnancy and promotion of fetal growth and viability. The use of transgenic rodents has greatly enhanced our understanding of placental development and function. However, embryonic lethality is often a confounding variable in determining whether a genetic modification adversely affected placental development. In these cases, it is beneficial to specifically manipulate the placental genome. The purpose of this review is to summarize available methodologies for specific genetic modification of the rodent placenta. By restricting genetic alterations to the trophoblast lineage, it is possible to gain a deeper understanding of placental development that perhaps will lead to gene-targeted therapies to rescue irregular placentation in transgenic animals or in women at high-risk for placenta-associated pregnancy complications. PMID:21256588

  17. Homeobox Genes in the Rodent Pineal Gland

    DEFF Research Database (Denmark)

    Rath, Martin Fredensborg; Rohde, Kristian; Klein, David C

    2013-01-01

    The pineal gland is a neuroendocrine gland responsible for nocturnal synthesis of melatonin. During early development of the rodent pineal gland from the roof of the diencephalon, homeobox genes of the orthodenticle homeobox (Otx)- and paired box (Pax)-families are expressed and are essential...... for normal pineal development consistent with the well-established role that homeobox genes play in developmental processes. However, the pineal gland appears to be unusual because strong homeobox gene expression persists in the pineal gland of the adult brain. Accordingly, in addition to developmental...... functions, homeobox genes appear to be key regulators in postnatal phenotype maintenance in this tissue. In this paper, we review ontogenetic and phylogenetic aspects of pineal development and recent progress in understanding the involvement of homebox genes in rodent pineal development and adult function...

  18. Participation of endocannabinoids in rapid suppression of stress responses by glucocorticoids in neonates.

    Science.gov (United States)

    Buwembo, A; Long, H; Walker, C-D

    2013-09-26

    In adult rodents, endocannabinoids (eCBs) regulate fast glucocorticoid (GC) feedback in the hypothalamus-pituitary adrenal (HPA) axis, acting as retrograde messengers that bind to cannabinoid receptors (CB1R) and inhibit glutamate release from presynaptic CRH neurons in the paraventricular nucleus of the hypothalamus (PVN). During the first two weeks of life, rat pups exhibit significant CRH and ACTH responses to stress although the adrenal GC output remains reduced. At the same time, pups also display increased sensitivity to GC feedback, but it is unclear whether eCBs play a role in mediating fast GC feedback in neonatal life. In our studies, we examined the role of eCBs in the rapid suppression of anoxia-induced ACTH release and determined whether eCB action could be modulated by the levels of circulating GCs present at the time of stress. PND8 pups were subjected to 3-min anoxia with AM251, a CB1R blocker, injected 30 min prior to stress onset. The effects of either metyrapone (MET) (a steroidogenic 11 beta-hydroxylase blocker) or methylprednisolone (PRED) (a synthetic GC) pretreatment on AM251 effect and the stress response were evaluated. Treatment with AM251 before stress onset tended to increase overall ACTH and CORT secretion, and also delayed the return to baseline ACTH. The AM251 effect on ACTH in PND8 pups was lost in MET-treated pups, who exhibited high basal and stimulated ACTH release and no CORT response to stress. Methylprednisolone suppressed ACTH stress responses although AM251 still delayed restoration of ACTH levels to the baseline. This suggests that the eCB effect on ACTH secretion in neonates is most evident when there is a dynamic fluctuation of corticosterone levels. Interestingly, AM251 increased basal and stimulated corticosterone secretion in all treatments including MET, suggestive of a direct action of CB1R blockade on adrenal steroidogenesis. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

  19. The glucocorticoid/aggression relationship in animals and humans: an analysis sensitive to behavioral characteristics, glucocorticoid secretion patterns, and neural mechanisms.

    Science.gov (United States)

    Haller, József

    2014-01-01

    Glucocorticoids control a wide array of biological processes from glucose homeostasis to neuronal function. The mechanisms mediating their effects are similarly varied and include rapid and transient nongenomic effects on calcium trafficking, various neurotransmitter receptors, and other membrane/cytoplasmic proteins, as well as slowly developing but durable genomic effects that are mediated by a large number of glucocorticoid-sensitive genes that are affected after variable lag-times. Given this complexity, we suggest that the aggression/glucocorticoid relationship cannot be reduced to the simple "stimulation/inhibition" question. Here, we review the effects of glucocorticoids on aggression by taking into account the complexities of glucocorticoid actions. Acute and chronic effects were differentiated because these are mediated by different mechanisms. The effects of chronic increases and decreases in glucocorticoid production were discussed separately, because the activation of mechanisms that are not normally activated and the loss of normal functions should not be confounded. Findings in healthy/normal subjects and those obtained in subjects that show abnormal forms of behavior or psychopathologies were also differentiated, because the effects of glucocorticoids are indirect, and largely depend on the properties of neurons they act upon, which are altered in subjects with psychopathologies. In addition, the conditions of glucocorticoid measurements were also thoroughly evaluated. Although the role of glucocorticoids in aggression is perceived as controversial by many investigators, a detailed analysis that is sensitive to glucocorticoid and behavioral measure as well as to the mediating mechanism suggests that this role is rather clear-cut; moreover, there is a marked similarity between animal and human findings.

  20. Neurogenetics of aggressive behavior: studies in rodents.

    Science.gov (United States)

    Takahashi, Aki; Miczek, Klaus A

    2014-01-01

    Aggressive behavior is observed in many animal species, such as insects, fish, lizards, frogs, and most mammals including humans. This wide range of conservation underscores the importance of aggressive behavior in the animals' survival and fitness, and the likely heritability of this behavior. Although typical patterns of aggressive behavior differ between species, there are several concordances in the neurobiology of aggression among rodents, primates, and humans. Studies with rodent models may eventually help us to understand the neurogenetic architecture of aggression in humans. However, it is important to recognize the difference between the ecological and ethological significance of aggressive behavior (species-typical aggression) and maladaptive violence (escalated aggression) when applying the findings of aggression research using animal models to human or veterinary medicine. Well-studied rodent models for aggressive behavior in the laboratory setting include the mouse (Mus musculus), rat (Rattus norvegicus), hamster (Mesocricetus auratus), and prairie vole (Microtus ochrogaster). The neural circuits of rodent aggression have been gradually elucidated by several techniques, e.g., immunohistochemistry of immediate-early gene (c-Fos) expression, intracranial drug microinjection, in vivo microdialysis, and optogenetics techniques. Also, evidence accumulated from the analysis of gene-knockout mice shows the involvement of several genes in aggression. Here, we review the brain circuits that have been implicated in aggression, such as the hypothalamus, prefrontal cortex (PFC), dorsal raphe nucleus (DRN), nucleus accumbens (NAc), and olfactory system. We then discuss the roles of glutamate and γ-aminobutyric acid (GABA), excitatory and inhibitory amino acids in the brain, as well as their receptors, in controlling aggressive behavior, focusing mainly on recent findings. At the end of this chapter, we discuss how genes can be identified that underlie individual

  1. Amaranth as Reinforcement Source: A Rodent Study

    OpenAIRE

    González-Rivera, Ivette; Trejo, Diana; Saavedra, Nuria; Padrón, Erika; Silva, David; Carrillo, Paulina; Arevalo, Oscar; Castro, César; Sánchez-Castillo, Hugo

    2017-01-01

    This study evaluates amaranth as an alternative to reinforcers which are currently used in experimental laboratories with rodents. We compared some elements such as consumer preference, motivation and reinforcing value of three types of food (two types of pellets and amaranth) through four experiments with free radial maze and free consumption in 11 Wistar rats. The results show that amaranth has a high reinforcing value. Also, there was a preference for amaranth consumption compared with the...

  2. [The Influence of Glucocorticoids on the Healing Processes in the Gastric Mucosa].

    Science.gov (United States)

    Podvigina, T T; Filaretova, L P

    2016-01-01

    In this review, we analyzed the data of literature about the glucocorticoid influences on the gastric erosion and ulcer healing. The data show that multiple injections of glucocorticoids at pharmacological doses delay gastric erosion and ulcer healing. However, according to experimental results endogenic glucocorticoids, on the contrary, play significant role in maintenance of gastric mucosal integrity. Thus, glucocorticoids may have dual effect on healing of gastric injury: contribute to healing process or delay them. The initial glucocorticoid action is physiological and consists in a participation in healing processes what is considered as component gastroprotective action of these hormones. During a long-lasting action of glucocorticoids, the physiological effect can be transformed into pathological one, delaying erosion and ulcer healing, and this contributes to the ulcerogenic action of glucocorticods.

  3. Adrenal Insufficiency Caused by Locally Applied Glucocorticoids-Myth or Fact?

    DEFF Research Database (Denmark)

    Dinsen, Stina; Klose, Marianne; Rasmussen, Åse Krogh

    2015-01-01

    can cause adrenal suppression after a single injection. The systemic effect of locally applied glucocorticoids depends on pharmacokinetic and -dynamic properties of the particular glucocorticoid as well as individual factors. Many of the symptoms in iatrogen adrenal insufficiency are unspecific......Case-reports have made it evident that both inhaled, percutaneous, intranasal, intraarticular and ophthalmic administered glucocorticoids have the potential to cause life threatening adrenal insufficiency. With few and sometimes conflicting data and study methodology the prevalence of adrenal...... insufficiency secondary to locally applied glucocorticoids is not clear. Adrenal insufficiency can only be correctly evaluated by a stimulation test, and has by this procedure been reported in up to 40-50% of patients treated with high-dose inhaled glucocorticoids. Medium- to low-dose inhaled glucocorticoids...

  4. Primary generalized familial and sporadic glucocorticoid resistance (Chrousos syndrome) and hypersensitivity.

    Science.gov (United States)

    Charmandari, Evangelia; Kino, Tomoshige; Chrousos, George P

    2013-01-01

    Familial or sporadic primary generalized glucocorticoid resistance or Chrousos syndrome is a rare genetic condition characterized by generalized, partial, target-tissue insensitivity to glucocorticoids and a consequent hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis. Primary generalized glucocorticoid hypersensitivity (PGGH) represents the mirror image of the former, and is characterized by generalized, partial, target-tissue hypersensitivity to glucocorticoids, and compensatory hypoactivation of the HPA axis. The molecular basis of both conditions has been ascribed to mutations in the human glucocorticoid receptor (hGR) gene, which impair the molecular mechanisms of hGR action and alter tissue sensitivity to glucocorticoids. This review summarizes the pathophysiology, molecular mechanisms and clinical aspects of Chrousos syndrome and PGGH. Copyright © 2013 S. Karger AG, Basel.

  5. The transcriptomics of glucocorticoid receptor signaling in developing zebrafish.

    Directory of Open Access Journals (Sweden)

    Dinushan Nesan

    Full Text Available Cortisol is the primary corticosteroid in teleosts that is released in response to stressor activation of the hypothalamus-pituitary-interrenal axis. The target tissue action of this hormone is primarily mediated by the intracellular glucocorticoid receptor (GR, a ligand-bound transcription factor. In developing zebrafish (Danio rerio embryos, GR transcripts and cortisol are maternally deposited into the oocyte prior to fertilization and influence early embryogenesis. To better understand of the molecular mechanisms involved, we investigated changes in the developmental transcriptome prior to hatch, in response to morpholino oligonucleotide knockdown of GR using the Agilent zebrafish microarray platform. A total of 1313 and 836 mRNA transcripts were significantly changed at 24 and 36 hours post fertilization (hpf, respectively. Functional analysis revealed numerous developmental processes under GR regulation, including neurogenesis, eye development, skeletal and cardiac muscle formation. Together, this study underscores a critical role for glucocorticoid signaling in programming molecular events essential for zebrafish development.

  6. Effects of Glucocorticoids on Apoptosis and Clearance of Apoptotic Cells

    Directory of Open Access Journals (Sweden)

    Aisleen McColl

    2007-01-01

    Full Text Available The glucocorticoid (GC drugs are one of the most commonly prescribed and effective anti-inflammatory agents used for the treatment of many inflammatory disorders through their ability to attenuate phlogistic responses. The glucocorticoid receptor (GCR primarily mediates GC actions via activation or repression of gene expression. GCs directly induce the expression of proteins displaying anti-inflammatory activities. However, the likely predominant effect of GCs is the repression of multiple inflammatory genes that invariably are overexpressed during nonresolving chronic inflammation. Although most GC actions are mediated through regulation of transcription, rapid nongenomic actions have also been reported. In addition, GCs modulate inflammatory cell survival, inducing apoptosis in immature thymocytes and eosinophils, while delaying constitutive neutrophil apoptosis. Importantly, GCs promote noninflammatory phagocytosis of apoptotic cell targets, a process important for the successful resolution of inflammation. Here, the effects and mechanisms of action of GC on inflammatory cell apoptosis and phagocytosis will be discussed.

  7. Glucocorticoid receptor action in metabolic and neuronal function.

    Science.gov (United States)

    Garabedian, Michael J; Harris, Charles A; Jeanneteau, Freddy

    2017-01-01

    Glucocorticoids via the glucocorticoid receptor (GR) have effects on a variety of cell types, eliciting important physiological responses via changes in gene expression and signaling. Although decades of research have illuminated the mechanism of how this important steroid receptor controls gene expression using in vitro and cell culture-based approaches, how GR responds to changes in external signals in vivo under normal and pathological conditions remains elusive. The goal of this review is to highlight recent work on GR action in fat cells and liver to affect metabolism in vivo and the role GR ligands and receptor phosphorylation play in calibrating signaling outputs by GR in the brain in health and disease. We also suggest that both the brain and fat tissue communicate to affect physiology and behavior and that understanding this "brain-fat axis" will enable a more complete understanding of metabolic diseases and inform new ways to target them.

  8. Leptin distribution and metabolism in the pregnant rat: transplacental leptin passage increases in late gestation but is reduced by excess glucocorticoids.

    Science.gov (United States)

    Smith, Jeremy T; Waddell, Brendan J

    2003-07-01

    Leptin is essential for the establishment of pregnancy and appears to promote fetal growth, but the mechanisms regulating fetal leptin exposure remain unclear. In rodents, indirect evidence suggests that fetal leptin is partly derived from the maternal circulation via transplacental passage. Indeed, the placenta expresses mRNA for Ob-Ra, one of the short forms of the leptin receptor (Ob-R(S)) important in leptin transport, and this expression increases markedly in late pregnancy. Therefore, we determined the transplacental passage of maternal leptin to the fetus in the rat and whether this transport increases near term in association with a rise in placental expression of Ob-R(S) protein. Because of the proposed role of leptin in promoting fetal growth, we also assessed the effect of glucocorticoid-induced fetal growth retardation on placental leptin transport. Anesthetized rats received a constant infusion of (125)I-leptin via a jugular cannula before and at d 16 and 22 of pregnancy (term = d 23); plasma samples were obtained at 10, 20, 40, 60, 80, and 100 min, and fetuses and placentas were collected at the time of the final sample. The metabolic clearance rate of leptin fell (P pregnancy. Over this same period, Ob-R(S) protein expression in the placental labyrinth zone increased by almost 2-fold. Transplacental leptin passage was reduced (P pregnancy. Consistent with the proposed role of leptin as a fetal growth factor, transplacental leptin passage is reduced in association with glucocorticoid-induced fetal growth retardation.

  9. [Rodent associated hantaviruses and hantavirus infections].

    Science.gov (United States)

    Kariwa, Hiroaki

    2017-01-01

    Hantaviruses belongs to the genus Hantavirus in the family Bunyaviridae are maintained in rodents and infects to humans by inhalation of the aerosol of infected rodent excreta. In this article, the epidemiology of hantavirus infection and the special relationship between rodent and hantavirus are described. Hantavirus infections include hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS). HFRS is characterized high fever, hemorrhage, and renal disorder. HFRS is distributed in East Asia, Europe, and Russia. While HCPS is characterized acute respiratory dysfunction and cardiogenic shock. The distribution of HCPS is limited in North and South Americas. In Japan's neighboring countries, such as Russia, China, and Korea, large numbers of HFRS patients are reported in association with multiple hantaviruses. In Japan, hantavirus infection has not been reported since 1985 but grey red-backed vole (Myodes rufocanus bedfordiae) inhabiting Hokkaido maintain one of the hantaviruses. Coevolution between hantavirus and host may have been occurred during a long period. The endemic areas of hantavirus infection are strongly associated with the distribution of host animal carrying pathogenic hantaviruses.

  10. Locomotor therapy with extended-release crystalline glucocorticoids

    Directory of Open Access Journals (Sweden)

    Vladimir Vasilyevich Badokin

    2013-01-01

    Full Text Available Topical glucocorticoid (GC therapy for locomotor diseases is an extremely important component of a comprehensive program to treat inflammatory and, to a lesser extent, degenerative diseases. It reduces the time of hospitalization by 5—10 days in this category of patients, has a prompt and potent anti-inflammatory effect, and shows predictable efficiency. This therapy shows good tolerability and high safety and prevents serious adverse reactions to GC treatment.

  11. Is There a Renaissance of Glucocorticoids in Rheumatoid Arthritis?

    Science.gov (United States)

    Kirwan, J R; Gunasekera, Wma

    2017-10-01

    The first therapeutic use of glucocorticoids was in a patient with severe rheumatoid arthritis and the symptomatic benefit was astounding. Adverse effects from increasingly large doses led to them being overshadowed, dismissed as inappropriate treatment, and ignored for 20 years - but in the last 2 decades, the accumulating evidence and clinical practice suggest there is a justified renaissance in their use as a first-line treatment. © 2017 American Society for Clinical Pharmacology and Therapeutics.

  12. Synthetic Glucocorticoids and Early Variations of Blood Pressure: A Population-Based Cohort Study.

    Science.gov (United States)

    Fardet, Laurence; Nazareth, Irwin; Petersen, Irene

    2015-07-01

    Endogenous glucocorticoids are known to increase blood pressure, but very little is known about the early effects of synthetic glucocorticoids (eg, prednisone, dexamethasone) on blood pressure. To assess longitudinal variations of blood pressure before and after initiation of systemic glucocorticoid therapy. Adult patients prescribed synthetic glucocorticoid therapy for at least 3 months and registered between 2004 and 2012 in The Health Improvement Network (THIN) primary care database. Systolic and diastolic blood pressure as measured in primary care. Among the 16,351 patients prescribed antihypertensive drug within the year before glucocorticoid initiation (women, 57.1%; age [mean ± SD], 72.0 ± 11.4 y), the mean (SD) blood pressure within the year before glucocorticoid initiation was 140 (18)/78 (9) mm Hg. It was 139 (19)/77 (11), 139 (19)/77 (10), and 139 (19)/77 (11) mm Hg during the first, second, and third months of exposure, respectively. We did not find any evidence of the effects of glucocorticoids on blood pressure in these patients. Among the 6914 patients not prescribed antihypertensive drug within the year before glucocorticoid initiation (women, 64.9%; age, 60.0 ± 17.8 y), the figures were 133 (17)/78 (10), 135 (20)/79 (11), 133 (19)/78 (11), and 133 (19)/78 (11) mm Hg before exposure and during the first, second, and third months of exposure, respectively. In this group of patients, glucocorticoid exposure was associated with a slight (glucocorticoid initiation. Prednisone/prednisolone use was associated with a higher risk of extreme increase in systolic blood pressure than the other synthetic glucocorticoids (odds ratio, 4.9 [95% confidence interval, 1.9-12.6]; P = .001). Contrary to what is usually thought, the increase of blood pressure during the first months of exposure to synthetic glucocorticoids seems clinically nonsignificant.

  13. Glucocorticoids and Preterm Hypoxic-Ischemic Brain Injury: The Good and the Bad

    Directory of Open Access Journals (Sweden)

    Laura Bennet

    2012-01-01

    Full Text Available Fetuses at risk of premature delivery are now routinely exposed to maternal treatment with synthetic glucocorticoids. In randomized clinical trials, these substantially reduce acute neonatal systemic morbidity, and mortality, after premature birth and reduce intraventricular hemorrhage. However, the overall neurodevelopmental impact is surprisingly unclear; worryingly, postnatal glucocorticoids are consistently associated with impaired brain development. We review the clinical and experimental evidence on how glucocorticoids may affect the developing brain and highlight the need for systematic research.

  14. Risk of cardiovascular events in people prescribed glucocorticoids with iatrogenic Cushing’s syndrome: cohort study

    OpenAIRE

    Fardet, Laurence; Petersen, Irene; Nazareth, Irwin

    2012-01-01

    Objective To investigate whether there is an increased risk of cardiovascular events in people who exhibit iatrogenic Cushing’s syndrome during treatment with glucocorticoids. Design Cohort study. Setting 424 UK general practices contributing to The Health Improvement Network database. Participants People prescribed systemic glucocorticoids and with a diagnosis of iatrogenic Cushing’s syndrome (n=547) and two comparison groups: those prescribed glucocorticoids and with no diagnosis of iatroge...

  15. Science review: Mechanisms of impaired adrenal function in sepsis and molecular actions of glucocorticoids

    OpenAIRE

    Prigent, Hélène; Maxime, Virginie; Annane, Djillali

    2004-01-01

    This review describes current knowledge on the mechanisms that underlie glucocorticoid insufficiency in sepsis and the molecular action of glucocorticoids. In patients with severe sepsis, numerous factors predispose to glucocorticoid insufficiency, including drugs, coagulation disorders and inflammatory mediators. These factors may compromise the hypothalamic–pituitary axis (i.e. secondary adrenal insufficiency) or the adrenal glands (i.e. primary adrenal failure), or may impair glucocorticoi...

  16. Antenatal glucocorticoids and neonatal inflammation-associated proteins.

    Science.gov (United States)

    Faden, Maheer; Holm, Mari; Allred, Elizabeth; Fichorova, Raina; Dammann, Olaf; Leviton, Alan

    2016-12-01

    To date, studies of the relationship between antenatal glucocorticoids (AGC) and neonatal inflammation in preterm newborns have been largely limited to umbilical cord blood specimens. To explore the association between exposure to antenatal glucocorticoids and concentrations of inflammation-related proteins in whole blood collected from very preterm newborns at multiple times during the first postnatal month. We measured the protein concentrations on postnatal day 1 (N=1118), day 7 (N=1138), day 14 (N=1030), day 21 (N=936) and day 28 (N=877) from infants born before the 28th week of gestation and explored the relationship between antenatal steroid receipt and protein concentrations in the highest and lowest quartiles. The creation of multinomial logistic regression models (adjusted for potential confounders) allowed us calculate odds ratios and 95% confidence intervals. Twenty of 420 assessments [21 (proteins)×2 (exposure levels: partial and full)×2 (quartile levels: top and bottom)×5 (days)] were statistically significant without any cohesive pattern. Among infants born before 28 weeks of gestational age, neither full, nor partial courses of antenatal glucocorticoids have a sustained anti-inflammatory effect. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. An epithelial circadian clock controls pulmonary inflammation and glucocorticoid action.

