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Sample records for agonist dexamethasone dex

  1. LXR agonist rescued the deficit in the proliferation of the cerebellar granule cells induced by dexamethasone.

    PubMed

    Bian, Xuting; Zhong, Hongyu; Li, Fen; Cai, Yulong; Li, Xin; Wang, Lian; Fan, Xiaotang

    2016-09-01

    Dexamethasone (DEX) exposure during early postnatal life produces permanent neuromotor and intellectual deficits and stunts cerebellar growth. The liver X receptor (LXR) plays important roles in CNS development. However, the effects of LXR on the DEX-mediated impairment of cerebellar development remain undetermined. Thus, mice were pretreated with LXR agonist TO901317 (TO) and were later exposed to DEX to evaluate its protective effects on DEX-mediated deficit during cerebellar development. The results showed that an acute exposure of DEX on postnatal day 7 resulted in a significant impairment in cerebellar development and decreased the proliferation of granule neuron precursors in the external granule layer of cerebellum. This effect was attenuated by pretreatment with TO. We further found that the decrease in the proliferation caused by DEX occurred via up-regulation of glucocorticoid receptor and p27kip1, which could be partially prevented by LXR agonist pretreatment. Overall, our results suggest that LXR agonist pretreatment could protect against DEX-induced deficits in cerebellar development in postnatal mice and may thus be perspective recruited to counteract such GC side effects. PMID:27369072

  2. The oral combination of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) is effective in relapsed/refractory multiple myeloma.

    PubMed

    García-Sanz, R; González-Porras, J R; Hernández, J M; Polo-Zarzuela, M; Sureda, A; Barrenetxea, C; Palomera, L; López, R; Grande-García, C; Alegre, A; Vargas-Pabón, M; Gutiérrez, O N; Rodríguez, J A; San Miguel, J F

    2004-04-01

    We evaluate the efficacy of the oral combination of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) in 71 refractory/relapsed multiple myeloma patients, including a prognostic analysis to predict both response and survival. Patients received thalidomide at escalating doses (200-800 mg/day), daily cyclophosphamide (50 mg/day) and pulsed dexamethasone (40 mg/day, 4 days every 3 weeks). On an intention-to-treat basis and using the EBMT response criteria, 2% patients reached complete response (CR), 55% partial response (PR) and 26% minor response (MR) yielding a total response (CR+PR+MR) rate of 83% after 3 months of therapy. After 6 months of therapy, responses were maintained including a 10% CR. The 2-year progression free and overall survival were 57 and 66%, respectively. A favorable response was associated with beta2 microglobulin < or =4 mg/dl, platelets >80 x 10(9)/l and nonrefractory disease. Regarding survival, low beta2 microglobulin (< or =4 mg/dl), age (< or =65 years) and absence of extramedullary myelomatous lesion were associated with a longer survival. Major adverse effects included constipation (24%), somnolence (18%), fatigue (17%) and infection (13%). Only 7% of patients developed a thrombo-embolic event. ThaCyDex is an oral regimen that induces a high response rate and long remissions, particularly in relapsing patients with beta2 microglobulin < or =4 mg/dl and < or =65 years. PMID:14973508

  3. 76 FR 7219 - Determination That DECASPRAY (Dexamethasone) Topical Aerosol, 0.04%, and AEROSEB-