    Science.gov (United States)

    Gibbs, Julie; Ince, Louise; Matthews, Laura; Mei, Junjie; Bell, Thomas; Yang, Nan; Saer, Ben; Begley, Nicola; Poolman, Toryn; Pariollaud, Marie; Farrow, Stuart; DeMayo, Francesco; Hussell, Tracy; Worthen, G Scott; Ray, David; Loudon, Andrew

    2014-08-01

    The circadian system is an important regulator of immune function. Human inflammatory lung diseases frequently show time-of-day variation in symptom severity and lung function, but the mechanisms and cell types underlying these effects remain unclear. We show that pulmonary antibacterial responses are modulated by a circadian clock within epithelial club (Clara) cells. These drive circadian neutrophil recruitment to the lung via the chemokine CXCL5. Genetic ablation of the clock gene Bmal1 (also called Arntl or MOP3) in bronchiolar cells disrupts rhythmic Cxcl5 expression, resulting in exaggerated inflammatory responses to lipopolysaccharide and an impaired host response to Streptococcus pneumoniae infection. Adrenalectomy blocks rhythmic inflammatory responses and the circadian regulation of CXCL5, suggesting a key role for the adrenal axis in driving CXCL5 expression and pulmonary neutrophil recruitment. Glucocorticoid receptor occupancy at the Cxcl5 locus shows circadian oscillations, but this is disrupted in mice with bronchiole-specific ablation of Bmal1, leading to enhanced CXCL5 expression despite normal corticosteroid secretion. The therapeutic effects of the synthetic glucocorticoid dexamethasone depend on intact clock function in the airway. We now define a regulatory mechanism that links the circadian clock and glucocorticoid hormones to control both time-of-day variation and the magnitude of pulmonary inflammation and responses to bacterial infection.

  18. Effects of glucocorticoids on glioma cells in culture. Minireview on cancer research.

    Science.gov (United States)

    Freshney, R I

    1984-01-01

    In vitro studies have shown that glucocorticoids have a cytostatic effect on glioma cells at high cell densities but enhance cell survival and proliferation at low cell densities. The cytostatic effect is not cytotoxic and may be mediated via a membrane modification altering cell-cell interaction. Cell interaction is also implicated in differentiation in glial cells and the inducing effect of glucocorticoids may be mediated in part by their effect on cell interaction. Induction of differentiation by glucocorticoids is accompanied by a reduction in malignancy-associated properties and the possibility has emerged that glucocorticoids may be an essential component in attempts to modify the malignant behaviour of glioma cells.

  19. Glucocorticoids suppress inflammation via the upregulation of negative regulator IRAK-M

    Science.gov (United States)

    Miyata, Masanori; Lee, Ji-Yun; Susuki-Miyata, Seiko; Wang, Wenzhuo Y.; Xu, Haidong; Kai, Hirofumi; Kobayashi, Koichi S.; Flavell, Richard A.; Li, Jian-Dong

    2015-01-01

    Glucocorticoids are among the most commonly used anti-inflammatory agents. Despite the enormous efforts in elucidating the glucocorticoid-mediated anti-inflammatory actions, how glucocorticoids tightly control overactive inflammatory response is not fully understood. Here we show that glucocorticoids suppress bacteria-induced inflammation by enhancing IRAK-M, a central negative regulator of Toll-like receptor signalling. The ability of glucocorticoids to suppress pulmonary inflammation induced by non-typeable Haemophilus influenzae is significantly attenuated in IRAK-M-deficient mice. Glucocorticoids improve the survival rate after a lethal non-typeable Haemophilus influenzae infection in wild-type mice, but not in IRAK-M-deficient mice. Moreover, we show that glucocorticoids and non-typeable Haemophilus influenzae synergistically upregulate IRAK-M expression via mutually and synergistically enhancing p65 and glucocorticoid receptor binding to the IRAK-M promoter. Together, our studies unveil a mechanism by which glucocorticoids tightly control the inflammatory response and host defense via the induction of IRAK-M and may lead to further development of anti-inflammatory therapeutic strategies. PMID:25585690

  20. The permissive role of glucocorticoids in neuroinflammatory priming: mechanisms and insights.

    Science.gov (United States)

    Frank, Matthew G; Watkins, Linda R; Maier, Steven F

    2015-08-01

    Glucocorticoids have been universally regarded as anti-inflammatory; however, a considerable number of studies now demonstrate that under some conditions, glucocorticoids are capable of potentiating neuroinflammatory processes (i.e. priming), a permissive function of glucocorticoids. The present review addresses recent evidence that provides insight into the mechanism(s) of glucocorticoid-induced neuroinflammatory priming. Glucocorticoids have been found to prime inflammasomes [i.e. nucleotide-binding domain, leucine-rich repeat, pyrin domain containing proteins-3 (NLRP3)], which are intracellular multiprotein complexes that mediate proinflammatory processes. Inflammasomes are activated by products of stressed or damaged cells. Interestingly, these products (damage-associated molecular patterns) are induced by stress and mediate stress-induced neuroinflammatory priming. In light of these findings, we propose a model of glucocorticoid-induced neuroinflammatory priming whereby stress and glucocorticoids induce cellular damage/stress in the brain, the products of which prime the NLRP3 inflammasome. Thus, glucocorticoid-induced priming of the NLRP3 inflammasome may mediate the potentiated neuroinflammatory response to a subsequent proinflammatory immune challenge. We propose that during a flight-or-flight response, available energy stores should be diverted to defensive behaviours, and it might be after the emergency is over that resources should be shifted to recuperation and host defense against infection. This is the scenario that would be promoted by elevated glucocorticoids reducing ongoing inflammation while simultaneously priming the NLRP3 inflammasome.

  1. Glucocorticoids suppress inflammation via the upregulation of negative regulator IRAK-M.

    Science.gov (United States)

    Miyata, Masanori; Lee, Ji-Yun; Susuki-Miyata, Seiko; Wang, Wenzhuo Y; Xu, Haidong; Kai, Hirofumi; Kobayashi, Koichi S; Flavell, Richard A; Li, Jian-Dong

    2015-01-14

    Glucocorticoids are among the most commonly used anti-inflammatory agents. Despite the enormous efforts in elucidating the glucocorticoid-mediated anti-inflammatory actions, how glucocorticoids tightly control overactive inflammatory response is not fully understood. Here we show that glucocorticoids suppress bacteria-induced inflammation by enhancing IRAK-M, a central negative regulator of Toll-like receptor signalling. The ability of glucocorticoids to suppress pulmonary inflammation induced by non-typeable Haemophilus influenzae is significantly attenuated in IRAK-M-deficient mice. Glucocorticoids improve the survival rate after a lethal non-typeable Haemophilus influenzae infection in wild-type mice, but not in IRAK-M-deficient mice. Moreover, we show that glucocorticoids and non-typeable Haemophilus influenzae synergistically upregulate IRAK-M expression via mutually and synergistically enhancing p65 and glucocorticoid receptor binding to the IRAK-M promoter. Together, our studies unveil a mechanism by which glucocorticoids tightly control the inflammatory response and host defense via the induction of IRAK-M and may lead to further development of anti-inflammatory therapeutic strategies.

  2. One hormone, two actions: anti- and pro-inflammatory effects of glucocorticoids.

    Science.gov (United States)

    Cruz-Topete, Diana; Cidlowski, John A

    2015-01-01

    Glucocorticoids are essential steroid hormones secreted from the adrenal gland in response to stress. Since their discovery in the 1940s, glucocorticoids have been widely prescribed to treat inflammatory disorders and hematological cancers. In the traditional view, glucocorticoids are regarded as anti-inflammatory molecules; however, emerging evidence suggests that glucocorticoid actions are more complex than previously anticipated. The anti-inflammatory activity of glucocorticoids is attributed to the repression of pro-inflammatory genes through signal transduction by their steroid receptor, the glucocorticoid receptor (GR). The mechanisms modulating the pro-inflammatory effects of glucocorticoids are not well understood. In this review, we discuss recent findings that provide insights into the mechanism by which GR signaling can play a dual role in the regulation of the immune response. We hypothesize that these apparently opposite processes are working together to prepare the immune system to respond to a stressor (pro-inflammatory effects) and subsequently restore homeostasis (anti-inflammatory effects). Finally, we propose that determining the mechanisms which underlie the tissue-specific effects of glucocorticoids will provide an excellent tool to develop more efficient and selective glucocorticoid therapies. © 2014 S. Karger AG, Basel.

  3. HES1 Is a Master Regulator of Glucocorticoid Receptor-Dependent Gene Expression

    Science.gov (United States)

    Revollo, Javier R.; Oakley, Robert H.; Lu, Nick Z.; Kadmiel, Mahita; Gandhavadi, Maheer; Cidlowski, John A.

    2014-01-01

    Hairy and enhancer of split-1 (HES1) is a basic helix-loop-helix transcription factor that is a key regulator of development and organogenesis. However, little is known about the role of HES1 after birth. Glucocorticoids, primary stress hormones that are essential for life, regulate numerous homeostatic processes that permit vertebrates to cope with physiological challenges. The molecular actions of glucocorticoids are mediated by glucocorticoid receptor-dependent regulation of nearly 25% of the genome. We now establish a genome wide molecular link between HES1 and glucocorticoid receptors that controls the ability of cells and animals to respond to stress. Glucocorticoid signaling rapidly and robustly silenced HES1 expression. This glucocorticoid-dependent repression of HES1 was necessary for the glucocorticoid receptor to regulate many of its target genes. Mice with conditional knockout of HES1 in the liver exhibited an expanded glucocorticoid receptor signaling profile and aberrant metabolic phenotype. Our results indicate that HES1 acts as a master repressor, the silencing of which is required for proper glucocorticoid signaling. PMID:24300895

  4. One Hormone Two Actions: Anti- and Pro-inflammatory Effects of Glucocorticoids

    Science.gov (United States)

    Cruz-Topete, Diana; Cidlowski, John A.

    2014-01-01

    Glucocorticoids are essential steroid hormones secreted from the adrenal gland in response to stress. Since their discovery in the 1940’s, glucocorticoids have been widely prescribed to treat inflammatory disorders and hematological cancers. In the traditional view, glucocorticoids are regarded as anti-inflammatory molecules; however, emerging evidence suggests that glucocorticoid actions are more complex than previously anticipated. The anti-inflammatory activity of glucocorticoids is attributed to the repression of pro-inflammatory genes through signal transduction by their steroid receptor, the glucocorticoid receptor (GR). The mechanisms modulating the pro-inflammatory effects of glucocorticoids are not well understood. In this review, we discuss recent findings that provide insights into the mechanism by which GR signaling can play a dual role in the regulation of the immune response. We hypothesize that these apparently opposite processes are working together to prepare the immune system to respond to a stressor (pro-inflammatory effects) and subsequently restore homeostasis (anti-inflammatory effects). Finally, we propose that determining the mechanisms which underlie the tissue-specific effects of glucocorticoids will provide an excellent tool to develop more efficient and selective glucocorticoid therapies. PMID:25227506

  5. The Interactome of the Glucocorticoid Receptor and Its Influence on the Actions of Glucocorticoids in Combatting Inflammatory and Infectious Diseases

    Science.gov (United States)

    Petta, Ioanna; Dejager, Lien; Ballegeer, Marlies; Lievens, Sam; Tavernier, Jan; Libert, Claude

    2016-01-01

    SUMMARY Glucocorticoids (GCs) have been widely used for decades as a first-line treatment for inflammatory and autoimmune diseases. However, their use is often hampered by the onset of adverse effects or resistance. GCs mediate their effects via binding to glucocorticoid receptor (GR), a transcription factor belonging to the family of nuclear receptors. An important aspect of GR's actions, including its anti-inflammatory capacity, involves its interactions with various proteins, such as transcription factors, cofactors, and modifying enzymes, which codetermine receptor functionality. In this review, we provide a state-of-the-art overview of the protein-protein interactions (PPIs) of GR that positively or negatively affect its anti-inflammatory properties, along with mechanistic insights, if known. Emphasis is placed on the interactions that affect its anti-inflammatory effects in the presence of inflammatory and microbial diseases. PMID:27169854

  6. Citral reduces nociceptive and inflammatory response in rodents

    Directory of Open Access Journals (Sweden)

    Lucindo J. Quintans-Júnior

    2011-04-01

    Full Text Available Citral (CIT, which contains the chiral enantiomers, neral (cis and geranial (trans, is the majority monoterpene from Lippia alba and Cymbopogon citratus. The present study aimed to evaluate CIT for antinociceptive and anti-inflammatory activities in rodents. Antinociceptive and anti-inflammatory effects were studied by measuring nociception through acetic acid and formalin tests, while inflammation was verified by inducing peritonitis and paw edema with carrageenan. All tested doses of CIT had significant protection (p<0.001 against acetic acid (0.8% induced nociceptive behavior and the effects were also similar to morphine while formalin induced nociception was significantly protected (p<0.05 only at higher dose (200 mg/kg of CIT in the first phase of the test. CIT significantly reduce (p<0.001 nociceptive behavior emanating from inflammation in second phase at all the doses.The pretreatment with CIT (100 and 200 mg/kg significantly reduced the paw edema induced by carrageenan. Moreover, systemic treatment with CIT (100 and 200 mg/kg significantly reduced (p<0.001 the leukocyte migration in the carrageenan-induced migration to the peritoneal cavity. Our investigation shows that CIT possess significant central and peripheral antinociceptive effects. It was also verified an anti-inflammatory activity. All together these results suggest that CIT might represent important tool for treatment of painful conditions.

  7. Citral reduces nociceptive and inflammatory response in rodents

    Directory of Open Access Journals (Sweden)

    Lucindo J. Quintans-Júnior

    2011-06-01

    Full Text Available Citral (CIT, which contains the chiral enantiomers, neral (cis and geranial (trans, is the majority monoterpene from Lippia alba and Cymbopogon citratus. The present study aimed to evaluate CIT for antinociceptive and anti-inflammatory activities in rodents. Antinociceptive and anti-inflammatory effects were studied by measuring nociception through acetic acid and formalin tests, while inflammation was verified by inducing peritonitis and paw edema with carrageenan. All tested doses of CIT had significant protection (p<0.001 against acetic acid (0.8% induced nociceptive behavior and the effects were also similar to morphine while formalin induced nociception was significantly protected (p<0.05 only at higher dose (200 mg/kg of CIT in the first phase of the test. CIT significantly reduce (p<0.001 nociceptive behavior emanating from inflammation in second phase at all the doses.The pretreatment with CIT (100 and 200 mg/kg significantly reduced the paw edema induced by carrageenan. Moreover, systemic treatment with CIT (100 and 200 mg/kg significantly reduced (p<0.001 the leukocyte migration in the carrageenan-induced migration to the peritoneal cavity. Our investigation shows that CIT possess significant central and peripheral antinociceptive effects. It was also verified an anti-inflammatory activity. All together these results suggest that CIT might represent important tool for treatment of painful conditions.

  8. The effects of dietary restriction on oxidative stress in rodents

    Science.gov (United States)

    Walsh, Michael E.; Shi, Yun; Van Remmen, Holly

    2013-01-01

    Oxidative stress is observed during aging and in numerous age-related diseases. Dietary restriction (DR) is a regimen that protects against disease and extends lifespan in multiple species. However, it is unknown how DR mediates its protective effects. One prominent and consistent effect of DR in a number of systems is the ability to reduce oxidative stress and damage. The purpose of this review is to comprehensively examine the hypothesis that dietary restriction reduces oxidative stress in rodents by decreasing reactive oxygen species (ROS) production and increasing antioxidant enzyme activity, leading to an overall reduction of oxidative damage to macromolecules. The literature reveals that the effects of DR on oxidative stress are complex and likely influenced by a variety of factors, including sex, species, tissue examined, types of ROS and antioxidant enzymes examined, and duration of DR. Here we present a comprehensive review of the existing literature on the effect of DR on mitochondrial ROS generation, antioxidant enzymes and oxidative damage. In a majority of studies, dietary restriction had little effect on mitochondrial ROS production or antioxidant activity. On the other hand, DR decreased oxidative damage in the majority of cases. Although the effects of DR on endogenous antioxidants are mixed, we find that glutathione levels are the most likely antioxidant to be increased by dietary restriction, which supports the emerging redox-stress hypothesis of aging. PMID:23743291

  9. Leptospira and Rodents in Cambodia: Environmental Determinants of Infection

    Science.gov (United States)

    Ivanova, Svilena; Herbreteau, Vincent; Blasdell, Kim; Chaval, Yannick; Buchy, Philippe; Guillard, Bertrand; Morand, Serge

    2012-01-01

    We investigated infection of rodents and shrews by Leptospira spp. in two localities of Cambodia (Veal Renh, Kaev Seima) and in four types of habitat (forests, non-flooded lands, lowland rain-fed paddy fields, houses) during the wet and the dry seasons. Habitat preference was common, and rodent and shrew species were found only in houses or in rain-fed paddy fields or in forests. Among 649 small mammals trapped belonging to 12 rodent species and 1 shrew species, 71 of 642 animals tested were carriers of Leptospira according to the 16S ribosomal RNA marker used. Rodent infection was higher in low-slope locations, corresponding to rain-fed paddy fields, especially in the rainy season and in Kaev Seima. Rodents (Rattus exulans) and shrews (Suncus murinus) inhabiting households showed significantly low levels of infections, whereas rodents living in and near to forests (shrubby wasteland, orchards) showed high levels of infection. PMID:22665613

  10. Stress in adolescence and drugs of abuse in rodent models: Role of dopamine, CRF, and HPA axis

    Science.gov (United States)

    Burke, Andrew R.; Miczek, Klaus A.

    2014-01-01

    Rationale Research on adolescence and drug abuse increased substantially in the past decade. However, drug-addiction related behaviors following stressful experiences during adolescence are less studied. We focus on rodent models of adolescent stress cross-sensitization to drugs of abuse. Objectives Review the ontogeny of behavior, dopamine, corticotropin-releasing factor (CRF), and the hypothalamic pituitary adrenal (HPA) axis in adolescent rodents. We evaluate evidence that stressful experiences during adolescence engender hypersensitivity to drugs of abuse and offer potential neural mechanisms. Results and Conclusions Much evidence suggests that final maturation of behavior, dopamine systems, and HPA axis occurs during adolescence. Stress during adolescence increases amphetamine- and ethanol-stimulated locomotion, preference, and self-administration under many conditions. The influence of adolescent stress on subsequent cocaine- and nicotine-stimulated locomotion and preference is less clear. The type of adolescent stress, temporal interval between stress and testing, species, sex, and the drug tested are key methodological determinants for successful cross-sensitization procedures. The sensitization of the mesolimbic dopamine system is proposed to underlie stress cross-sensitization to drugs of abuse in both adolescents and adults through modulation by CRF. Reduced levels of mesocortical dopamine appear to be a unique consequence of social stress during adolescence. Adolescent stress may reduce the final maturation of cortical dopamine through D2 dopamine receptor regulation of dopamine synthesis or glucocorticoid-facilitated pruning of cortical dopamine fibers. Certain rodent models of adolescent adversity are useful for determining neural mechanisms underlying the cross-sensitization to drugs of abuse. PMID:24370534

  11. Glucocorticoids exert context-dependent effects on cells of the joint in vitro.

    Science.gov (United States)

    Madsen, Suzi H; Andreassen, Kim V; Christensen, Søren T; Karsdal, Morten A; Sverdrup, Francis M; Bay-Jensen, Anne-Christine; Henriksen, Kim

    2011-12-11

    Glucocorticoids are known to attenuate bone formation in vivo leading to decreased bone volume and increased risk of fractures, whereas effects on the joint tissue are less characterized. However, glucocorticoids appear to have a reducing effect on inflammation and pain in osteoarthritis. This study aimed at characterizing the effect of glucocorticoids on chondrocytes, osteoclasts, and osteoblasts. We used four model systems to investigate how glucocorticoids affect the cells of the joint; two intact tissues (femoral head- and cartilage-explants), and two separate cell cultures of osteoblasts (2T3-pre-osteoblasts) and osteoclasts (CD14(+)-monocytes). The model systems were cultured in the presence of two glucocorticoids; prednisolone or dexamethasone. To induce anabolic and catabolic conditions, cultures were activated by insulin-like growth factor I/bone morphogenetic protein 2 and oncostatin M/tumor necrosis factor-α, respectively. Histology and markers of bone- and cartilage-turnover were used to evaluate effects of glucocorticoid treatment. Prednisolone treatment decreased collagen type-II degradation in immature cartilage, whereas glucocorticoids did not affect collagen type-II in mature cartilage. Glucocorticoids had an anti-catabolic effect on catabolic-activated cartilage from a bovine stifle joint and murine femoral heads. Glucocorticoids decreased viability of all bone cells, leading to a reduction in osteoclastogenesis and bone resorption; however, bone morphogenetic protein 2-stimulated osteoblasts increased bone formation, as opposed to non-stimulated osteoblasts. Using highly robust in vitro models of bone and cartilage turnover, we suggest that effects of glucocorticoids highly depend on the activation and differential stage of the cell targeted in the joint. Present data indicated that glucocorticoid treatment may be beneficial for articular cartilage, although detrimental effects on bone should be taken into account. Copyright © 2011 Elsevier Inc

  12. Transcriptional regulation of human dual specificity protein phosphatase 1 (DUSP1) gene by glucocorticoids.

    Science.gov (United States)

    Shipp, Lauren E; Lee, Joyce V; Yu, Chi-Yi; Pufall, Miles; Zhang, Pili; Scott, Donald K; Wang, Jen-Chywan

    2010-10-29

    Glucocorticoids are potent anti-inflammatory agents commonly used to treat inflammatory diseases. They convey signals through the intracellular glucocorticoid receptor (GR), which upon binding to ligands, associates with genomic glucocorticoid response elements (GREs) to regulate transcription of associated genes. One mechanism by which glucocorticoids inhibit inflammation is through induction of the dual specificity phosphatase-1 (DUSP1, a.k.a. mitogen-activated protein kinase phosphatase-1, MKP-1) gene. We found that glucocorticoids rapidly increased transcription of DUSP1 within 10 minutes in A549 human lung adenocarcinoma cells. Using chromatin immunoprecipitation (ChIP) scanning, we located a GR binding region between -1421 and -1118 upstream of the DUSP1 transcription start site. This region is active in a reporter system, and mutagenesis analyses identified a functional GRE located between -1337 and -1323. We found that glucocorticoids increased DNase I hypersensitivity, reduced nucleosome density, and increased histone H3 and H4 acetylation within genomic regions surrounding the GRE. ChIP experiments showed that p300 was recruited to the DUSP1 GRE, and RNA interference experiments demonstrated that reduction of p300 decreased glucocorticoid-stimulated DUSP1 gene expression and histone H3 hyperacetylation. Furthermore, overexpression of p300 potentiated glucocorticoid-stimulated activity of a reporter gene containing the DUSP1 GRE, and this coactivation effect was compromised when the histone acetyltransferase domain was mutated. ChIP-reChIP experiments using GR followed by p300 antibodies showed significant enrichment of the DUSP1 GRE upon glucocorticoid treatment, suggesting that GR and p300 are in the same protein complex recruited to the DUSP1 GRE. Our studies identified a functional GRE for the DUSP1 gene. Moreover, the transcriptional activation of DUSP1 by glucocorticoids requires p300 and a rapid modification of the chromatin structure surrounding

  13. Synergistic stimulation of myogenesis by glucocorticoid and IGF-I signaling.

    Science.gov (United States)

    Pansters, N A; Langen, R C; Wouters, E F; Schols, A M

    2013-05-01

    Muscle wasting is associated with poor prognosis in chronic obstructive pulmonary disease (COPD). Exercise stimulates muscle recovery, but its efficacy is variable, depending on the clinical condition and medical treatment. Systemic glucocorticoids, commonly administered in high doses during acute disease exacerbations or as maintenance treatment in end-stage disease, are known to contribute to muscle wasting. As muscle mass recovery involves insulin-like growth factor (IGF)-I signaling, which can be stimulated by anabolic steroids, the impact of glucocorticoids and the effect of simultaneous IGF-I stimulation by anabolic steroids on muscle recovery and growth were investigated. The effects of, and interactions between, glucocorticoid and IGF-I signaling on skeletal muscle growth were assessed in differentiating C2C12 myocytes. As proof of principle, we performed a post hoc analysis stratifying patients by glucocorticoid use of a clinical trial investigating the efficacy of anabolic steroid supplementation on muscle recovery in muscle-wasted patients with COPD. Glucocorticoids strongly impaired protein synthesis signaling, myotube formation, and muscle-specific protein expression. In contrast, in the presence of glucocorticoids, IGF-I synergistically stimulated myotube fusion and myofibrillar protein expression, which corresponded with restored protein synthesis signaling by IGF-I and increased transcriptional activation of muscle-specific genes by glucocorticoids. In COPD patients on maintenance glucocorticoid treatment, the clinical trial also revealed an enhanced effect of anabolic steroids on muscle mass and respiratory muscle strength. In conclusion, synergistic effects of anabolic steroids and glucocorticoids on muscle recovery may be caused by relief of the glucocorticoid-imposed blockade on protein synthesis signaling, allowing effective translation of glucocorticoid-induced accumulation of muscle-specific gene transcripts.

  14. Euthanasia using gaseous agents in laboratory rodents.

    Science.gov (United States)

    Valentim, A M; Guedes, S R; Pereira, A M; Antunes, L M

    2016-08-01

    Several questions have been raised in recent years about the euthanasia of laboratory rodents. Euthanasia using inhaled agents is considered to be a suitable aesthetic method for use with a large number of animals simultaneously. Nevertheless, its aversive potential has been criticized in terms of animal welfare. The data available regarding the use of carbon dioxide (CO2), inhaled anaesthetics (such as isoflurane, sevoflurane, halothane and enflurane), as well as carbon monoxide and inert gases are discussed throughout this review. Euthanasia of fetuses and neonates is also addressed. A table listing currently available information to ease access to data regarding euthanasia techniques using gaseous agents in laboratory rodents was compiled. Regarding better animal welfare, there is currently insufficient evidence to advocate banning or replacing CO2 in the euthanasia of rodents; however, there are hints that alternative gases are more humane. The exposure to a volatile anaesthetic gas before loss of consciousness has been proposed by some scientific studies to minimize distress; however, the impact of such a measure is not clear. Areas of inconsistency within the euthanasia literature have been highlighted recently and stem from insufficient knowledge, especially regarding the advantages of the administration of isoflurane or sevoflurane over CO2, or other methods, before loss of consciousness. Alternative methods to minimize distress may include the development of techniques aimed at inducing death in the home cage of animals. Scientific outcomes have to be considered before choosing the most suitable euthanasia method to obtain the best results and accomplish the 3Rs (replacement, reduction and refinement). © The Author(s) 2015.

  15. Glucocorticoid Effects on Memory Consolidation Depend on Functional Interactions between the Medial Prefrontal Cortex and Basolateral Amygdala

    NARCIS (Netherlands)

    Roozendaal, Benno; McReynolds, Jayme R.; Van der Zee, Eddy A.; Lee, Sangkwan; McGaugh, James L.; McIntyre, Christa K.

    2009-01-01

    Considerable evidence indicates that the basolateral complex of the amygdala (BLA) interacts with efferent brain regions in mediating glucocorticoid effects on memory consolidation. Here, we investigated whether glucocorticoid influences on the consolidation of memory for emotionally arousing

  16. Glucocorticoid administration for Graves' hyperthyroidism treated by radioiodine. A questionnaire survey among members of the European Thyroid Association

    NARCIS (Netherlands)

    Lazarus, J. H.; Bartalena, L.; Marcocci, C.; Kahaly, G. J.; Krassas, G.; Wiersinga, W. M.; Baldeschi, L.; Boboridis, K.; Boschi, A.; Currò, N.; Daumerie, C.; Dickinson, A. J.; Eckstein, A.; Kendall-Taylor, P.; Lane, C. M.; Ludgate, M. E.; Mann, K.; Marinò, M.; Mourits, M. P.; Nardi, M.; Neoh, C.; Orgiazzi, J.; Pearce, S.; Perros, P.; Pinchera, A.; Pitz, S.; Salvi, M.; Sivelli, P.; Stahl, M.; von Arx, G.

    2010-01-01

    Background: Glucocorticoid prophylaxis is required in some instances after radioiodine (RAI) treatment for Graves' hyperthyroidism to prevent progression of Graves' orbitopathy (GO). However, no randomized clinical trial has been performed to ascertain the optimum glucocorticoid therapy. Aim and

  17. The glucocorticoid receptor in the distal nephron is not necessary for the development or maintenance of dexamethasone-induced hypertension

    OpenAIRE

    Goodwin, Julie E.; Zhang, Junhui; Velazquez, Heino; Geller, David S.

    2010-01-01

    Glucocorticoids are used as a treatment for a variety of conditions and hypertension is a well-recognized side effect of their use. The mechanism of glucocorticoid-induced hypertension is incompletely understood and has traditionally been attributed to promiscuous activation of the mineralocorticoid receptor by cortisol. Multiple lines of evidence, however, point to the glucocorticoid receptor as an important mediator as well. We have developed a mouse model of glucocorticoid-induced hyperten...

  18. Polymorphisms in the glucocorticoid receptor gene and their associations with metabolic parameters and body composition

    NARCIS (Netherlands)

    S.W.J. Lamberts (Steven); E.F.C. van Rossum (Liesbeth)

    2004-01-01

    textabstractMost actions of glucocorticoids (GCs) are mediated by the glucocorticoid receptor (GR). The interindividual response to GCs varies considerably, as demonstrated by a variable suppressive response to 0.25-mg dexamethasone (DEX). Several polymorphisms in the gene coding

  19. Glucocorticoid-induced osteoporosis: an update on current pharmacotherapy and future directions

    NARCIS (Netherlands)

    Bultink, I.E.M.; Baden, M.; Lems, W.F.

    2013-01-01

    Introduction: Glucocorticoid-induced osteoporosis (GIOP) is one of the most devastating side-effects of glucocorticoid (GC) use, as it is associated with an increased fracture risk. The importance of GIOP as a health problem is underlined by the frequent use of GC treatment in patients with various

  20. Heritable variation in circulating glucocorticoids and endocrine flexibility in a free-living songbird.

    Science.gov (United States)

    Stedman, J M; Hallinger, K K; Winkler, D W; Vitousek, M N

    2017-09-01

    Phenotypic flexibility is a central way that organisms cope with challenging and changing environments. As endocrine signals mediate many phenotypic traits, heritable variation in hormone levels, or their context-dependent flexibility, could present an important target for selection. Several studies have estimated the heritability of circulating glucocorticoid levels under acute stress conditions, but little is known about the potential for either baseline hormone levels or rapid endocrine flexibility to evolve. Here, we assessed the potential for selection to operate on the elevation (circulating hormone levels) and flexibility of glucocorticoid reaction norms to acute restraint stress. Multivariate animal models revealed low but significant heritability in baseline (h 2  = 0.13-0.14) and stress-induced glucocorticoids (h 2  = 0.18), and moderate heritability in glucocorticoid flexibility in response to acute stress (h 2  = 0.38) in free-living juvenile tree swallows (Tachycineta bicolor; n = 408). Baseline glucocorticoids were not genetically correlated with either stress-induced glucocorticoids or glucocorticoid flexibility. These findings indicate that baseline glucocorticoids and the acute stress response are distinct traits that can be independently shaped by selection. Microevolutionary changes that influence the expression or flexibility of these endocrine mediators of phenotype may be an important way that populations adapt to changing environments and novel threats. © 2017 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2017 European Society For Evolutionary Biology.

  1. Glucocorticoids Enhance Taste Aversion Memory via Actions in the Insular Cortex and Basolateral Amygdala

    Science.gov (United States)

    Miranda, Maria Isabel; Quirarte, Gina L.; Rodriguez-Garcia, Gabriela; McGaugh, James L.; Roozendaal, Benno

    2008-01-01

    It is well established that glucocorticoid hormones strengthen the consolidation of hippocampus-dependent spatial and contextual memory. The present experiments investigated glucocorticoid effects on the long-term formation of conditioned taste aversion (CTA), an associative learning task that does not depend critically on hippocampal function.…

  2. Bone metabolism in patients with systemic lupus erythematosus. Effect of disease activity and glucocorticoid treatment

    DEFF Research Database (Denmark)

    Hansen, M; Halberg, P; Kollerup, G

    1998-01-01

    and in the distal forearm. A weak correlation was found between the BMD of the femoral neck and the total consumption of glucocorticoids. Apart from this finding the BMD was uninfluenced by treatment with glucocorticoids and cyclophosphamide. No significant changes of BMD were found during the follow-up period...

  3. Recent advances in the molecular mechanisms causing primary generalized glucocorticoid resistance.

    Science.gov (United States)

    Nicolaides, Nicolas; Lamprokostopoulou, Agaristi; Sertedaki, Amalia; Charmandari, Evangelia

    2016-01-01

    Primary Generalized Glucocorticoid Resistance is a rare condition characterized by generalized, partial, target tissue insensitivity to glucocorticoids owing to inactivating mutations, insertions or deletions in the human glucocorticoid receptor (hGR) gene (NR3C1). Recent advances in molecular and structural biology have enabled us to elucidate the molecular mechanisms of action of the mutant receptors and to understand how certain conformational alterations of the defective hGRs result in generalized glucocorticoid resistance. Furthermore, our ever-increasing understanding of the molecular mechanisms of glucocorticoid action indicates that the glucocorticoid signaling pathway is a stochastic system that plays a fundamental role in maintaining both basal and stress-related homeostasis. In this review, we summarize the clinical manifestations and molecular pathogenesis of Primary Generalized Glucocorticoid Resistance, we present our recent findings from the functional characterization of three novel heterozygous point mutations in the NR3C1 gene, and we discuss the diagnostic approach and therapeutic management of the condition. When the condition is suspected, we recommend sequencing analysis of the NR3C1 gene as well as of other genes encoding proteins involved in the glucocorticoid signal transduction. The tremendous progress of next-generation sequencing will undoubtedly uncover novel hGR partners or cofactors.

  4. Use of systemic glucocorticoids and the risk of major osteoporotic fractures in patients with sarcoidosis

    NARCIS (Netherlands)

    Oshagbemi, Olorunfemi A; Driessen, J H M; Pieffers, A.; Wouters, E F M; Geusens, P.; Vestergaard, P.; van den Bergh, J; Franssen, F M E; de Vries, F

    2017-01-01

    This study revealed the risk of major osteoporotic fracture in patients with sarcoidosis exposed to glucocorticoids. Current use of glucocorticoids was associated with a risk of fracture, with no difference between patients with and without sarcoidosis. Sarcoidosis per se was not associated with an

  5. Fatal and non-fatal adverse events of glucocorticoid therapy for Graves' orbitopathy

    DEFF Research Database (Denmark)

    Marcocci, Claudio; Watt, Torquil; Altea, Maria Antonietta

    2012-01-01

    The objective of this study was to investigate the side effects of glucocorticoid (GC) therapy observed by European thyroidologists during the treatment of Graves' orbitopathy (GO).......The objective of this study was to investigate the side effects of glucocorticoid (GC) therapy observed by European thyroidologists during the treatment of Graves' orbitopathy (GO)....

  6. Allelic polymorphism of glucocorticoid receptor NR3C1 (GR: from molecular biology to clinical implications

    Directory of Open Access Journals (Sweden)

    Orlovsky M. A.

    2012-09-01

    Full Text Available Polymorphism of stress-related genes is a key factor determining difference in the stress reactivity and resistance among humans. Glucocorticoid receptors are important actors of stress responses. This review is focused on the molecular biology and clinical implications of glucocorticoid receptor gene polymorphism.

  7. Long-term effects of perinatal glucocorticoid treatment on the heart

    NARCIS (Netherlands)

    Vries, W.B. de

    2006-01-01

    Long-term effects of perinatal glucocorticoid treatment on the heart Chronic lung disease in the extremely preterm baby is still a major complication in neonatal intensive care medicine. Perinatal (ante- and neonatal) glucocorticoids are widely used to prevent severe infant respiratory syndrome and

  8. Instructions for producing a mouse model of glucocorticoid-induced osteoporosis

    DEFF Research Database (Denmark)

    Thiele, S.; Baschant, U.; Rauch, A.

    2014-01-01

    Glucocorticoids are effective drugs used for the treatment of inflammatory diseases such as rheumatoid arthritis or asthma. Furthermore, they regulate various physiological processes, including bone remodeling. However, long-term high- and even low-dose glucocorticoid use is associated with a com...

  9. Live cell imaging unveils multiple domain requirements for in vivo dimerization of the glucocorticoid receptor

    DEFF Research Database (Denmark)

    Presman, Diego M; Ogara, M Florencia; Stortz, Martín

    2014-01-01

    Glucocorticoids are essential for life, but are also implicated in disease pathogenesis and may produce unwanted effects when given in high doses. Glucocorticoid receptor (GR) transcriptional activity and clinical outcome have been linked to its oligomerization state. Although a point mutation wi...

  10. Maternal PTSD associates with greater glucocorticoid sensitivity in offspring of Holocaust survivors.

    Science.gov (United States)

    Lehrner, Amy; Bierer, Linda M; Passarelli, Vincent; Pratchett, Laura C; Flory, Janine D; Bader, Heather N; Harris, Iris R; Bedi, Aarti; Daskalakis, Nikolaos P; Makotkine, Iouri; Yehuda, Rachel

    2014-02-01

    Intergenerational effects of trauma have been observed clinically in a wide range of populations, and parental PTSD has been associated with an increased risk for psychopathology in offspring. In studies of Holocaust survivor offspring, parental PTSD, and particularly maternal PTSD, has been associated with increased risk for PTSD, low basal urinary cortisol excretion and enhanced cortisol suppression in response to dexamethasone. Such findings implicate maternally derived glucocorticoid programming in the intergenerational transmission of trauma-related consequences, potentially resulting from in utero influences or early life experiences. This study investigated the relative influence of Holocaust exposure and PTSD in mothers and fathers on glucocorticoid sensitivity in offspring. Eighty Holocaust offspring and 15 offspring of non-exposed Jewish parents completed evaluations and provided blood and urine samples. Glucocorticoid sensitivity was evaluated using the lysozyme suppression test (LST), an in vitro measure of glucocorticoid receptor sensitivity in a peripheral tissue, the dexamethasone suppression test (DST), and 24-h urinary cortisol excretion. Maternal PTSD was associated with greater glucocorticoid sensitivity in offspring across all three measures of glucocorticoid function. An interaction of maternal and paternal PTSD on the DST and 24-h urinary cortisol showed an effect of decreased glucocorticoid sensitivity in offspring with paternal, but not maternal, PTSD. Although indirect, these findings are consistent with the hypothesis that epigenetic programming may be involved in the intergenerational transmission of trauma-related effects on glucocorticoid regulation. Published by Elsevier Ltd.

  11. A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined with Enzalutamide in Castrate-Resistant Prostate Cancer

    Science.gov (United States)

    2016-12-01

    AWARD NUMBER: W81XWH-14-1-0021 TITLE: A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined...Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined with Enzalutamide in Castrate-Resistant Prostate Cancer 5b. GRANT NUMBER...receptor (AR) targeted therapies, prostate cancer adapts. One way it adapts is by upregulating another hormone receptor, the glucocorticoid receptor

  12. Expression and function of nuclear receptor coregulators in brain : understanding the cell-specific effects of glucocorticoids

    NARCIS (Netherlands)

    Laan, Siem van der

    2008-01-01

    Currently, the raising awareness of the role of glucocorticoids in the onset of numerous (neuro)-pathologies constitutes the increasing necessity of understanding the mechanisms of action of glucocorticoids in bodily processes and brain functioning. Glucocorticoids mediate their effects by binding

  13. Genetic and in vivo determinants of glucocorticoid sensitivity in relation to clinical outcome of childhood nephrotic syndrome

    NARCIS (Netherlands)

    Teeninga, N.; van Holthe, J.E.; van den Akker, E.L.T.; Kersten, M.C.; Boersma, E.; Krabbe, H.G.; Knoers, N.V.A.M.; van der Heijden, A.J.; Koper, J.W.; Nauta, J.

    2014-01-01

    Following initial glucocorticoid treatment, the clinical course in children with nephrotic syndrome is highly variable. Intrinsic sensitivity to glucocorticoids might be a determinant of this variability. Functional polymorphisms of the glucocorticoid receptor gene NR3C1 have been associated with

  14. Kinetics of glucocorticoid exposure in developing zebrafish: A tracer study.

    Science.gov (United States)

    Steenbergen, Peter Johannes; Bardine, Nabila; Sharif, Faiza

    2017-09-01

    In the current study the dynamics of glucocorticoid uptake by zebrafish chorionated embryos from the surrounding medium were studied, using 2.5 μM cortisol or dexamethasone solutions complemented with their tritiated variant. We measured the uptake of radioactive cortisol by embryos during a 1 h submersion. Interestingly, the signal in chorionated embryos was 85% (exposure: 1-2 hpf) or 78% (exposure: 48-49 hpf) of the signal present in an equal volume medium. By comparing embryos measured without chorion, we found that 18-20% of the radioactivity present in chorionated embryos is actually bound to the chorion or located in the perivitelline space. Consequently, embryonic tissue contains radioactivity levels of 60% of a similar volume of medium after 1 h incubation. During early developmental stages (1-48 hpf) exposure of more than 24 h in cortisol was needed to achieve radioactivity levels similar to an equal volume of medium within the embryonic tissue and more than 48 h for dexamethasone. In glucocorticoid-free medium, radioactivity dropped rapidly below 10% for both glucocorticoids, suggesting that the major portion of the embryonic radioactivity was a result of simple diffusion. During later developmental stages (48-96 hpf) initial uptake dynamics were similar, but showed a decrease of tissue radioactivity to 20% of an equal volume of medium after hatching, probably due to development and activation of the hypothalamic pituitary interrenal axis. Uptake is dependent on the developmental stage of the embryo. Furthermore, the presence of the chorion during exposure should be taken into account even when small lipophilic molecules are being tested. Copyright © 2017. Published by Elsevier Ltd.

  15. Impact of Stress and Glucocorticoids on Schema-Based Learning.

    Science.gov (United States)

    Kluen, Lisa Marieke; Nixon, Patricia; Agorastos, Agorastos; Wiedemann, Klaus; Schwabe, Lars

    2017-05-01

    Pre-existing knowledge, a 'schema', facilitates the encoding, consolidation, and retrieval of schema-relevant information. Such schema-based memory is key to every form of education and provides intriguing insights into the integration of new information and prior knowledge. Stress is known to have a critical impact on memory processes, mainly through the action of glucocorticoids and catecholamines. However, whether stress and these major stress mediators affect schema-based learning is completely unknown. To address this question, we performed two experiments, in which participants acquired a schema on day 1 and learned schema-related as well as schema-unrelated information on day 2. In the first experiment, participants underwent a stress or control manipulation either immediately or about 25 min before schema-based memory testing. The second experiment tested whether glucocorticoid and/or noradrenergic activation is sufficient to modulate schema-based memory. To this end, participants received orally a placebo, hydrocortisone, the α2-adrenoceptor-antagonist yohimbine, leading to increased noradrenergic stimulation, or both drugs, before completing the schema-based memory test. Our data indicate that stress, irrespective of the exact timing of the stress exposure, impaired schema-based learning, while leaving learning of schema-unrelated information intact. A very similar effect was obtained after hydrocortisone, but not yohimbine, administration. These data show that stress disrupts participants' ability to benefit from prior knowledge during learning and that glucocorticoid activation is sufficient to produce this effect. Our findings provide novel insights into the impact of stress and stress hormones on the dynamics of human memory and have important practical implications, specifically for educational contexts.

  16. Different response to glucocorticoid therapy in autoimmune diseases of CNS

    Directory of Open Access Journals (Sweden)

    Stanojević Željka

    2016-01-01

    Full Text Available Th17 cells and interleukin (IL-17, their signature cytokine, have the main role in the pathogenesis of autoimmune diseases of the central nervous system such as multiple sclerosis and experimental autoimmune encephalomyelitis (EAE. The effect of glucocorticoids (GC on expression and production of IL-17 has not been thoroughly tested yet. Also, the site of action of GC is not precisely defined. This paper presents the main results of the Doctoral thesis devoted to studies of GC on the production of IL-17 in the model of EAE, induced in susceptible laboratory animals. Methylprednisolone (MP, a synthetic glucocorticoid, inhibit in vitro production of IL-17 in mitogen-stimulated lymph node cells (LNC as well as in myelin basic protein (MBP-stimulated draining LNC in dose- dependent manner. However, under the same conditions inhibitory effect of the MP on production and expression of the genes for IFN-γ, a cytokine that TH1 cells generate, is significantly more pronounced. Interestingly, when we analyzed effects of MP applied in vivo in EAE, the same phenomenon was observed: the proportion of IFN-γ producing, but not all of IL-17 cells were reduced in cells isolated from MP treated rats in comparison to control rats which indicates that MP achieves its effects not only in the peripheral lymphoid tissues, but also in target tissue. Different sensitivities of Th1 and Th17 cells that are major cellular sources of IFN-γ or IL-17 in the effect of the GC has been observed in other animal models and in human disease. Understanding the molecular mechanisms underlying the relative resistance of Th17 cells on the operation of GC is very important for the development of new strategies in the treatment of those forms of autoimmune and chronic diseases that are resistant to the effect of glucocorticoids.

  17. Glucocorticoid Receptor Binding Induces Rapid and Prolonged Large-Scale Chromatin Decompaction at Multiple Target Loci

    Directory of Open Access Journals (Sweden)

    Alasdair W. Jubb

    2017-12-01

    Full Text Available Glucocorticoids act by binding to the glucocorticoid receptor (GR, which binds to specific motifs within enhancers of target genes to activate transcription. Previous studies have suggested that GRs can promote interactions between gene promoters and distal elements within target loci. In contrast, we demonstrate here that glucocorticoid addition to mouse bone-marrow-derived macrophages produces very rapid chromatin unfolding detectable by fluorescence in situ hybridization (FISH at loci associated with GR binding. Rapid chromatin decompaction was generally not dependent on transcription at those loci that are known to be inducible in both mouse and human macrophages and was sustained for up to 5 days following ligand removal. Chromatin decompaction was not dependent upon persistent GR binding, which decayed fully after 24 hr. We suggest that sustained large-scale chromatin reorganization forms an important part of the response to glucocorticoid and might contribute to glucocorticoid sensitivity and resistance.

  18. The effects of glucocorticoid on microarchitecture, collagen, mineral and mechanical properties of sheep femur cortical bone

    DEFF Research Database (Denmark)

    Ding, Ming; Danielsen, Carl C; Overgaard, Søren

    2010-01-01

    The effects of glucocorticoid on microarchitecture, collagen, mineral and mechanical properties of sheep femur cortical bone – Validation of large animal model for tissue engineering and biomaterial research Ming Ding,1* Carl Christian Danielsen,2 Søren Overgaard1 1Orthopaedic Research Laboratory...... by glucocorticoid treatment and the changes in properties of cancellous bone were comparable with those observed in humans after long-term glucocorticoid treatment. However, the influence on cortical bone has not been thoroughly elucidated. This study aimed to investigate the influence of glucocorticoid on sheep...... cortical bone after long-term treatment. Specifically, we quantify the microarchitecture, mechanical properties, collagen and mineral quality of sheep cortical bone. We hypothesized that glucocorticoid treatment also had significant influences on cortical bone that might increase risk of fracture...

  19. Glucocorticoids maintain human osteoclasts in the active mode of their resorption cycle

    DEFF Research Database (Denmark)

    Søe, Kent; Delaissé, Jean-Marie

    2010-01-01

    that glucocorticoids deeply modify this resorptive behavior. First, glucocorticoids gradually induce excavations with a trenchlike morphology while reducing the time-dependent increase in excavation numbers. This indicates that glucocorticoids make osteoclasts elongate the excavations they initiated rather than...... migrating to a new resorption site, as in control conditions. Second, the round excavations in control conditions contain undegraded demineralized collagen as repeatedly reported earlier, whereas the excavations with a trenchlike morphology generated under glucocorticoid exposure appear devoid of leftovers...... of demineralized collagen. This indicates that collagenolysis proceeds generally at a lower rate than demineralization under control conditions, whereas collagenolysis rates are increased up to the level of demineralization rates in the presence of glucocorticoids. Taking these observations together leads...

  20. When and for how long should glucocorticoids be used in rheumatoid arthritis? International guidelines and recommendations.

    Science.gov (United States)

    Gaujoux-Viala, Cécile; Gossec, Laure

    2014-05-01

    Glucocorticoids are widely used in rheumatoid arthritis (RA); however, their effectiveness and safety is still a subject of debate. In particular, when to introduce glucocorticoids, but also when and how to taper them, are important questions for clinicians. In this paper, we will discuss the place of glucocorticoids in the European League Against Rheumatism (EULAR) recommendations for the management of RA and review the literature that was the basis for these recommendations. The recommendations cover the introduction of glucocorticoids (and for whom they are recommended), doses and duration of treatment, and tapering strategies. Items still on the research agenda include more data on safety, particularly for long-term use, and small doses of glucocorticoids. © 2014 New York Academy of Sciences.

  1. The five Rs of glucocorticoid action during inflammation: ready, reinforce, repress, resolve, and restore.

    Science.gov (United States)

    Busillo, John M; Cidlowski, John A

    2013-03-01

    Glucocorticoids are essential for maintaining homeostasis and regulate a wide variety of physiological processes. Therapeutically, synthetic glucocorticoids are widely prescribed for the treatment of inflammation, autoimmune disorders, and malignancies of lymphoid origin. In this review we examine emerging evidence highlighting both proinflammatory and anti-inflammatory actions of glucocorticoids on both the innate and adaptive immune systems. We incorporate these findings into the more traditional anti-inflammatory role attributed to glucocorticoids, and propose how the two seemingly disparate processes seamlessly work together to resolve cellular responses to inflammatory stimuli. These ideas provide a framework by which glucocorticoids ready and reinforce the innate immune system, and repress the adaptive immune system, to help to resolve inflammation and restore homeostasis. Published by Elsevier Ltd.

  2. Glucocorticoid treatment earlier in childhood and adolescence show dose-response associations with diurnal cortisol levels

    DEFF Research Database (Denmark)

    Vestergaard, Martin; Holm, Sara K; Uldall, Peter

    2017-01-01

    Heightened levels of glucocorticoids in children and adolescents have previously been linked to prolonged changes in the diurnal regulation of the stress-hormone cortisol, a glucocorticoid regulated by the hypothalamic-pituitary-adrenal-axis (HPA-axis). To address this question, we examined...... the salivary cortisol awakening response (CAR) and daily cortisol output in 36 children and adolescents (25 girls/11 boys) aged 7-16 years previously treated with glucocorticoids for nephrotic syndrome or rheumatic disorder and 36 healthy controls. Patients and controls did not significantly differ in the CAR...... patients showed a positive linear relationship with the mean daily glucocorticoid doses administered during treatment. The observed dose-response associations suggest that glucocorticoid therapy during childhood and adolescence might trigger long-term changes in HPA-axis regulation, which may differ...

  3. Glucocorticoids Inhibit Wound Healing: Novel Mechanism of Action.

    Science.gov (United States)

    Slominski, Andrzej T; Zmijewski, Michal A

    2017-05-01

    Jozic et al. describe mechanisms of glucocorticoid (GC) downregulation of wound healing by interaction with the membrane bound GC receptor, followed by stimulation of β-catenin and c-myc pathways. Targeting the membrane bound GC receptor or the recently discovered interaction of GC with mineralocorticoid receptors may counteract negative effects of GC on the skin barrier and potentially could serve as a remedy for age-related skin atrophy. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  4. Hypersensitivity Reactions from Excipients in Systemic Glucocorticoid Formulations

    DEFF Research Database (Denmark)

    Calogiuri, Gianfranco; Garvey, Lene H; Romita, Paolo

    2016-01-01

    Glucocorticoids are the most widely used drugs for the treatment of hypersensitivity, however these drugs themselves and the excipients contained in commercial corticosteroid formulations are able to induce severe immediate-type hypersensitivity reactions. Reactions involving excipients have been...... confirmed to be IgE mediated by the demonstration of specific-IgE to excipients such as carboxymethylcellulose and lactose. In case of hypersensitivity reactions to corticosteroid preparations, a complete allergy work-up with skin tests and/or challenge tests should include testing excipients as well...

  5. Glucocorticoid resistance as a major drive in sepsis pathology.

    Science.gov (United States)

    Dendoncker, Karen; Libert, Claude

    2017-06-01

    Sepsis is an acute systemic inflammatory disease. Glucocorticoids (GCs), which function by binding to the GC receptor GR have very powerful anti-inflammatory activities, yet they are hardly useful in sepsis. We can thus consider sepsis as a GC resistant disease. We here review the literature which has investigated this GC resistance, and summarize the mechanisms of GC resistance that have been observed in other diseases and in experimental models. We also discuss the importance of GC resistance in sepsis, in terms of the contribution of this phenomenon to the pathogenesis of sepsis. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Glucocorticoids enhance stability of human growth hormone mRNA.

    OpenAIRE

    Paek, I; Axel, R

    1987-01-01

    We have studied the control of expression of the human growth hormone (hGH) gene introduced into the chromosomes of mouse fibroblasts. Cell lines transformed with the hGH gene expressed low levels of intact hGH mRNA and secreted hGH protein into the medium. Although the level of expression of hGH mRNA was low, the gene remained responsive to induction by glucocorticoid hormones. To localize the sequences responsible for induction and to determine the mechanism by which these cis-acting sequen...

  7. Antenatal glucocorticoid treatment and polymorphisms of the glucocorticoid and mineralocorticoid receptors are associated with IQ and behavior in young adults born very preterm.

    Science.gov (United States)

    van der Voorn, Bibian; Wit, Jan M; van der Pal, Sylvia M; Rotteveel, Joost; Finken, Martijn J J

    2015-02-01

    Preterm survivors exhibit neurodevelopmental impairments. Whether this association is influenced by antenatal glucocorticoid treatment and glucocorticoid sensitivity is unknown. This study aimed to study the effects of antenatal glucocorticoid treatment and glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) polymorphisms on behavior and intelligence quotient (IQ). This study was part of the 19-year follow-up of the Project On Preterm and Small-for-gestational-age birth cohort. Multicenter study. Three hundred forty-four 19-year-olds born very preterm (gestational age IQ (digital Multicultural Capacity Test-intermediate level). Data were analyzed by linear regression and presented as regression coefficient (95% confidence interval [CI]). Sex ratio, GR (R23K; N363S) and MR (-2G/C; I180V) genotypes were equally distributed between treated and nontreated subjects. Independent of treatment, R23K carriers had improved IQ scores (β 9.3; 95% CI, 3.4 to 15.1) and a tendency toward more favorable total problem behavior scores (β -8.5; 95% CI, -17.3 to 0.2) ; -2G/C CC carriers had poorer IQ scores (β -6.2; 95% CI, -10.5 to -1.9); I180V carriers had more favorable internalizing behavior scores (β -2.0; 95% CI, -3.9 to -0.1). Antenatal glucocorticoid treatment was associated with more unfavorable behavior scores, especially internalizing behavior (β 2.4; 95% CI, 0.3 to 4.5). Interaction between GR and MR polymorphisms and antenatal glucocorticoid treatment was observed, with poorer IQ scores for exposed N363S carriers; poorer intellectual subdomain scores for exposed I180V-carriers; more favorable total problem behavior scores for exposed R23K carriers. Genetic variations in glucocorticoid sensitivity and antenatal glucocorticoid treatment are associated with IQ and behavior in young adult preterm survivors.

  8. Glucocorticoid-induced reversal of interleukin-1β-stimulated inflammatory gene expression in human oviductal cells.

    Directory of Open Access Journals (Sweden)

    Stéphanie Backman

    Full Text Available Studies indicate that high-grade serous ovarian carcinoma (HGSOC, the most common epithelial ovarian carcinoma histotype, originates from the fallopian tube epithelium (FTE. Risk factors for this cancer include reproductive parameters associated with lifetime ovulatory events. Ovulation is an acute inflammatory process during which the FTE is exposed to follicular fluid containing both pro- and anti-inflammatory molecules, such as interleukin-1 (IL1, tumor necrosis factor (TNF, and cortisol. Repeated exposure to inflammatory cytokines may contribute to transforming events in the FTE, with glucocorticoids exerting a protective effect. The global response of FTE cells to inflammatory cytokines or glucocorticoids has not been investigated. To examine the response of FTE cells and the ability of glucocorticoids to oppose this response, an immortalized human FTE cell line, OE-E6/E7, was treated with IL1β, dexamethasone (DEX, IL1β and DEX, or vehicle and genome-wide gene expression profiling was performed. IL1β altered the expression of 47 genes of which 17 were reversed by DEX. DEX treatment alone altered the expression of 590 genes, whereas combined DEX and IL1β treatment altered the expression of 784 genes. Network and pathway enrichment analysis indicated that many genes altered by DEX are involved in cytokine, chemokine, and cell cycle signaling, including NFκΒ target genes and interacting proteins. Quantitative real time RT-PCR studies validated the gene array data for IL8, IL23A, PI3 and TACC2 in OE-E6/E7 cells. Consistent with the array data, Western blot analysis showed increased levels of PTGS2 protein induced by IL1β that was blocked by DEX. A parallel experiment using primary cultured human FTE cells indicated similar effects on PTGS2, IL8, IL23A, PI3 and TACC2 transcripts. These findings support the hypothesis that pro-inflammatory signaling is induced in FTE cells by inflammatory mediators and raises the possibility that

  9. Synovial DKK1 expression is regulated by local glucocorticoid metabolism in inflammatory arthritis.

    Science.gov (United States)

    Hardy, Rowan; Juarez, Maria; Naylor, Amy; Tu, Jinwen; Rabbitt, Elizabeth H; Filer, Andrew; Stewart, Paul M; Buckley, Christopher D; Raza, Karim; Cooper, Mark S

    2012-10-18

    Inflammatory arthritis is associated with increased bone resorption and suppressed bone formation. The Wnt antagonist dickkopf-1 (DKK1) is secreted by synovial fibroblasts in response to inflammation and this protein has been proposed to be a master regulator of bone remodelling in inflammatory arthritis. Local glucocorticoid production is also significantly increased during joint inflammation. Therefore, we investigated how locally derived glucocorticoids and inflammatory cytokines regulate DKK1 synthesis in synovial fibroblasts during inflammatory arthritis. We examined expression and regulation of DKK1 in primary cultures of human synovial fibroblasts isolated from patients with inflammatory arthritis. The effect of TNFα, IL-1β and glucocorticoids on DKK1 mRNA and protein expression was examined by real-time PCR and ELISA. The ability of inflammatory cytokine-induced expression of the glucocorticoid-activating enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) to sensitise fibroblasts to endogenous glucocorticoids was explored. Global expression of Wnt signalling and target genes in response to TNFα and glucocorticoids was assessed using a custom array. DKK1 expression in human synovial fibroblasts was directly regulated by glucocorticoids but not proinflammatory cytokines. Glucocorticoids, but not TNFα, regulated expression of multiple Wnt agonists and antagonists in favour of inhibition of Wnt signalling. However, TNFα and IL-1β indirectly stimulated DKK1 production through increased expression of 11β-HSD1. These results demonstrate that in rheumatoid arthritis synovial fibroblasts, DKK1 expression is directly regulated by glucocorticoids rather than TNFα. Consequently, the links between synovial inflammation, altered Wnt signalling and bone remodelling are not direct but are dependent on local activation of endogenous glucocorticoids.

  10. Transforming growth factor-β impairs glucocorticoid activity in the A549 lung adenocarcinoma cell line.

    Science.gov (United States)

    Salem, S; Harris, T; Mok, J S L; Li, M Y S; Keenan, C R; Schuliga, M J; Stewart, A G

    2012-08-01

    The lung adenocarcinoma cell line, A549, undergoes epithelial-mesenchymal cell transition (EMT) in response to TGF-β. Glucocorticoids do not prevent the EMT response, but TGF-β induced resistance to the cytokine-regulatory action of glucocorticoids. We sought to characterize the impairment of glucocorticoid response in A549 cells. A549 cells were exposed to TGF-β for up to 96 h before glucocorticoid treatment and challenge with IL-1α to assess glucocorticoid regulation of IL-6 and CXCL8 production. Nuclear localization of the glucocorticoid receptor α (GRα) was ascertained by immunofluorescence and Western blotting. Transactivation of the glucocorticoid response element (GRE) was measured with a transfected GRE-secreted human placental alkaline phosphatase reporter. TGF-β (40-400 pM) reduced the maximum inhibitory effect of dexamethasone on IL-1α-induced IL-6 and CXCL8 production. The impaired glucocorticoid response was detected with 4 h of TGF-β (40 pM) exposure (and 4 h IL-1α to induce CXCL8 expression) and therefore was not secondary to EMT, a process that requires longer incubation periods and higher concentrations of TGF-β. TGF-β also impaired dexamethasone regulation of granulocyte-macrophage colony-stimulating factor in thrombin-stimulated BEAS-2B epithelial cells. Impaired regulation of CXCL8 was associated with markedly reduced GRE transactivation and reduced induction of mRNA for IκBα, the glucocorticoid-inducible leucine zipper and the epithelial sodium channel (SCNN1A). The expression, cellular levels and nuclear localization of GRα were reduced by TGF-β. We have identified mechanisms underlying the impairment of responses to glucocorticoids by TGF-β in the A549 and BEAS-2B cell lines. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

  11. Acute stress enhances heterodimerization and binding of corticosteroid receptors at glucocorticoid target genes in the hippocampus.

    Science.gov (United States)

    Mifsud, Karen R; Reul, Johannes M H M

    2016-10-04

    A stressful event results in secretion of glucocorticoid hormones, which bind to mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) in the hippocampus to regulate cognitive and affective responses to the challenge. MRs are already highly occupied by low glucocorticoid levels under baseline conditions, whereas GRs only become substantially occupied by stress- or circadian-driven glucocorticoid levels. Currently, however, the binding of MRs and GRs to glucocorticoid-responsive elements (GREs) within hippocampal glucocorticoid target genes under such physiological conditions in vivo is unknown. We found that forced swim (FS) stress evoked increased hippocampal RNA expression levels of the glucocorticoid-responsive genes FK506-binding protein 5 (Fkbp5), Period 1 (Per1), and serum- and glucocorticoid-inducible kinase 1 (Sgk1). Chromatin immunoprecipitation (ChIP) analysis showed that this stressor caused substantial gene-dependent increases in GR binding and surprisingly, also MR binding to GREs within these genes. Different acute challenges, including novelty, restraint, and FS stress, produced distinct glucocorticoid responses but resulted in largely similar MR and GR binding to GREs. Sequential and tandem ChIP analyses showed that, after FS stress, MRs and GRs bind concomitantly to the same GRE sites within Fkbp5 and Per1 but not Sgk1 Thus, after stress, MRs and GRs seem to bind to GREs as homo- and/or heterodimers in a gene-dependent manner. MR binding to GREs at baseline seems to be restricted, whereas after stress, GR binding may facilitate cobinding of MR. This study reveals that the interaction of MRs and GRs with GREs within the genome constitutes an additional level of complexity in hippocampal glucocorticoid action beyond expectancies based on ligand-receptor interactions.

  12. Novel aspects of hypothalamic-pituitary-adrenal axis regulation and glucocorticoid actions

    Science.gov (United States)

    Uchoa, Ernane Torres; Aguilera, Greti; Herman, James P.; Fiedler, Jenny L.; Deak, Terrence; Cordeiro de Sousa, Maria Bernardete

    2014-01-01

    Normal hypothalamic-pituitary-adrenal (HPA) axis activity leading to rhythmic and episodic release of adrenal glucocorticoids is essential for body homeostasis and survival during stress. Acting through specific intracellular receptors in the brain and periphery, glucocorticoids regulate behavior, metabolic, cardiovascular, immune, and neuroendocrine activities. In contrast to chronic elevated levels, circadian and acute stress-induced increases in glucocorticoids are necessary for hippocampal neuronal survival and memory acquisition and consolidation, through inhibiting apoptosis, facilitating glutamate transmission and inducing immediate early genes and spine formation. In addition to its metabolic actions leading to increasing energy availability, glucocorticoids have profound effects on feeding behavior, mainly through modulation of orexigenic and anorixegenic neuropeptides. Evidence is also emerging that in addition to the recognized immune suppressive actions of glucocorticoids by counteracting adrenergic proinflammatory actions, circadian elevations have priming effects in the immune system, potentiating acute defensive responses. In addition, negative feedback by glucocorticoids involves multiple mechanisms leading to limiting HPA axis activation and preventing deleterious effects of excessive glucocorticoid production. Adequate glucocorticoid secretion to meet body demands is tightly regulated by a complex neural circuitry controlling hypothalamic corticotrophin releasing hormone (CRH) and vasopressin secretion, the main regulators of pituitary adrenocorticotrophic hormone (ACTH). Rapid feedback mechanisms, likely involving non-genomic actions of glucocorticoids, mediate immediate inhibition of hypothalamic CRH and ACTH secretion, while intermediate and delayed mechanisms mediated by genomic actions involve modulation of limbic circuitry and peripheral metabolic messengers. Consistent with their key adaptive roles, HPA axis components are evolutionarily

  13. Population dynamics of Rodents and Insectivores in lowland tropical ...

    African Journals Online (AJOL)

    ADOWIE PERE

    2018-03-19

    Mar 19, 2018 ... ABSTRACT: The community structure of rodents and insectivores in the lowland tropical rainforest of Okomu. National Park, Edo State, Nigeria was assessed using a combination of live-trapping and sighting techniques during the dry and wet seasons. Seventeen species (14 species of rodent, 3 species of ...

  14. Population dynamics of Rodents and Insectivores in lowland tropical ...

    African Journals Online (AJOL)

    The community structure of rodents and insectivores in the lowland tropical rainforest of Okomu National Park, Edo State, Nigeria was assessed using a combination of live-trapping and sighting techniques during the dry and wet seasons. Seventeen species (14 species of rodent, 3 species of insectivores) were captured, ...

  15. Public Health and Rodents: A Game of Cat and Mouse

    NARCIS (Netherlands)

    Meerburg, B.G.

    2015-01-01

    Rodents are the most abundant order of living mammals, distributed on every continent except Antarctic and represent 43 % of all mammalian species. Beside causing food losses and infrastructural damage, rodents can harbour pathogens that may cause serious problems to human and animal health.

  16. Visual Landmarks Facilitate Rodent Spatial Navigation in Virtual Reality Environments

    Science.gov (United States)

    Youngstrom, Isaac A.; Strowbridge, Ben W.

    2012-01-01

    Because many different sensory modalities contribute to spatial learning in rodents, it has been difficult to determine whether spatial navigation can be guided solely by visual cues. Rodents moving within physical environments with visual cues engage a variety of nonvisual sensory systems that cannot be easily inhibited without lesioning brain…

  17. Measuring behaviour in rodents: towards translational neuropsychiatric research

    NARCIS (Netherlands)

    Homberg, J.R.

    2013-01-01

    Rodent behavioural tasks are indispensable to advance the understanding of gene x environment interactions in neuropsychiatric disorders and the discovery of new therapeutic strategies. Yet, the actual translation of rodent data to humans, and thereby the understanding of the pathophysiology of

  18. Ecology of rodents at an old quarry in Zambia

    African Journals Online (AJOL)

    A number of studies have been carried out on rodent com- munities in tropical Africa but few show the demographic and behavioural strategies of species in a community. This paper describes results of an ecological study of small rodents in secondary grassland at an old quarry. Kill- trapping was conducted at the study site ...

  19. Rodent-borne diseases and their risks for public health

    NARCIS (Netherlands)

    Meerburg, B.G.; Singleton, G.R.; Kijlstra, A.

    2009-01-01

    Rodents are the most abundant and diversified order of living mammals in the world. Already since the Middle Ages we know that they can contribute to human disease, as black rats were associated with distribution of plague. However, also in modern times rodents form a threat for public health. In

  20. Dietary patterns of two herbivorous rodents: Otomys unisulcatus and ...

    African Journals Online (AJOL)

    1990-06-05

    Jun 5, 1990 ... Differences and overlap in the diets of two sympatric, herbivorous rodents Otomys unisulcatus and. Parotomys brantsii ... overlap between rodent's diets are a function of food availability in the different habitats. It is suggested ..... preference for perennials, as reported for Thomomys bottae. (Gettinger 1984).

  1. Helminthes parasites of rodents caught around human habitats in ...

    African Journals Online (AJOL)

    Helminthes parasites of rodents caught around human habitats in Jos, Plateau state, Nigeria. ... Animal Production Research Advances ... The prevalence rates of helminth parasites in the four species of rodents caught were 82.53% in Xerus erythropus (ground squirrel) 38.30% in Thryonomys swinderianus (cane rat) ...

  2. Seed predation by nocturnal rodents in an African savanna ecosystem

    African Journals Online (AJOL)

    The small mammal community in Acacia savanna consists of three omnivorous nocturnal rodent species, Mastomys natalensis, Saccostomus campestris and Aethomys chrysophilus, which eat varying proportions of seed in their diet. From a seed removal experiment, it was found that rodents preferentially selected Acacia ...

  3. The utility of Plasmodium berghei as a rodent model for anti-merozoite malaria vaccine assessment

    Science.gov (United States)

    Goodman, Anna L.; Forbes, Emily K.; Williams, Andrew R.; Douglas, Alexander D.; de Cassan, Simone C.; Bauza, Karolis; Biswas, Sumi; Dicks, Matthew D. J.; Llewellyn, David; Moore, Anne C.; Janse, Chris J.; Franke-Fayard, Blandine M.; Gilbert, Sarah C.; Hill, Adrian V. S.; Pleass, Richard J.; Draper, Simon J.

    2013-01-01

    Rodent malaria species Plasmodium yoelii and P. chabaudi have been widely used to validate vaccine approaches targeting blood-stage merozoite antigens. However, increasing data suggest the P. berghei rodent malaria may be able to circumvent vaccine-induced anti-merozoite responses. Here we confirm a failure to protect against P. berghei, despite successful antibody induction against leading merozoite antigens using protein-in-adjuvant or viral vectored vaccine delivery. No subunit vaccine approach showed efficacy in mice following immunization and challenge with the wild-type P. berghei strains ANKA or NK65, or against a chimeric parasite line encoding a merozoite antigen from P. falciparum. Protection was not improved in knockout mice lacking the inhibitory Fc receptor CD32b, nor against a Δsmac P. berghei parasite line with a non-sequestering phenotype. An improved understanding of the mechanisms responsible for protection, or failure of protection, against P. berghei merozoites could guide the development of an efficacious vaccine against P. falciparum. PMID:23609325

  4. Helminths in rodents from Wet Markets in Thailand

    Directory of Open Access Journals (Sweden)

    Ribas A.

    2016-12-01

    Full Text Available Only a few surveys have ever been carried out of the helminths of the commensal rodents found in the traditional wet markets that play such an important part of daily life in South-east Asia. The potential of rodents as reservoirs of zoonoses including helminths is of great interest since in these markets humans and rodents come into closer contact than in other environments and food may be indirectly contaminated via rodent faeces. Helminths in a total of 98 rats belonging to two species (Rattus norvegicus and Rattus exulans were surveyed in eight traditional wet markets in Udon Thani, Thailand. Thirteen species of helminths were recovered, seven of which are potentially zoo-notic, with an overall prevalence of 89.8 %. Our results show that rodents in wet markets could pose a threat to human health as potential reservoirs of zoonotic helminthiases.

  5. The bioeconomics of controlling an African rodent pest species

    DEFF Research Database (Denmark)

    Skonhoft, Anders; Leirs, Herwig; Andreassen, Harry P

    2006-01-01

    The paper treats the economy of controlling an African pest rodent, the multimammate rat, causing major damage in maize production. An ecological population model is presented and used as a basis for the economic analyses carried out at the village level using data from Tanzania. This model...... incorporates both density-dependent and density-independent (stochastic) factors. Rodents are controlled by applying poison, and the costs are made up of the cost of poison plus the damage to maize production. We analyse how the present-value costs of maize production are affected by various rodent control...... strategies, by varying the duration and timing of rodenticide application. Our numerical results suggest that it is economically beneficial to control the rodent population. In general, the most cost-effective duration of controlling the rodent population is 3-4 months every year, and especially at the end...

  6. [Pinus koraiensis seed consumption by rodents and birds].

    Science.gov (United States)

    Yao, Xiao-lin; Piao, Zheng-ji; Li, Bu-hang; Zhang, Jian; Wang, Xu-gao; Ye, Ji; Hao, Zhan-qing

    2008-08-01

    An investigation from 2006 to 2007 was made on the Pinus koraiensis seed consumption by rodents and birds in the broad-leaved P. koraiensis mixed forest and birch forest at the same altitude in Changbai Mountains. The results showed that in broad-leaved P. koraiensis mixed forest, rodents consumed more pinecone seeds than birds; while in birch forest, birds did more than rodents. In the two forests, the total number of pinecone seeds consumed by rodents was significantly higher than that consumed by birds (P < 0.01). In addition, rodents consumed more embedded seeds in broad-leaved P. koraiensis mixed forest than in birch forest, and the consumption amount in the two forests decreased with increasing embedded depth.

  7. Safety and tolerability of high doses of glucocorticoides

    Directory of Open Access Journals (Sweden)

    Rakić Branislava D.

    2016-01-01

    Full Text Available Introduction: Treatment of acute lymphoblastic leukemia includes the use of high doses of glucocorticoides (prednisone and dexamethasone, which significantly increase the success of therapy due to lymphocytolitic effect. The aim: The aim of the study was to determine tolerability of high doses of prednisone and dexamethasone in children with acute lymphoblastic leukemia and the structure and the intensity of adverse effects, occurred after application of these medicines. Subjects and methods: In a prospective study, we analyzed adverse effects of high doses of glucocorticoides in children suffering acute lymphoblastic leukemia treated in the Institute for Child and Youth Health Care of Vojvodina, since December 2010. until October 2014, were analyzed. This study included 18 patients, aged from 2 to 15 years. Results: Hyperglycemia appeared in 89% of patients treated with prednisone and in 61% of patients treated with dexamethasone. In order to control the high blood glucose level (above 10 mmol /L, in 11% of patients insulin was used. Hypertension appeared in 28% patients treated with prednisone and dexamethasone. Antihypertensives were needed for regulation in 17% patients. Hypopotassemia and hypocalcaemia were significantly more expressed after the use of prednisone in comparison to dexamethasone. In 11% of patients, the treatment with dexamethasone caused depressive behavior, followed by agitation. Conclusion: Adverse effects of dexamethasone and prednisone, administered in high doses in children with ALL were known, expected and reversible. Adverse reactions usually disappeared spontaneously or after short-term symptomatic therapy.

  8. Characterization of a novel non-steroidal glucocorticoid receptor antagonist

    International Nuclear Information System (INIS)

    Li, Qun-Yi; Zhang, Meng; Hallis, Tina M.; DeRosier, Therese A.; Yue, Jian-Min; Ye, Yang; Mais, Dale E.; Wang, Ming-Wei

    2010-01-01

    Selective antagonists of the glucocorticoid receptor (GR) are desirable for the treatment of hypercortisolemia associated with Cushing's syndrome, psychic depression, obesity, diabetes, neurodegenerative diseases, and glaucoma. NC3327, a non-steroidal small molecule with potent binding affinity to GR (K i = 13.2 nM), was identified in a high-throughput screening effort. As a full GR antagonist, NC3327 greatly inhibits the dexamethasone (Dex) induction of marker genes involved in hepatic gluconeogenesis, but has a minimal effect on matrix metalloproteinase 9 (MMP-9), a GR responsive pro-inflammatory gene. Interestingly, the compound recruits neither coactivators nor corepressors to the GR complex but competes with glucocorticoids for the interaction between GR and a coactivator peptide. Moreover, NC3327 does not trigger GR nuclear translocation, but significantly blocks Dex-induced GR transportation to the nucleus, and thus appears to be a 'competitive' GR antagonist. Therefore, the non-steroidal compound, NC3327, may represent a new class of GR antagonists as potential therapeutics for a variety of cortisol-related endocrine disorders.

  9. An epistatic ratchet constrains the direction of glucocorticoid receptor evolution

    Energy Technology Data Exchange (ETDEWEB)

    Bridgham, Jamie T.; Ortlund, Eric A.; Thornton, Joseph W.; (Emory-MED); (Oregon)

    2010-10-28

    The extent to which evolution is reversible has long fascinated biologists. Most previous work on the reversibility of morphological and life-history evolution has been indecisive, because of uncertainty and bias in the methods used to infer ancestral states for such characters. Further, despite theoretical work on the factors that could contribute to irreversibility, there is little empirical evidence on its causes, because sufficient understanding of the mechanistic basis for the evolution of new or ancestral phenotypes is seldom available. By studying the reversibility of evolutionary changes in protein structure and function, these limitations can be overcome. Here we show, using the evolution of hormone specificity in the vertebrate glucocorticoid receptor as a case-study, that the evolutionary path by which this protein acquired its new function soon became inaccessible to reverse exploration. Using ancestral gene reconstruction, protein engineering and X-ray crystallography, we demonstrate that five subsequent 'restrictive' mutations, which optimized the new specificity of the glucocorticoid receptor, also destabilized elements of the protein structure that were required to support the ancestral conformation. Unless these ratchet-like epistatic substitutions are restored to their ancestral states, reversing the key function-switching mutations yields a non-functional protein. Reversing the restrictive substitutions first, however, does nothing to enhance the ancestral function. Our findings indicate that even if selection for the ancestral function were imposed, direct reversal would be extremely unlikely, suggesting an important role for historical contingency in protein evolution.

  10. Glucocorticoids modulate human brown adipose tissue thermogenesis in vivo.

    Science.gov (United States)

    Scotney, Hannah; Symonds, Michael E; Law, James; Budge, Helen; Sharkey, Don; Manolopoulos, Konstantinos N

    2017-05-01

    Brown adipose tissue (BAT) is a thermogenic organ with substantial metabolic capacity and has important roles in the maintenance of body weight and metabolism. Regulation of BAT is primarily mediated through the β-adrenoceptor (β-AR) pathway. The in vivo endocrine regulation of this pathway in humans is unknown. The objective of our study was to assess the in vivo BAT temperature responses to acute glucocorticoid administration. We studied 8 healthy male volunteers, not pre-selected for BAT presence or activity and without prior BAT cold-activation, on two occasions, following an infusion with hydrocortisone (0.2mg.kg -1 .min -1 for 14h) and saline, respectively. Infusions were given in a randomized double-blind order. They underwent assessment of supraclavicular BAT temperature using infrared thermography following a mixed meal, and during β-AR stimulation with isoprenaline (25ng.kg fat-free mass -1 .min -1 for 60min) in the fasting state. During hydrocortisone infusion, BAT temperature increased both under fasting basal conditions and during β-AR stimulation. We observed a BAT temperature threshold, which was not exceeded despite maximal β-AR activation. We conclude that BAT thermogenesis is present in humans under near-normal conditions. Glucocorticoids modulate BAT function, representing important physiological endocrine regulation of body temperature at times of acute stress. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  11. Glucocorticoid augmentation of prolonged exposure therapy: rationale and case report

    Directory of Open Access Journals (Sweden)

    Laura Pratchett

    2010-12-01

    Full Text Available Rationale: Prolonged exposure (PE therapy has been found to reduce symptoms of posttraumatic stress disorder (PTSD; however, it is difficult for many patients to engage fully in the obligatory retelling of their traumatic experiences. This problem is compounded by the fact that habituation and cognitive restructuring – the main mechanisms through which PE is hypothesized to work – are not instantaneous processes, and often require several weeks before the distress associated with imaginal exposure abates. Case reports: Two cases are described that respectively illustrate the use of hydrocortisone and placebo, in combination with PE, for the treatment of combat-related PTSD. Based on known effects of glucocorticoids on learning and memory performance, we hypothesized that augmentation with hydrocortisone would improve the therapeutic effects of PE by hastening “new” learning and facilitating decreases in the emotional impact of fear memories during the course of treatment. The veteran receiving hydrocortisone augmentation of PE displayed an accelerated and ultimately greater decline in PTSD symptoms than the veteran receiving placebo. Conclusions: While no general conclusion can be derived from comparison of two patients, the findings are consistent with the rationale for augmentation. These case reports support the potential for an appropriately designed and powered clinical trial to examine the efficacy of glucocorticoids in augmenting the effects of psychotherapy for PTSD.

  12. Serum cholesterol selectively regulates glucocorticoid sensitivity through activation of JNK.

    Science.gov (United States)

    Yang, Nan; Caratti, Giorgio; Ince, Louise M; Poolman, Toryn M; Trebble, Peter J; Holt, Cathy M; Ray, David W; Matthews, Laura C

    2014-11-01

    Glucocorticoids (Gc) are potent anti-inflammatory agents with wide clinical application. We have previously shown that increased serum concentration significantly attenuates regulation of a simple Gc-responsive reporter. We now find that glucocorticoid receptor (GR) regulation of some endogenous transactivated but not transrepressed genes is impaired, suggesting template specificity. Serum did not directly affect GR expression, activity or trafficking, implicating GR crosstalk with other signalling pathways. Indeed, a JNK inhibitor completely abolished the serum effect. We identified the Gc modulating serum component as cholesterol. Cholesterol loading mimicked the serum effect, which was readily reversed by JNK inhibition. Chelation of serum cholesterol with methyl-β-cyclodextrin or inhibition of cellular cholesterol synthesis with simvastatin potentiated the Gc response. To explore the effect in vivo we used ApoE(-/-) mice, a model of hypercholesterolaemia. Consistent with our in vitro studies, we find no impact of elevated cholesterol on the expression of GR, or on the hypothalamic-pituitary-adrenal axis, measured by dexamethasone suppression test. Instead we find selective Gc resistance on some hepatic target genes in ApoE(-/-) mice. Therefore, we have discovered an unexpected role for cholesterol as a selective modulator of Gc action in vivo. Taken together these findings reveal a new environmental constraint on Gc action with relevance to both inflammation and cancer. © 2014 The authors.

  13. Characterization of a novel non-steroidal glucocorticoid receptor antagonist

    Energy Technology Data Exchange (ETDEWEB)

    Li, Qun-Yi; Zhang, Meng [The National Center for Drug Screening, Shanghai (China); State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China); Hallis, Tina M.; DeRosier, Therese A. [Cell Systems Division, Invitrogen, Madison, WI (United States); Yue, Jian-Min; Ye, Yang [State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China); Mais, Dale E. [The National Center for Drug Screening, Shanghai (China); MPI Research, Mattawan, MI (United States); Wang, Ming-Wei, E-mail: wangmw@mail.shcnc.ac.cn [The National Center for Drug Screening, Shanghai (China); State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China)

    2010-01-15

    Selective antagonists of the glucocorticoid receptor (GR) are desirable for the treatment of hypercortisolemia associated with Cushing's syndrome, psychic depression, obesity, diabetes, neurodegenerative diseases, and glaucoma. NC3327, a non-steroidal small molecule with potent binding affinity to GR (K{sub i} = 13.2 nM), was identified in a high-throughput screening effort. As a full GR antagonist, NC3327 greatly inhibits the dexamethasone (Dex) induction of marker genes involved in hepatic gluconeogenesis, but has a minimal effect on matrix metalloproteinase 9 (MMP-9), a GR responsive pro-inflammatory gene. Interestingly, the compound recruits neither coactivators nor corepressors to the GR complex but competes with glucocorticoids for the interaction between GR and a coactivator peptide. Moreover, NC3327 does not trigger GR nuclear translocation, but significantly blocks Dex-induced GR transportation to the nucleus, and thus appears to be a 'competitive' GR antagonist. Therefore, the non-steroidal compound, NC3327, may represent a new class of GR antagonists as potential therapeutics for a variety of cortisol-related endocrine disorders.

  14. Glucocorticoid regulation of transcription at an amplified, episomal promoter

    Energy Technology Data Exchange (ETDEWEB)

    Ostrowski, M.C.; Richard-Foy, H.; Wolford, R.G.; Berard, D.S.; Hager, G.L.

    1983-11-01

    The mouse mammary tumor virus long terminal repeat (MMTV LTR) has been introduced into cultured murine cells, using the 69% transforming fragment of bovine papiloma virus type 1 (BVP). Transformed cells contain up to 200 copies of the chimeric molecules per diploid genome. The restriction endonuclease map of the acquired recombinants, as well as the physical structure of the DNA, indicates that the LTR-BVP molecules present in these cells occur exclusively as unintegrated, extrachromosomal episome. When a 72-base pair direct repeat ''enhancer'' element (derived from the Harvey sarcoma retrovirus) was included in the MMTV LTR-BPV chimeric plasmids, DNA acquired through transfection, with a single exception, was integrated or rearranged or both. Two approaches showed that the MMTV LTR present in the episomal state was capable of supporting glucocorticoid hormone-regulated transcription. The authors have therefore demonstrated the hormone response for the first time in a totally defined primary sequence environment. Significant differences both in the basal level of MMTV-initiated transcription and in the extend of glucocorticoid induction were observed in individual cell lines with similar episomal copy numbers. These phenotypic variations suggest that epigenetic structure is an important component of the mechanism of regulation.

  15. Annexin A1 in blood mononuclear cells from patients with coronary artery disease: Its association with inflammatory status and glucocorticoid sensitivity.

    Directory of Open Access Journals (Sweden)

    Ida Bergström

    Full Text Available Annexin A1 (AnxA1 is a key player in resolution of inflammation and a mediator of glucocorticoid actions. In atherosclerotic tissue, increased expression of AnxA1 has been associated with protective plaque-stabilizing effects. Here, we investigated the expression of AnxA1 in peripheral blood mononuclear cells (PBMCs from patients with coronary artery disease (CAD. Blood was collected from 57 patients with stable CAD (SCAD and 41 healthy controls. We also included a minor group (n = 10 with acute coronary syndrome (ACS. AnxA1 mRNA was measured in PBMCs. Expression of AnxA1 protein (total and surface-bound and glucocorticoid receptors (GR were detected in PBMC subsets by flow cytometry. Also, salivary cortisol, interleukin(IL-6 and IL-10 in plasma, and LPS-induced cytokine secretion from PBMCs, with or without dexamethasone, were assessed. AnxA1 mRNA was found to be slightly increased in PBMCs from SCAD patients compared with controls. However, protein expression of AnxA1 or GRs in PBMC subsets did not differ between SCAD patients and controls, despite SCAD patients showing a more proinflammatory cytokine profile ex vivo. Only surface expression of AnxA1 on monocytes correlated with dexamethasone-mediated suppression of cytokines. In ACS patients, a marked activation of AnxA1 was seen involving both gene expression and translocation of protein to cell surface probably reflecting a rapid glucocorticoid action modulating the acute inflammatory response in ACS. To conclude, surface expression of AnxA1 on monocytes may reflect the degree of glucocorticoid sensitivity. Speculatively, "normal" surface expression of AnxA1 indicates that anti-inflammatory capacity is impaired in SCAD patients.

  16. Annexin A1 in blood mononuclear cells from patients with coronary artery disease: Its association with inflammatory status and glucocorticoid sensitivity.

    Science.gov (United States)

    Bergström, Ida; Lundberg, Anna K; Jönsson, Simon; Särndahl, Eva; Ernerudh, Jan; Jonasson, Lena

    2017-01-01

    Annexin A1 (AnxA1) is a key player in resolution of inflammation and a mediator of glucocorticoid actions. In atherosclerotic tissue, increased expression of AnxA1 has been associated with protective plaque-stabilizing effects. Here, we investigated the expression of AnxA1 in peripheral blood mononuclear cells (PBMCs) from patients with coronary artery disease (CAD). Blood was collected from 57 patients with stable CAD (SCAD) and 41 healthy controls. We also included a minor group (n = 10) with acute coronary syndrome (ACS). AnxA1 mRNA was measured in PBMCs. Expression of AnxA1 protein (total and surface-bound) and glucocorticoid receptors (GR) were detected in PBMC subsets by flow cytometry. Also, salivary cortisol, interleukin(IL)-6 and IL-10 in plasma, and LPS-induced cytokine secretion from PBMCs, with or without dexamethasone, were assessed. AnxA1 mRNA was found to be slightly increased in PBMCs from SCAD patients compared with controls. However, protein expression of AnxA1 or GRs in PBMC subsets did not differ between SCAD patients and controls, despite SCAD patients showing a more proinflammatory cytokine profile ex vivo. Only surface expression of AnxA1 on monocytes correlated with dexamethasone-mediated suppression of cytokines. In ACS patients, a marked activation of AnxA1 was seen involving both gene expression and translocation of protein to cell surface probably reflecting a rapid glucocorticoid action modulating the acute inflammatory response in ACS. To conclude, surface expression of AnxA1 on monocytes may reflect the degree of glucocorticoid sensitivity. Speculatively, "normal" surface expression of AnxA1 indicates that anti-inflammatory capacity is impaired in SCAD patients.

  17. Epidemiology of Leptospira Transmitted by Rodents in Southeast Asia

    Science.gov (United States)

    Mielcarek, Mathilde; Tatard, Caroline; Chaval, Yannick; Suputtamongkol, Yupin; Buchy, Philippe; Jittapalapong, Sathaporn; Herbreteau, Vincent; Morand, Serge

    2014-01-01

    Background Leptospirosis is the most common bacterial zoonoses and has been identified as an important emerging global public health problem in Southeast Asia. Rodents are important reservoirs for human leptospirosis, but epidemiological data is lacking. Methodology/Principal Findings We sampled rodents living in different habitats from seven localities distributed across Southeast Asia (Thailand, Lao PDR and Cambodia), between 2009 to 2010. Human isolates were also obtained from localities close to where rodents were sampled. The prevalence of Leptospira infection was assessed by real-time PCR using DNA extracted from rodent kidneys, targeting the lipL32 gene. Sequencing rrs and secY genes, and Multi Locus Variable-number Tandem Repeat (VNTR) analyses were performed on DNA extracted from rat kidneys for Leptospira isolates molecular typing. Four species were detected in rodents, L. borgpetersenii (56% of positive samples), L. interrogans (36%), L. kirschneri (3%) and L. weilli (2%), which were identical to human isolates. Mean prevalence in rodents was approximately 7%, and largely varied across localities and habitats, but not between rodent species. The two most abundant Leptospira species displayed different habitat requirements: L. interrogans was linked to humid habitats (rice fields and forests) while L. borgpetersenii was abundant in both humid and dry habitats (non-floodable lands). Conclusion/Significance L. interrogans and L. borgpetersenii species are widely distributed amongst rodent populations, and strain typing confirmed rodents as reservoirs for human leptospirosis. Differences in habitat requirements for L. interrogans and L. borgpetersenii supported differential transmission modes. In Southeast Asia, human infection risk is not only restricted to activities taking place in wetlands and rice fields as is commonly accepted, but should also include tasks such as forestry work, as well as the hunting and preparation of rodents for consumption, which

  18. Application of experimental stressors in laboratory rodents.

    Science.gov (United States)

    Heinrichs, Stephen C; Koob, George F

    2006-02-01

    This unit presents eight separate stressor protocols for laboratory rodents. Stress induction is a critical element in the study of neural and neuroendocrine mechanisms involved in establishing and maintaining a state of stress. The first four procedures, immobilization, footshock, swimming, and noise, involve acute exposure to noxious stimuli. The next three procedures, social isolation, resident/intruder aggression, and maternal deprivation, induce social disruption by withdrawal from a group housing condition, attack within the unfamiliar territory of a dominant male, or segregation of a preweanling pup from its mother, respectively. The final procedure, sleep deprivation, involves passive denial of the opportunity to sleep. Support protocols are provided to address the need for environmental acclimation and calming procedures prior to any stress-related studies (including, for rats, handling of the animals as a calming measure) and to detail a simple method of quantifying the response to a given stressor by direct measurement of levels of the stress hormones adrenocorticotropic hormone (ACTH) and corticosterone.

  19. Cell-specific expression of the glucocorticoid receptor within granular convoluted tubules of the rat submaxillary gland

    Energy Technology Data Exchange (ETDEWEB)

    Antakly, T.; Zhang, C.X.; Sarrieau, A.; Raquidan, D. (McGill Univ., Montreal, Quebec (Canada))

    1991-01-01

    The submaxillary gland, a heterogeneous tissue composed essentially of two functionally distinct cell types (tubular epithelial and acinar), offers an interesting system in which to study the mechanisms of steroid-dependent growth and differentiation. One cell type, the granular convoluted tubular (GCT) cell, secretes a large number of physiologically important polypeptides, including epidermal and nerve growth factors. Two steroids, androgens and glucocorticoids, greatly influence the growth, differentiation, and secretory activity of GCT cells. Because glucocorticoids can partially mimic or potentiate androgen effects, it has been thought that glucocorticoids act via androgen receptors. Since the presence of glucocorticoid receptors is a prerequisite for glucocorticoid action, we have investigated the presence and cellular distribution of glucocorticoid receptors within the rat submaxillary gland. Binding experiments using (3H)dexamethasone revealed the presence of high affinity binding sites in rat submaxillary tissue homogenates. Most of these sites were specifically competed by dexamethasone, corticosterone, and a pure glucocorticoid agonist RU 28362. Neither testosterone nor dihydrotestosterone competed for glucocorticoid binding. The cellular distribution of glucocorticoid receptors within the submaxillary gland was investigated by immunocytochemistry, using two highly specific glucocorticoid receptor antibodies. The receptor was localized in the GCT cells, but not in the acinar cells of rat and mouse submaxillary tissue sections. In GCT cells, the glucocorticoid receptor colocalized with several secretory polypeptides, including epidermal growth factor, nerve growth factor, alpha 2u-globulin, and atrial natriuretic factor.

  20. Long-term safety, efficacy, and patient acceptability of teriparatide in the management of glucocorticoid-induced osteoporosis

    Directory of Open Access Journals (Sweden)

    Dore RK

    2013-05-01

    Full Text Available Robin K DoreDavid Geffen School of Medicine, University of California, Los Angeles, CA, USAAbstract: Glucocorticoids are commonly prescribed medications to treat multiple diseases across many medical specialties. One of the most common yet largely unappreciated side effect of glucocorticoid use is increased risk of fracture. Many different therapies are indicated to prevent and treat this condition; many guidelines exist that suggest appropriate use of both glucocorticoids and the medications approved to prevent this common side effect of glucocorticoid therapy. Nevertheless, 30%–50% of patients on long-term glucocorticoid therapy sustain a fracture. Teriparatide, recombinant human parathyroid hormone (1–34, is a daily self-injectable therapy for 24 months approved for use in patients taking long-term glucocorticoids. Teriparatide has been shown to increase bone mineral density and reduce vertebral fracture risk in glucocorticoid-treated patients. Glucocorticoids have many adverse effects on bone that teriparatide has been shown to prevent or negate. Given the fact that preventive therapy for glucocorticoid-induced osteoporosis is often not prescribed, one wonders whether a daily self-injectable therapy for this condition would be prescribed by physicians and accepted by patients. This article reviews the epidemiology, pathophysiology, treatment, guidelines, and persistence data (when available for patients with glucocorticoid-induced osteoporosis treated with teriparatide.Keywords: glucocorticoid-induced osteoporosis, teriparatide, anabolic, PTH, parathyroid hormone

  1. Cell-specific expression of the glucocorticoid receptor within granular convoluted tubules of the rat submaxillary gland

    International Nuclear Information System (INIS)

    Antakly, T.; Zhang, C.X.; Sarrieau, A.; Raquidan, D.

    1991-01-01

    The submaxillary gland, a heterogeneous tissue composed essentially of two functionally distinct cell types (tubular epithelial and acinar), offers an interesting system in which to study the mechanisms of steroid-dependent growth and differentiation. One cell type, the granular convoluted tubular (GCT) cell, secretes a large number of physiologically important polypeptides, including epidermal and nerve growth factors. Two steroids, androgens and glucocorticoids, greatly influence the growth, differentiation, and secretory activity of GCT cells. Because glucocorticoids can partially mimic or potentiate androgen effects, it has been thought that glucocorticoids act via androgen receptors. Since the presence of glucocorticoid receptors is a prerequisite for glucocorticoid action, we have investigated the presence and cellular distribution of glucocorticoid receptors within the rat submaxillary gland. Binding experiments using [3H]dexamethasone revealed the presence of high affinity binding sites in rat submaxillary tissue homogenates. Most of these sites were specifically competed by dexamethasone, corticosterone, and a pure glucocorticoid agonist RU 28362. Neither testosterone nor dihydrotestosterone competed for glucocorticoid binding. The cellular distribution of glucocorticoid receptors within the submaxillary gland was investigated by immunocytochemistry, using two highly specific glucocorticoid receptor antibodies. The receptor was localized in the GCT cells, but not in the acinar cells of rat and mouse submaxillary tissue sections. In GCT cells, the glucocorticoid receptor colocalized with several secretory polypeptides, including epidermal growth factor, nerve growth factor, alpha 2u-globulin, and atrial natriuretic factor

  2. Radioreceptor assay for evaluation of the plasma glucocorticoid activity of natural and synthetic steroids in man

    International Nuclear Information System (INIS)

    Ballard, P.L.; Carter, J.P.; Graham, B.S.; Baxter, J.D.

    1975-01-01

    An assay for plasma glucocorticoid activity has been developed using specific glucocorticoid receptors. Unlike other assays for cortisol and certain synthetic corticosteroids, this radioreceptor assay measures the glucocorticoid activity of all natural and synthetic steroids. Steroids extracted from as little as 0.05 ml of plasma are incubated with 3 H-dexamethasone and cytosol receptors from cultured rat hepatoma cells. From 0.5 to 50 ng of cortisol are accurately detected. Glucocorticoid activities of adult plasmas determined by the assay correlate closely with corticoid levels obtained in the CBG-isotope and fluorometric assays. Other steroids are measured in proportion to both concentration and potency as glucocorticoids. Relative activities include: cortisol 100, dexamethasone 940, prednisolone 230, prednisone 3, estradiol 1 and androstenedione 1. A similar ranking of steroids was found using receptors from a human source (fetal lung). The assay has been useful in detecting glucocorticoid activity in unidentified medications and in measuring plasma glucocorticoid levels after administration of synthetic corticosteroids. (auth)

  3. Glucocorticoids and renal Na+ transport: implications for hypertension and salt sensitivity

    Science.gov (United States)

    Hunter, Robert W; Ivy, Jessica R; Bailey, Matthew A

    2014-01-01

    The clinical manifestations of glucocorticoid excess include central obesity, hyperglycaemia, dyslipidaemia, electrolyte abnormalities and hypertension. A century on from Cushing's original case study, these cardinal features are prevalent in industrialized nations. Hypertension is the major modifiable risk factor for cardiovascular and renal disease and reflects underlying abnormalities of Na+ homeostasis. Aldosterone is a master regulator of renal Na+ transport but here we argue that glucocorticoids are also influential, particularly during moderate excess. The hypothalamic–pituitary–adrenal axis can affect renal Na+ homeostasis on multiple levels, systemically by increasing mineralocorticoid synthesis and locally by actions on both the mineralocorticoid and glucocorticoid receptors, both of which are expressed in the kidney. The kidney also expresses both of the 11β-hydroxysteroid dehydrogenase (11βHSD) enzymes. The intrarenal generation of active glucocorticoid by 11βHSD1 stimulates Na+ reabsorption; failure to downregulate the enzyme during adaption to high dietary salt causes salt-sensitive hypertension. The deactivation of glucocorticoid by 11βHSD2 underpins the regulatory dominance for Na+ transport of mineralocorticoids and defines the ‘aldosterone-sensitive distal nephron’. In summary, glucocorticoids can stimulate renal transport processes conventionally attributed to the renin–angiotensin–aldosterone system. Importantly, Na+ and volume homeostasis do not exert negative feedback on the hypothalamic–pituitary–adrenal axis. These actions are therefore clinically relevant and may contribute to the pathogenesis of hypertension in conditions associated with elevated glucocorticoid levels, such as the metabolic syndrome and chronic stress. PMID:24535442

  4. "Official View" on Glucocorticoids in Rheumatoid Arthritis: A Systematic Review of International Guidelines and Consensus Statements.

    Science.gov (United States)

    Palmowski, Yannick; Buttgereit, Thomas; Dejaco, Christian; Bijlsma, Johannes W; Matteson, Eric L; Voshaar, Marieke; Boers, Maarten; Buttgereit, Frank

    2017-08-01

    To describe the perception of the current role of systemic glucocorticoids in the management of rheumatoid arthritis (RA) by examining their importance and the current level of evidence in recent guidelines, and to identify open questions to be addressed in future guidelines and research projects. We conducted a systematic literature review using the databases Ovid Embase, PubMed Medline, and Cochrane Library for guidelines on the pharmacologic treatment of RA. Retrieved articles were evaluated regarding their quality using the Appraisal of Guidelines for Research and Evaluation II tool and scrutinized for all relevant information concerning the use of glucocorticoids. All guidelines agree that glucocorticoids, especially if given at low doses and for a short duration, are an appropriate option in the treatment of RA. However, many recommendations remain vague, as reliable and detailed evidence is scarce. Important aspects of glucocorticoid therapy are partially or completely neglected, and the existing nomenclature is not used uniformly. Quality evaluation revealed flaws in many articles, concerning not only glucocorticoid-specific recommendations but also guideline quality in general. Current recommendations for use of glucocorticoids in the management of RA are suboptimal. More rigorous evaluation of doses, timing, and duration of their use is needed. Existing nomenclature on glucocorticoid therapy should be used uniformly. © 2016, American College of Rheumatology.

  5. A Role for Glucocorticoids in Stress-Impaired Reproduction: Beyond the Hypothalamus and Pituitary

    Science.gov (United States)

    Whirledge, Shannon

    2013-01-01

    In addition to the well-characterized role of the sex steroid receptors in regulating fertility and reproduction, reproductive events are also mediated by the hypothalamic-pituitary-adrenal axis in response to an individual's environment. Glucocorticoid secretion in response to stress contributes to the well-characterized suppression of the hypothalamic-pituitary-gonadal axis through central actions in the hypothalamus and pituitary. However, both animal and in vitro studies indicate that other components of the reproductive system are also regulated by glucocorticoids. Furthermore, in the absence of stress, it appears that homeostatic glucocorticoid signaling plays a significant role in reproduction and fertility in all tissues comprising the hypothalamic-pituitary-gonadal axis. Indeed, as central regulators of the immune response, glucocorticoids are uniquely poised to integrate an individual's infectious, inflammatory, stress, nutritional, and metabolic status through glucocorticoid receptor signaling in target tissues. Endocrine signaling between tissues regulating the immune and stress response and those determining reproductive status provides an evolutionary advantage, facilitating the trade-off between reproductive investment and offspring fitness. This review focuses on the actions of glucocorticoids in tissues important for fertility and reproduction, highlighting recent studies that show glucocorticoid signaling plays a significant role throughout the hypothalamic-pituitary-gonadal axis and characterizing these effects as permissive or inhibitory in terms of facilitating reproductive success. PMID:24064362

  6. Glucocorticoids Suppress Selected Components of the Senescence-Associated Secretory Phenotype

    Science.gov (United States)

    Laberge, Remi-Martin; Zhou, Lili; Sarantos, Melissa R.; Rodier, Francis; Freund, Adam; de Keizer, Peter L.J.; Liu, Su; Demaria, Marco; Cong, Yu-Sheng; Kapahi, Pankaj; Desprez, Pierre-Yves; Hughes, Robert E.; Campisi, Judith

    2012-01-01

    SUMMARY Cellular senescence suppresses cancer by arresting the proliferation of cells at risk for malignant transformation. Recently, senescent cells were shown to secrete numerous cytokines, growth factors and proteases that can alter the tissue microenvironment and may promote age-related pathology. To identify small molecules that suppress the senescence-associated secretory phenotype (SASP), we developed a screening protocol using normal human fibroblasts and a library of compounds that are approved for human use. Among the promising library constituents was the glucocorticoid corticosterone. Both corticosterone and the related glucocorticoid cortisol decreased the production and secretion of selected SASP components, including several pro-inflammatory cytokines. Importantly, the glucocorticoids suppressed the SASP without reverting the tumor suppressive growth arrest, and were efficacious whether cells were induced to senesce by ionizing radiation or strong mitogenic signals delivered by oncogenic RAS or MAP kinase kinase 6 overexpression. Suppression of the prototypical SASP component IL-6 required the glucocorticoid receptor, which, in the presence of ligand, inhibited IL-1α signaling and NF-κB transactivation activity. Accordingly, co-treatments combining glucocorticoids with the glucocorticoid antagonist RU-486 or recombinant IL-1α efficiently reestablished NF-κB transcriptional activity and IL-6 secretion. Our findings demonstrate feasibility of screening for compounds that inhibit the effects of senescent cells. They further show that glucocorticoids inhibit selected components of the SASP, and suggest that corticosterone and cortisol, two FDA-approved drugs, might exert their effects in part by suppressing senescence-associated inflammation. PMID:22404905

  7. [Treating Radiation Peumonitis by Zlyin Huoxue Granule Combined Glucocorticoids and Antibiotics: a Clinical Observation].

    Science.gov (United States)

    Liu, Li-hua; Chen, Shao-shui; Ning, Fang-ling

    2015-10-01

    To observe the clinical effect of Ziyin Huoxue Granule (ZHG) combined glucocorticoids and antibiotics in treatment of radiation pneumonitis. Totally 70 radiation pneumonitis patients were assigned to the treatment group and the control group according to random digit table, 35 in each group. All patients received glucocorticoids and antibiotics. Patients in the treatment group additionally took ZHG, one dose per day for 4 successive weeks. Watters clinical-radiologic-physiologic (CRP) score, Karnofsky Performance Status Scale (KPS) , and acute radiation injury classification [set by Radiation Therapy Oncology Group (RTOG)] were observed in the two groups before and after treatment. The application time for antibiotics and glucocorticoids was compared between the two groups. All patients completed this trial, and nobody dropped out or died. There was no statistical difference in Watters-CRP scores, KPS, or RTOG between the two groups before treatment (P > 0.05). Compared with before treatment in the same group, RTOG classification was obviously improved in the two groups (P glucocorticoids was reduced (P 0.05). ZHG combined glucocorticoids and antibiotics was superior in treating radiation pneumonitis to using glucocorticoids or antibiotics alone in elevating Watters-CRP scores, shortening the application time for glucocorticoids and antibiotics, and improving patients' physical conditions.

  8. 5α-Reductase Type 2 Regulates Glucocorticoid Action and Metabolic Phenotype in Human Hepatocytes.

    Science.gov (United States)

    Nasiri, Maryam; Nikolaou, Nikolaos; Parajes, Silvia; Krone, Nils P; Valsamakis, George; Mastorakos, George; Hughes, Beverly; Taylor, Angela; Bujalska, Iwona J; Gathercole, Laura L; Tomlinson, Jeremy W

    2015-08-01

    Glucocorticoids and androgens have both been implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD); androgen deficiency in males, androgen excess in females, and glucocorticoid excess in both sexes are associated with NAFLD. Glucocorticoid and androgen action are regulated at a prereceptor level by the enzyme 5α-reductase type 2 (SRD5A2), which inactivates glucocorticoids to their dihydrometabolites and converts T to DHT. We have therefore explored the role of androgens and glucocorticoids and their metabolism by SRD5A2 upon lipid homeostasis in human hepatocytes. In both primary human hepatocytes and human hepatoma cell lines, glucocorticoids decreased de novo lipogenesis in a dose-dependent manner. Whereas androgen treatment (T and DHT) increased lipogenesis in cell lines and in primary cultures of human hepatocytes from female donors, it was without effect in primary hepatocyte cultures from men. SRD5A2 overexpression reduced the effects of cortisol to suppress lipogenesis and this effect was lost following transfection with an inactive mutant construct. Conversely, pharmacological inhibition using the 5α-reductase inhibitors finasteride and dutasteride augmented cortisol action. We have demonstrated that manipulation of SRD5A2 activity can regulate lipogenesis in human hepatocytes in vitro. This may have significant clinical implications for those patients prescribed 5α-reductase inhibitors, in particular augmenting the actions of glucocorticoids to modulate hepatic lipid flux.

  9. Glucocorticoid Signaling in Health and Disease: Insights From Tissue-Specific GR Knockout Mice.

    Science.gov (United States)

    Whirledge, Shannon; DeFranco, Donald B

    2018-01-01

    Glucocorticoids are adrenally produced hormones critically involved in development, general physiology, and control of inflammation. Since their discovery, glucocorticoids have been widely used to treat a variety of inflammatory conditions. However, high doses or prolonged use leads to a number of side effects throughout the body, which preclude their clinical utility. The primary actions of glucocorticoids are mediated by the glucocorticoid receptor (GR), a transcription factor that regulates many complex signaling pathways. Although GR is nearly ubiquitous throughout the body, glucocorticoids exhibit cell- and tissue-specific effects. For example, glucocorticoids stimulate glucose production in the liver, reduce glucose uptake in the skeletal muscle, and decrease insulin secretion from the pancreatic β-cells. Mouse models represent an important approach to understanding the dynamic functions of GR signaling in normal physiology, disease, and resistance. In the absence of a viable GR null model, gene-targeting techniques utilizing promoter-driven recombination have provided an opportunity to characterize the tissue-specific actions of GR. The aim of the present review is to describe the organ systems in which GR has been conditionally deleted and summarize the functions ascribed to glucocorticoid action in those tissues. Copyright © 2018 Endocrine Society.

  10. A case report: Familial glucocorticoid deficiency associated with familial focal segmental glomerulosclerosis

    Directory of Open Access Journals (Sweden)

    Ram Nanik

    2012-12-01

    Full Text Available Abstract Background Familial glucocorticoid deficiency (FGD is a rare autosomal recessive disorder characterized by isolated glucocorticoid deficiency in the presence of normal plasma renin and aldosterone level. Focal segmental glomerulosclerosis (FSGS is a form of glomerular disease associated with proteinuria and nephritic syndrome. This is the first case of familial glucocorticoid deficiency associated with familial focal segmental glomerulosclerosis. Case presentation An eight month old boy presented with increased genital pigmentation. Initial investigation revealed that he was glucocorticoid deficient and was started on hydrocortisone and fludrocortisone with a diagnosis of primary adrenal insufficiency. Later fludrocortisone was withdrawn and he was diagnosed to have isolated glucocorticoid deficiency. He later developed focal segmental glomerulosclerosis for which he underwent renal transplantation at the age of five years. Now at the age of twelve years, this boy is doing well on hydrocortisone treatment. His two siblings and a first degree cousin also had isolated glucocorticoid deficiency. One of the above two siblings died due to renal failure secondary to focal segmental glomerulosclerosis. Conclusion Patients with familial glucocorticoid deficiency should be carefully followed for development of features of nephrotic syndrome.

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

    Science.gov (United States)

    Whirledge, Shannon; Kisanga, Edwina P; Taylor, Robert N; Cidlowski, John A

    2017-11-01

    Successful pregnancy relies on dynamic control of cell signaling 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 (E2) coregulate thousands of genes. Recently, glucocorticoids and E2 were shown to coregulate 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 E2 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 messenger RNA and protein and recruitment of the glucocorticoid receptor (GR) and activated polymerase 2 to the promoter of LEFTY1. Glucocorticoid-mediated recruitment of GR was dependent on pioneer factors FOXA1 and FOXA2. E2 was found to antagonize glucocorticoid-mediated induction of LEFTY1 by reducing recruitment of GR, FOXA1, FOXA2, and activated polymerase 2 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 molecular mechanism by which E2 antagonizes GR-dependent induction of specific genes by preventing the recruitment of the pioneer factors FOXA1 and FOXA2 in a physiologically relevant model. Copyright © 2017 Endocrine Society.

  12. Stress Levels of Glucocorticoids Inhibit LHβ-Subunit Gene Expression in Gonadotrope Cells

    Science.gov (United States)

    Breen, Kellie M.; Thackray, Varykina G.; Hsu, Tracy; Mak-McCully, Rachel A.; Coss, Djurdjica

    2012-01-01

    Increased glucocorticoid secretion is a common response to stress and has been implicated as a mediator of reproductive suppression upon the pituitary gland. We utilized complementary in vitro and in vivo approaches in the mouse to investigate the role of glucocorticoids as a stress-induced intermediate capable of gonadotrope suppression. Repeated daily restraint stress lengthened the ovulatory cycle of female mice and acutely reduced GnRH-induced LH secretion and synthesis of LH β-subunit (LHβ) mRNA, coincident with increased circulating glucocorticoids. Administration of a stress level of glucocorticoid, in the absence of stress, blunted LH secretion in ovariectomized female mice, demonstrating direct impairment of reproductive function by glucocorticoids. Supporting a pituitary action, glucocorticoid receptor (GR) is expressed in mouse gonadotropes and treatment with glucocorticoids reduces GnRH-induced LHβ expression in immortalized mouse gonadotrope cells. Analyses revealed that glucocorticoid repression localizes to a region of the LHβ proximal promoter, which contains early growth response factor 1 (Egr1) and steroidogenic factor 1 sites critical for GnRH induction. GR is recruited to this promoter region in the presence of GnRH, but not by dexamethasone alone, confirming the necessity of the GnRH response for GR repression. In lieu of GnRH, Egr1 induction is sufficient for glucocorticoid repression of LHβ expression, which occurs via GR acting in a DNA- and dimerization-independent manner. Collectively, these results expose the gonadotrope as an important neuroendocrine site impaired during stress, by revealing a molecular mechanism involving Egr1 as a critical integrator of complex formation on the LHβ promoter during GnRH induction and GR repression. PMID:22851703

  13. Neutrophils are not less sensitive than other blood leukocytes to the genomic effects of glucocorticoids.

    Science.gov (United States)

    Hirsch, Gaelle; Lavoie-Lamoureux, Anouk; Beauchamp, Guy; Lavoie, Jean-Pierre

    2012-01-01

    Neutrophils are generally considered less responsive to glucocorticoids compared to other inflammatory cells. The reported increase in human neutrophil survival mediated by these drugs partly supports this assertion. However, it was recently shown that dexamethasone exerts potent anti-inflammatory effects in equine peripheral blood neutrophils. Few comparative studies of glucocorticoid effects in neutrophils and other leukocytes have been reported and a relative insensitivity of neutrophils to these drugs could not be ruled out. We assessed glucocorticoid-responsiveness in equine and human peripheral blood neutrophils and neutrophil-depleted leukocytes. Blood neutrophils and neutrophil-depleted leukocytes were isolated from 6 healthy horses and 4 human healthy subjects. Cells were incubated for 5 h with or without LPS (100 ng/mL) alone or combined with hydrocortisone, prednisolone or dexamethasone (10(-8) M and 10(-6) M). IL-1β, TNF-α, IL-8, glutamine synthetase and GR-α mRNA expression was quantified by qPCR. Equine neutrophils were also incubated for 20 h with or without the three glucocorticoids and cell survival was assessed by flow cytometry and light microscopy on cytospin preparations. We found that glucocorticoids down-regulated LPS-induced pro-inflammatory mRNA expression in both cell populations and species. These drugs also significantly increased glutamine synthetase gene expression in both equine cell populations. The magnitude of glucocorticoid response between cell populations was generally similar in both species. We also showed that dexamethasone had a comparable inhibitory effect on pro-inflammatory gene expression in both human and equine neutrophils. As reported in other species, glucocorticoids significantly increase the survival in equine neutrophils. Glucocorticoids exert genomic effects of similar magnitude on neutrophils and on other blood leukocytes. We speculate that the poor response to glucocorticoids observed in some chronic

  14. The role of endogenous glucocorticoids in glucose metabolism and immune status of MIF-deficient mice.

    Science.gov (United States)

    Nikolic, Ivana; Vujicic, Milica; Saksida, Tamara; Berki, Timea; Stosic-Grujicic, Stanislava; Stojanovic, Ivana

    2013-08-15

    Macrophage migration inhibitory factor (MIF)-deficient mice develop glucose intolerance and hyperglycemia, but remain entirely responsive to exogenous insulin in adult age. Furthermore, as a consequence of MIF deficiency, the immune response in these mice is predominantly anti-inflammatory. Since MIF is a natural counter-regulator of glucocorticoid action, and it is known that excessive concentration of glucocorticoids contribute both to beta cell dysfunction and immunosuppression, we hypothesized that MIF absence enables elevation of glucocorticoids which in turn caused the observed condition. Our results confirm that MIF-knockout (MIF-KO) mice possess higher levels of circulating corticosterone, but lower expression of glucocorticoid receptor in pancreatic islets, liver and adipose tissue to the one observed in wild type (WT) mice. A significant up-regulation of glucocorticoid receptor expression was however noticed in MIF-deficient lymph node cells. The inhibition of glucocorticoid receptor by RU486 improved tolerance to glucose in MIF-KO mice and restored euglycemia. Although RU486 treatment did not alter the level of glucose receptor GLUT2, it enhanced insulin secretion and up-regulated insulin-triggered Akt phosphorylation within hepatic tissue. Finally, inhibition of glucocorticoid receptor changed anti-inflammatory phenotype of MIF-KO lymphocytes toward a physiological profile. Our results indicate that deregulated glucocorticoid secretion and glucocorticoid receptor expression in the absence of MIF possibly contributes to the development of glucose intolerance and immunosuppression in MIF-KO mice. However, since MIF-KO mice respond normally to insulin and their beta cell function is within physiological range, additional cause for glucose intolerance could be sought in the possible malfunction of their insulin. © 2013 Elsevier B.V. All rights reserved.

  15. Endocarp thickness affects seed removal speed by small rodents in a warm-temperate broad-leafed deciduous forest, China

    Science.gov (United States)

    Zhang, Hongmao; Zhang, Zhibin

    2008-11-01

    Seed traits are important factors affecting seed predation by rodents and thereby the success of recruitment. Seeds of many tree species have hard hulls. These are thought to confer mechanical protection, but the effect of endocarp thickness on seed predation by rodents has not been well investigated. Wild apricot ( Prunus armeniaca), wild peach ( Amygdalus davidiana), cultivated walnut ( Juglans regia), wild walnut ( Juglans mandshurica Maxim) and Liaodong oak ( Quercus liaotungensis) are very common tree species in northwestern Beijing city, China. Their seeds vary greatly in size, endocarp thickness, caloric value and tannin content. This paper aims to study the effects of seed traits on seed removal speed of these five tree species by small rodents in a temperate deciduous forest, with emphasis on the effect of endocarp thickness. The results indicated that speed of removal of seeds released at stations in the field decreased significantly with increasing endocarp thickness. We found no significant correlations between seed removal speed and other seed traits such as seed size, caloric value and tannin content. In seed selection experiments in small cages, Père David's rock squirrel ( Sciurotamias davidianus), a large-bodied, strong-jawed rodent, selected all of the five seed species, and the selection order among the five seed species was determined by endocarp thickness and the ratio of endocarp mass/seed mass. In contrast, the Korean field mouse ( Apodemus peninsulae) and Chinese white-bellied rat ( Niviventer confucianus), with relatively small bodies and weak jaws, preferred to select small seeds like acorns of Q. liaotungensis and seeds of P. armeniaca, indicating that rodent body size is also an important factor affecting food selection based on seed size. These results suggest endocarp thickness significantly reduces seed removal speed by rodents and then negatively affects dispersal fitness of seeds before seed removal of tree species in the study

  16. Skeletal muscle secreted factors prevent glucocorticoid-induced osteocyte apoptosis through activation of β-catenin

    Directory of Open Access Journals (Sweden)

    K Jähn

    2012-09-01

    Full Text Available It is a widely held belief that the sole effect of muscle on bone is through mechanical loading. However, as the two tissues are intimately associated, we hypothesized that muscle myokines may have positive effects on bone. We found that factors produced by muscle will protect osteocytes from undergoing cell death induced by dexamethasone (dex, a glucocorticoid known to induce osteocyte apoptosis thereby compromising their capacity to regulate bone remodeling. Both the trypan blue exclusion assay for cell death and nuclear fragmentation assay for apoptosis were used. MLO-Y4 osteocytes, primary osteocytes, and MC3T3 osteoblastic cells were protected against dex-induced apoptosis by C2C12 myotube conditioned media (MT-CM or by CM from ex vivo electrically stimulated, intact extensor digitorum longus (EDL or soleus muscle derived from 4 month-old mice. C2C12 MT-CM, but not undifferentiated myoblast CM prevented dex-induced cell apoptosis and was potent down to 0.1 % CM. The CM from EDL muscle electrically stimulated tetanically at 80 Hz was more potent (10 fold in prevention of dex-induced osteocyte death than CM from soleus muscle stimulated at the same frequency or CM from EDL stimulated at 1 Hz. This suggests that electrical stimulation increases production of factors that preserve osteocyte viability and that type II fibers are greater producers than type I fibers. The muscle factor(s appears to protect osteocytes from cell death through activation of the Wnt/β-catenin pathway, as MT-CM induces β-catenin nuclear translocation and β-catenin siRNA abrogated the positive effects of MT-CM on dex-induced apoptosis. We conclude that muscle cells naturally secrete factor(s that preserve osteocyte viability.

  17. Interaction between acari ectoparasites and rodents in Suez Governorate, Egypt.

    Science.gov (United States)

    Younis, T A; Fayad, M E; el Hariry, M A; Morsy, T A

    1995-08-01

    From the medical point of view, the relation between man and rodents comes in the priority. Some rodent populations are wild but others are commensal and live in close association with man. They steal his food and conveying many zoonotic diseases. Their arthropod ectoparasites play an important role in conveying or transmitting these zoonotic diseases. Several disorders and diseases of man are tick borne relapsing fever, Rocky mountain spotted fever, Lyme disease, and many others. Besides numerous species of mites occasionally infest man. They transmit several diseases as Rickettsia tsutsugamushi fever, epidemic haemorrhagic fever, and they cause severe allergic reaction. The results obtained are summarized in the following (1) Six species and subspecies of rodents were detected. In a descending order of abundance, they were (a) Rattus norvegicus, (b) Rattus rattus alexandrinus (c) Rattus rattus frugivorous (d) Acomys cahirinus (e) Gerbillus gerbillus asyutensis (f) Mus m. praetextus. (2) The most common rodent was R. norvegicus and the least common was M. musculus. (3) The collected ticks and mites were 2 genera of tick larvae; Rhipicephalus species and Hyalomma species. The collected mites were Ornithonyssus bacoti and Laelaps nuttali. (4) Most of the tick larvae were collected from wild rodents; Gerbillus g. asyutensis. (5) Most of the mites were collected from commensal rodents particularly R. norvegicus. Descriptive morphology and illustrations were given to the collected rodents and their acari ectoparasites.

  18. Ectoparasites of rodents captured in bandar abbas, southern iran.

    Science.gov (United States)

    Kia, Eb; Moghddas-Sani, H; Hassanpoor, H; Vatandoost, H; Zahabiun, F; Akhavan, Aa; Hanafi-Bojd, Aa; Telmadarraiy, Z

    2009-01-01

    Rodents play important role as host of ectoparasites and reservoir of different zoonotic diseases. The aim of this study was to asses the infestation of commensal rodents with ectoparasites in Bandar Abbas, a port city located in the northern part of the Persian Gulf in Iran. Rodents were captured using live traps during the study period in year 2007. After transferring the rodents to the laboratory, they were identified and then their ectoparasites were collected and mounted for species identification using appropriate systematic keys. A total of 77 rodents were identified including Rattus norvegicus (74%), R. rattus (16.9%), Mus musculus (7.8%) and one hamster. Among all rodents, 40.3% were found infested with ectoparasites. A total of 69 ectoparasites were collected comprising flea, lice, mite and tick. Two species of fleas; Xenopsylla cheopis and X. astia were identified with higher index of X. astia. Two genera of ticks including Hyalomma sp. and Rhipicephalus sp. were identified. Laelaps nuttalli was the only mite found. The Polyplax spinulosa was considered as lice ectoparasite. Among all arthropods collected, flea and lice had the most and the least frequency, respectively. Nearly all rodent species were infested with Xenopsylla. These fleas are important due to their role in plague and murine typhus transmission. Ticks are important due to their role in CCHF (Crimean-Congo Hemorrhagic Fever), theileriosis, babesiosis, anaplasmosis and ehrlichiosis transmission .Monitoring of ectoparaiste infestation is important for preparedness and early warning preparation for possible control of arthropod-borne diseases.

  19. Mid-Childhood Bone Mass After Exposure to Repeat Doses of Antenatal Glucocorticoids: A Randomized Trial.

    Science.gov (United States)

    McKinlay, Christopher J D; Cutfield, Wayne S; Battin, Malcolm R; Dalziel, Stuart R; Crowther, Caroline A; Harding, Jane E

    2017-05-01

    Treatment of women at risk for preterm birth with repeat doses of glucocorticoids reduces neonatal morbidity, but could have adverse effects on skeletal development. We assessed whether exposure to repeat antenatal betamethasone alters bone mass in children whose mothers participated in the Australasian Collaborative Trial of Repeat Doses of Corticosteroids. Women were randomized to a single dose of betamethasone or placebo, ≥7 days after an initial course of glucocorticoids, repeated each week that they remained at risk for preterm birth at glucocorticoids does not alter bone mass in mid-childhood. Copyright © 2017 by the American Academy of Pediatrics.

  20. The Ups and Downs of Glucocorticoid Signaling | Center for Cancer Research

    Science.gov (United States)

    Glucocorticoids are steroids that react to stress by regulating inflammation and controlling metabolism. Because of their anti-inflammatory and immunosuppressive properties, corticosteroids are among the most frequently prescribed drugs. Glucocorticoids are often used to treat arthritis and autoimmune diseases and are also given in combination with other drugs to treat cancers—such as leukemias and lymphomas—or to alleviate side effects from chemotherapy and radiation. In humans, a glucocorticoid called cortisol is released from the adrenal gland approximately every hour to send signals to cells throughout the body. This pulsed release of hormone is called ultradian secretion.  

  1. Pathway interactions between MAPKs, mTOR, PKA, and the glucocorticoid receptor in lymphoid cells

    Directory of Open Access Journals (Sweden)

    Thompson E Brad

    2007-03-01

    Full Text Available Abstract Background Glucocorticoids are frequently used as a primary chemotherapeutic agent in many types of human lymphoid malignancies because they induce apoptosis through activation of the glucocorticoid receptor, with subsequent alteration of a complex network of cellular mechanisms. Despite clinical usage for over fifty years, the complete mechanism responsible for glucocorticoid-related apoptosis or resistance remains elusive. The mitogen-activated protein kinase pathway is a signal transduction network that influences a variety of cellular responses through phosphorylation of specific target substrates, including the glucocorticoid receptor. In this study we have evaluated the pharmaceutical scenarios which converge on the mitogen-activated protein kinase pathway to alter glucocorticoid sensitivity in clones of human acute lymphoblastic CEM cells sensitive and refractory to apoptosis in response to the synthetic glucocorticoid dexamethasone. Results The glucocorticoid-resistant clone CEM-C1-15 displays a combination of high constitutive JNK activity and dexamethasone-induced ERK activity with a weak induction of p38 upon glucocorticoid treatment. The cells become sensitive to glucocorticoid-evoked apoptosis after: (1 inhibition of JNK and ERK activity, (2 stimulation of the cAMP/PKA pathway with forskolin, or (3 inhibition of mTOR with rapamycin. Treatments 1–3 in combination with dexamethasone alter the intracellular balance of phospho-MAPKs by lowering JNK phosphorylation and increasing the level of glucocorticoid receptor phosphorylated at serine 211, a modification known to enhance receptor activity. Conclusion Our data support the hypothesis that mitogen-activated protein kinases influence the ability of certain malignant lymphoid cells to undergo apoptosis when treated with glucocorticoid. Activated/phosphorylated JNK and ERK appear to counteract corticoid-dependent apoptosis. Inhibiting these MAPKs restores corticoid sensitivity

  2. Histone demethylase UTX counteracts glucocorticoid deregulation of osteogenesis by modulating histone-dependent and -independent pathways.

    Science.gov (United States)

    Wang, Feng-Sheng; Lian, Wei-Shiung; Lee, Mel S; Weng, Wen-Tsan; Huang, Ying-Hsien; Chen, Yu-Shan; Sun, Yi-Chih; Wu, Shing-Long; Chuang, Pei-Chin; Ko, Jih-Yang

    2017-05-01

    Excess glucocorticoid administration impairs osteogenic activities, which raises the risk of osteoporotic disorders. Epigenetic methylation of DNA and histone regulates the lineage commitment of progenitor cells. This study was undertaken to delineate the actions of histone lysine demethylase 6a (UTX) with regard to the glucocorticoid impediment of osteogenic differentiation. Osteogenic progenitor cells responded to supraphysiological glucocorticoid by elevating CpG dinucleotide methylation proximal to transcription start sites within Runx2 and osterix promoters and Wnt inhibitor Dickkopf-1 (Dkk1) expression concomitant with low UTX expression. 5'-Aza-deoxycystidine demethylation of Runx2 and osterix promoters abolished the glucocorticoid inhibition of mineralized matrix accumulation. Gain of UTX function attenuated the glucocorticoid-induced loss of osteogenic differentiation, whereas UTX silencing escalated adipogenic gene expression and adipocyte formation. UTX sustained osteogenic gene transcription through maintaining its occupancy to Runx2 and osterix promoters. It also mitigated the trimethylation of histone 3 at lysine 27 (H3K27me3), which reduced H3K27me3 enrichment to Dkk1 promoter and thereby lowered Dkk1 transcription. Modulation of β-catenin and Dkk1 actions restored UTX signaling in glucocorticoid-stressed cells. In vivo, UTX inhibition by exogenous methylprednisolone and GSK-J4 administration, an effect that disturbed H3K27me3, β-catenin, Dkk1, Runx2, and osterix levels, exacerbated trabecular microarchitecture loss and marrow adiposity. Taken together, glucocorticoid reduction of UTX function hindered osteogenic differentiation. Epigenetic hypomethylation of osteogenic transcription factor promoters and H3K27 contributed to the UXT alleviation of Dkk1 transcription and osteogenesis in glucocorticoid-stressed osteogenic progenitor cells. Control of UTX action has an epigenetic perspective of curtailing glucocorticoid impairment of osteogenic

  3. Sulforaphane reverses glucocorticoid-induced apoptosis in osteoblastic cells through regulation of the Nrf2 pathway

    Directory of Open Access Journals (Sweden)

    Lin H

    2014-07-01

    Full Text Available Hao Lin,1,* Bo Wei,1,* Guangsheng Li,1 Jinchang Zheng,1 Jiecong Sun,1 Jiaqi Chu,2 Rong Zeng,1 Yanru Niu21Department of Spinal Surgery, Affiliated Hospital of Guangdong Medical College, Zhanjiang, People’s Republic of China; 2Laboratory Institute of Minimally Invasive Orthopedic Surgery, Affiliated Hospital of Guangdong Medical College, Zhanjiang, People’s Republic of China *These authors contributed equally to this work Abstract: Apoptosis of osteoblasts triggered by high-dose glucocorticoids (GCs has been identified as a major cause of osteoporosis. However, the underlying molecular mechanisms accounting for this action remain elusive, which has impeded the prevention and cure of this side effect. Sulforaphane (SFP is a naturally occurring isothiocyanate that has huge health benefits for humans. In this study, by using osteoblastic MC3T3-E1 cells as a model, we demonstrate the protective effects of SFP against dexamethasone (Dex-induced apoptosis and elucidate the underlying molecular mechanisms. The results show that SFP could effectively inhibit the Dex-induced growth inhibition and release of lactate dehydrogenase in MC3T3-E1 cells. Treatment with Dex induced caspase-dependent apoptosis in MC3T3-E1 cells, as evidenced by an increase in the Sub-G1 phase, chromatin condensation, and deoxyribonucleic acid fragmentation, which were significantly suppressed by coincubation with SFP. Mitochondria-mediated apoptosis pathway contributed importantly to Dex-induced apoptosis, as revealed by the activation of caspase-3/-9 and subsequent cleavage of poly adenosine diphosphate ribose polymerase, which was also effectively blocked by SFP. Moreover, treatments of Dex strongly induced overproduction of reactive oxygen species and inhibited the expression of nuclear factor erythroid 2-related factor 2 (Nrf2 and the downstream effectors HO1 and NQO1. However, cotreatment with SFP effectively reversed this action of Dex. Furthermore, silencing of Nrf2 by

  4. A pilot study evaluating therapeutic response of different dosage of oral glucocorticoid in two children with familial glucocorticoid deficiency presenting with diffuse mucocutaneous hyperpigmentation

    Directory of Open Access Journals (Sweden)

    Uttam Kumar Sarkar

    2017-01-01

    Full Text Available Introduction: Familial glucocorticoid deficiency (FGD is a rare autosomal recessive potentially life-threatening condition, characterized by glucocorticoid deficiency, preserved aldosterone/renin secretion, and secondary rise in plasma adrenocorticotropic hormone level. This occurs due to either mutation in adrenocorticotropic receptor (25%, FGD Type-1 or in the MC2 receptor accessory protein (15%–20%. However, in about 50% patients, no identifiable mutations have been identified. Clinically, it manifests with weakness, fatigue, weight loss, anorexia, nausea, vomiting, diarrhea, abdominal pain, hypoglycemia, and hypothermia. Progressive mucocutaneous pigmentation is a conspicuous presentation. Repeated hypoglycemia may result in seizure, persistent neurological, severe mental disability, and even sudden death. Standard therapy is oral glucocorticoids (10–15 mg/m2. Patients and Results: Two familial cases of FGD were put on progressively increasing doses of oral glucocorticoids (10 mg, 15 mg, and 20 mg/m2/day, each for 6 weeks to achieve the best response without any adverse effects. One patient had excellent improvement with 15 mg/m2/day, and another required 20 mg/m2/day. The latter patient had excellent overall improvement with only moderate improvement in pigmentation. Conclusion: Glucocorticoids replacement with optimum dose is necessary in FGD to promote physical and neurological growth and to prevent adrenal crises, hypotension, hypoglycemia, and sudden death. Higher dose than mentioned in literature (15 mg/m2/day may be required in selected cases. Mucocutaneous pigmentation may require even higher dose than we used. More studies are required.

  5. TNF suppresses acute intestinal inflammation by inducing local glucocorticoid synthesis

    Science.gov (United States)

    Noti, Mario; Corazza, Nadia; Mueller, Christoph; Berger, Barbara

    2010-01-01

    Although tumor necrosis factor (α) (TNF) exerts proinflammatory activities in a variety of diseases, including inflammatory bowel disease, there is increasing evidence for antiinflammatory actions of TNF. In contrast, glucocorticoids (GCs) are steroid hormones that suppress inflammation, at least in part by regulating the expression and action of TNF. We report that TNF induces extraadrenal production of immunoregulatory GCs in the intestinal mucosa during acute intestinal inflammation. The absence of TNF results in a lack of colonic GC synthesis and exacerbation of dextran sodium sulfate–induced colitis. TNF seems to promote local steroidogenesis by directly inducing steroidogenic enzymes in intestinal epithelial cells. Therapeutic administration of TNF induces GC synthesis in oxazolone-induced colitis and ameliorates intestinal inflammation, whereas inhibition of intestinal GC synthesis abrogates the therapeutic effect of TNF. These data show that TNF suppresses the pathogenesis of acute intestinal inflammation by promoting local steroidogenesis. PMID:20439544

  6. Psychological stress and aging: role of glucocorticoids (GCs).

    Science.gov (United States)

    Hasan, K M Mehedi; Rahman, Md Shaifur; Arif, K M T; Sobhani, Mahbub E

    2012-12-01

    Psychological stress has extreme adverse consequences on health. However, the molecular mechanisms that mediate and accelerate the process of aging due to stress hormone are not well defined. This review has focused on diverse molecular paths that come out in response to chronic psychological stress via releasing of excessive glucocorticoids (GCs), involved in the aging process. GCs suppress transcription of nuclear cell adhesion molecules which impair synaptic plasticity, memory formation, and cognitive ability. Again, GCs promote muscle atrophy by means of motivating ubiquitin proteasome system and can repress muscle protein synthesis by inhibition of PI3-kinase/Akt pathway. GCs also inhibit interleukin-2 synthesis through suppressing T cell receptor signal that leads to loss of T cell activation, proliferation, and B-cell activation. Moreover, GCs increase the expression of collagenase-3, RANK ligand, and colony stimulating factor-1 that induce bone resorption. In general, stress-induced GCs can play causal role for aging and age-related disorders.

  7. The role of glucocorticoids in sodium retention in cirrhotic patients

    DEFF Research Database (Denmark)

    Hansen, Martin Højmark; Kristensen, Steffen Skott; Schaffalitzky de Muckadell, Ove B

    2012-01-01

    sodium retention evident in cirrhosis. The aim was to elucidate the role of glucocorticoids in sodium retention in decompensated cirrhotic patients. Methods. A randomized, double-blind, placebo-controlled, crossover study was performed in nine patients with alcoholic cirrhosis of the liver. A washout...... interval of 14 days separated the two periods. After a basal period of 36 h, dexamethasone (0.5 mg every 6 h) or placebo was given for two days. Urine was collected for 12 h periods, and the concentrations of sodium, potassium, creatinine, cortisol and cortisol metabolites were determined. Blood samples...... for hemoglobin, glucose, sodium, potassium, creatinine, aldosterone and cortisol were obtained daily. Results. Dexamethasone treatment decreased S-cortisol 92.3% (82.9-93.4%) (median and range) compared with that in the basal period. Natriuresis (dexamethasone - placebo) increased 55.1 (-26.4-168.7) mmol...

  8. Role of glucocorticoids in increased muscle glutamine production in starvation

    Science.gov (United States)

    Tischler, Marc E.; Henriksen, Erik J.; Cook, Paul H.

    1988-01-01

    The role of glucocorticoids in the synthesis of muscle glutamine during starvation was investigated in adrenalectomized fasted rats injected with cortisol (1 mg/100 g body weight). It was found that administration of cortisol in vivo increased (compared to nontreated starved adrenalectomized controls) the glutamine/glutamate ratio and the activity of glutamine synthetase in the diaphragm and the extensor digitorum muscles, and that these effects were abolished by prior treatment with actinomycin D or proflavine. The results obtained in in vitro experiments, using fresh-frozen soleus, extensor digitorum longus, and diaphragm muscle preparations, supported the in vivo indications of the cortisol-enhanced glutamine synthesis and protein turnover in starved adrenalectomized animals.

  9. Effects of antenatal glucocorticoids on the developing brain.

    Science.gov (United States)

    Carson, Ross; Monaghan-Nichols, A Paula; DeFranco, Donald B; Rudine, Anthony C

    2016-10-01

    Glucocorticoids (GCs) regulate distinct physiological processes in the developing fetus, in particular accelerating organ maturation that enables the fetus to survive outside the womb. In preterm birth, the developing fetus does not receive sufficient exposure to endogenous GCs in utero for proper organ development predisposing the neonate to complications including intraventricular hemorrhage, respiratory distress syndrome (RDS) and necrotizing enterocolitis (NEC). Synthetic GCs (sGCs) have proven useful in the prevention of these complications since they are able to promote the rapid maturation of underdeveloped organs present in the fetus. While these drugs have proven to be clinically effective in the prevention of IVH, RDS and NEC, they may also trigger adverse developmental side effects. This review will examine the current clinical use of antenatal sGC therapy in preterm birth, their placental metabolism, and their effects on the developing brain. Published by Elsevier Inc.

  10. Glucocorticoid: A potential role in microgravity-induced bone loss

    Science.gov (United States)

    Yang, Jiancheng; Yang, Zhouqi; Li, Wenbin; Xue, Yanru; Xu, Huiyun; Li, Jingbao; Shang, Peng

    2017-11-01

    Exposure of animals and humans to conditions of microgravity, including actual spaceflight and simulated microgravity, results in numerous negative alterations to bone structure and mechanical properties. Although there are abundant researches on bone loss in microgravity, the explicit mechanism is not completely understood. At present, it is widely accepted that the absence of mechanical stimulus plays a predominant role in bone homeostasis disorders in conditions of weightlessness. However, aside from mechanical unloading, nonmechanical factors such as various hormones, cytokines, dietary nutrition, etc. are important as well in microgravity induced bone loss. The stress-induced increase in endogenous glucocorticoid (GC) levels is inevitable in microgravity environments. Moreover, it is well known that GCs have a detrimental effect to bone health at excess concentrations. Therefore, GC plays a potential role in microgravity-induced bone loss. This review summarizeds several studies and their prospective solutions to this hypothesis.

  11. New possibilities for the treatment of glucocorticoid-induced osteoporosis

    Directory of Open Access Journals (Sweden)

    I.A. Baranova

    2014-01-01

    Full Text Available Glucocorticoid-induced osteoporosis (GIO is the most common cause of secondary osteoporosis (OP and a main cause of drug-induced OP. Fractures of the skeleton are registered in 30–50% of patients who have taken oral glucocorticoids (GCs for a long time, during which the frac- tures develop with the use of any daily GC dose and with higher bone mineral density (BMD than in postmenopausal OP. In patients who have taken oral GCs long or in high daily doses, decrease of BMD and low bone tissue quality leading to fractures are largely associated with the reduction of bone formation. This gives proof to the administration of antiosteoporotic agents that enhance the formation of bone during its remodeling. Teriparatide, a recombinant human parathyroid hormone, enhances osteoblast function, decreases the apoptosis of osteoblasts and osteocytes, increases the differentiation of osteoblast precursors, and can prevent the negative effect of exogenous GCs on bone. According to clinical trials results, teriparatide treatment increases BMD and reduces the risk of vertebral fractures in patients who have taken oral GCs long. In accordance of the clinical recommendations for the diagnosis, prevention, and treatment of GIO, which have been developed by the Russian Osteoporosis Association jointly with the Association of Rheumatologists of Russia and the Russian Respiratory Society, teriparatide is the drug of first choice for the treatment of GIO in men and women at high risk for fractures (with the history of fragility fractures or having high FRAX 10-year absolute fracture risk. Teriparatide may be prescribed in case of previous antiosteoporotic treatment failure (new fractures occurring during treatment and/or continuing to decrease BMD, as well as when other drugs to treat OP are intolerable or when there are contraindications to their use. 

  12. Inflammation in Parkinson’s disease: Role of glucocorticoids

    Directory of Open Access Journals (Sweden)

    Maria Trinidad eHerrero

    2015-04-01

    Full Text Available Chronic inflammation is a major characteristic feature of Parkinson’s disease (PD. Studies in PDpatients show evidence of augmented levels of potent pro-inflammatory molecules e.g. TNF-α, iNOS,IL-1β whereas in experimental Parkinsonism it has been consistently demonstrated that dopaminergicneurons are particularly vulnerable to activated glia releasing these toxic factors. Recent geneticstudies point to the role of immune system in the etiology of PD, thus in combination withenvironmental factors, both peripheral and CNS-mediated immune responses could play importantroles in onset and progression of PD. Whereas microglia, astrocytes and infiltrating T cells are knownto mediate chronic inflammation, the roles of other immune-competent cells are less well understood.Inflammation is a tightly controlled process. One major effector system of regulation is HPA axis.Glucocorticoids released from adrenal glands upon stimulation of HPA axis, in response to either cellinjury or presence of pathogen, activate their receptor, GR. GR regulates inflammation both throughdirect transcriptional action on target genes and by indirectly inhibiting transcriptional activities oftranscriptional factors such as NF-kB, AP-1 or interferon regulatory factors. In PD patients, the HPAaxis is unbalanced and the cortisol levels are significantly increased, implying a deregulation of GRfunction in immune cells. In experimental Parkinsonism, the activation of microglial GR has a crucialeffect in diminishing microglial cell activation and reducing dopaminergic degeneration. Moreover,glucocorticoids are also known to regulate human brain vasculature as well as blood brain barrierpermeability, any dysfunction in their actions may influence infiltration of cytotoxic moleculesresulting in increased vulnerability of dopamine neurons in PD. Overall, deregulation ofGR actions is likely important in dopamine neuron degeneration throughestablishment of chronic inflammation.

  13. Management of glucocorticoids-induced osteoporosis: role of teriparatide

    Directory of Open Access Journals (Sweden)

    Silvia Migliaccio

    2009-04-01

    Full Text Available Silvia Migliaccio1, Marina Brama1, Nazzarena Malavolta21Dipartimento di Fisiopatologia Medica, Policlinico Umberto I, Università degli Studi Sapienza di Roma, Italy; 2Dipartimento di Medicina Interna, Policlinico S Orsola Malpighi, Bologna, ItalyAbstract: Glucocorticoids (GC-induced osteoporosis (GIOP is the most common cause of secondary osteoporosis, which leads to an increased fracture risk in patients. The normal bone turnover depends on a balance between osteoblasts and osteoclasts activity and GC can cause a rapid bone loss, decreasing bone formation and increasing bone resorption. The decreased bone formation is mainly due to the GC-induced apoptosis of both osteoblasts and osteocytes, while the increased bone resorption is due to the increased life-span of pre-existing osteoclasts. Bisphosphonates are clearly effective in preventing and treating GIOP but anabolic therapeutic strategies are the new promising therapeutic alternative. Experimental and clinical studies indicate that teriparatide, the active (1–34 parathyroid hormone (PTH molecule, is efficacious for the treatment of GIOP, being able to induce an increase in bone mass in these patients. Intermittent administration of human PTH (1–34 stimulates bone formation by increasing osteoblast number. Additionally, human PTH (1–34 modulates the level and/or activity of locally produced growth factors and cytokines. Teriparatide has been demonstrated in several clinical studies to significantly decrease the incidence of fractures in patients affected by GIOP. It has recently received an indication for GIOP and its label indication has also been expanded.Keywords: glucocorticoids, osteoblasts, osteoclasts, osteoporosis, teriparatide

  14. The different roles of glucocorticoids in the hippocampus and hypothalamus in chronic stress-induced HPA axis hyperactivity.

    Directory of Open Access Journals (Sweden)

    Li-Juan Zhu

    Full Text Available Hypothalamus-pituitary-adrenal (HPA hyperactivity is observed in many patients suffering from depression and the mechanism underling the dysfunction of HPA axis is not well understood. Chronic stress has a causal relationship with the hyperactivity of HPA axis. Stress induces the over-synthesis of glucocorticoids, which will arrive at all the body containing the brain. It is still complicated whether glucocorticoids account for chronic stress-induced HPA axis hyperactivity and in which part of the brain the glucocorticoids account for chronic stress-induced HPA axis hyperactivity. Here, we demonstrated that glucocorticoids were indispensable and sufficient for chronic stress-induced hyperactivity of HPA axis. Although acute glucocorticoids elevation in the hippocampus and hypothalamus exerted a negative regulation of HPA axis, we found that chronic glucocorticoids elevation in the hippocampus but not in the hypothalamus accounted for chronic stress-induced hyperactivity of HPA axis. Chronic glucocorticoids exposure in the hypothalamus still exerted a negative regulation of HPA axis activity. More importantly, we found mineralocorticoid receptor (MR - neuronal nitric oxide synthesis enzyme (nNOS - nitric oxide (NO pathway mediated the different roles of glucocorticoids in the hippocampus and hypothalamus in regulating HPA axis activity. This study suggests that the glucocorticoids in the hippocampus play an important role in the development of HPA axis hyperactivity and the glucocorticoids in the hypothalamus can't induce hyperactivity of HPA axis, revealing new insights into understanding the mechanism of depression.

  15. The Different Roles of Glucocorticoids in the Hippocampus and Hypothalamus in Chronic Stress-Induced HPA Axis Hyperactivity

    Science.gov (United States)

    Liu, Xiao; Chen, Chen; Han, Zhou; Wu, Hai-Yin; Jing, Xing; Zhou, Hai-Hui; Suh, Hoonkyo; Zhu, Dong-Ya; Zhou, Qi-Gang

    2014-01-01

    Hypothalamus-pituitary-adrenal (HPA) hyperactivity is observed in many patients suffering from depression and the mechanism underling the dysfunction of HPA axis is not well understood. Chronic stress has a causal relationship with the hyperactivity of HPA axis. Stress induces the over-synthesis of glucocorticoids, which will arrive at all the body containing the brain. It is still complicated whether glucocorticoids account for chronic stress-induced HPA axis hyperactivity and in which part of the brain the glucocorticoids account for chronic stress-induced HPA axis hyperactivity. Here, we demonstrated that glucocorticoids were indispensable and sufficient for chronic stress-induced hyperactivity of HPA axis. Although acute glucocorticoids elevation in the hippocampus and hypothalamus exerted a negative regulation of HPA axis, we found that chronic glucocorticoids elevation in the hippocampus but not in the hypothalamus accounted for chronic stress-induced hyperactivity of HPA axis. Chronic glucocorticoids exposure in the hypothalamus still exerted a negative regulation of HPA axis activity. More importantly, we found mineralocorticoid receptor (MR) - neuronal nitric oxide synthesis enzyme (nNOS) - nitric oxide (NO) pathway mediated the different roles of glucocorticoids in the hippocampus and hypothalamus in regulating HPA axis activity. This study suggests that the glucocorticoids in the hippocampus play an important role in the development of HPA axis hyperactivity and the glucocorticoids in the hypothalamus can't induce hyperactivity of HPA axis, revealing new insights into understanding the mechanism of depression. PMID:24831808

  16. NPFFR2 Activates the HPA Axis and Induces Anxiogenic Effects in Rodents

    Directory of Open Access Journals (Sweden)

    Ya-Tin Lin

    2017-08-01

    Full Text Available Neuropeptide FF (NPFF belongs to the RFamide family and is known as a morphine-modulating peptide. NPFF regulates various hypothalamic functions through two receptors, NPFFR1 and NPFFR2. The hypothalamic-pituitary-adrenal (HPA axis participates in physiological stress response by increasing circulating glucocorticoid levels and modulating emotional responses. Other RFamide peptides, including neuropeptide AF, neuropeptide SF and RFamide related peptide also target NPFFR1 or NPFFR2, and have been reported to activate the HPA axis and induce anxiety- or depression-like behaviors. However, little is known about the action of NPFF on HPA axis activity and anxiety-like behaviors, and the role of the individual receptors remains unclear. In this study, NPFFR2 agonists were used to examine the role of NPFFR2 in activating the HPA axis in rodents. Administration of NPFFR2 agonists, dNPA (intracerebroventricular, ICV and AC-263093 (intraperitoneal, IP, time-dependently (in rats and dose-dependently (in mice increased serum corticosteroid levels and the effects were counteracted by the NPFF receptor antagonist, RF9 (ICV, as well as corticotropin-releasing factor (CRF antagonist, α-helical CRF(9-41 (intravenous, IV. Treatment with NPFFR2 agonist (AC-263093, IP increased c-Fos protein expression in the hypothalamic paraventricular nucleus and induced an anxiogenic effect, which was evaluated in mice using an elevated plus maze. These findings reveal, for the first time, that the direct action of hypothalamic NPFFR2 stimulates the HPA axis and triggers anxiety-like behaviors.

  17. Regulation of hippocampal neurogenesis by systemic factors including stress, glucocorticoids, sleep, and inflammation

    NARCIS (Netherlands)

    Lucassen, P.J.; Oomen, C.; van Dam, A.-M.; Czéh, B.; Gage, F.H.; Kempermann, G.; Song, H.

    2008-01-01

    This review summarizes and discusses the regulation of adult neurogenesis and hippocampal cellular plasticity by systemic factors. We focus on the role of stress, glucocorticoids, and related factors such as sleep deprivation and inflammation.

  18. The effects of glucocorticoid on microarchitecture, collagen, mineral and mechanical properties of sheep femur cortical bone

    DEFF Research Database (Denmark)

    Ding, Ming; Danielsen, Carl Christian; Overgaard, Søren

    2012-01-01

    of 3 months without treatment. Group 3 was left untreated and served as controls. All sheep received a restricted diet with low calcium and phosphorus. At sacrifice, cortical bone samples from the femur midshaft of each sheep were harvested, micro-CT scanned and subjected to three-point bending....... Collagen content was significantly increased in the glucocorticoid-2 compared with the glucocorticoid-1 and control groups. Bone mineral content did not differ between the groups. Neither the three-point bending mechanical properties nor the tensile mechanical properties differed significantly between...... the groups, while there was a trend towards decreasing bending mechanical properties in the glucocorticoid-2 group. In conclusion, 7 months of glucocorticoid treatment with malnutrition had a significant impact on the cortical microarchitecture of the sheep femur midshaft. These observed changes occurred 3...

  19. Increase in prophylaxis of glucocorticoid-induced osteoporosis by pharmacist feedback : a randomised controlled trial

    NARCIS (Netherlands)

    Klop, C; de Vries, F|info:eu-repo/dai/nl/303546670; Vinks, T; Kooij, M J|info:eu-repo/dai/nl/357575695; van Staa, T P|info:eu-repo/dai/nl/304827762; Bijlsma, J W J; Egberts, A C G|info:eu-repo/dai/nl/162850050; Bouvy, M L|info:eu-repo/dai/nl/153182210

    UNLABELLED: The aim of this study was to determine whether feedback by pharmacists to prescribers of patients eligible for glucocorticoid-induced osteoporosis prophylaxis would stimulate the prescribing of osteoporosis prophylaxis. The intervention did not significantly increase the prescribing of

  20. Molecular Integration of Incretin and Glucocorticoid Action Reverses Immunometabolic Dysfunction and Obesity

    NARCIS (Netherlands)

    Quarta, Carmelo; Clemmensen, Christoffer; Zhu, Zhimeng; Yang, Bin; Joseph, Sini S.; Lutter, Dominik; Yi, Chun-Xia; Graf, Elisabeth; García-Cáceres, Cristina; Legutko, Beata; Fischer, Katrin; Brommage, Robert; Zizzari, Philippe; Franklin, Bernardo S.; Krueger, Martin; Koch, Marco; Vettorazzi, Sabine; Li, Pengyun; Hofmann, Susanna M.; Bakhti, Mostafa; Bastidas-Ponce, Aimée; Lickert, Heiko; Strom, Tim M.; Gailus-Durner, Valerie; Bechmann, Ingo; Perez-Tilve, Diego; Tuckermann, Jan; Hrabě de Angelis, Martin; Sandoval, Darleen; Cota, Daniela; Latz, Eicke; Seeley, Randy J.; Müller, Timo D.; DiMarchi, Richard D.; Finan, Brian; Tschöp, Matthias H.

    2017-01-01

    Chronic inflammation has been proposed to contribute to the pathogenesis of diet-induced obesity. However, scarce therapeutic options are available to treat obesity and the associated immunometabolic complications. Glucocorticoids are routinely employed for the management of inflammatory diseases,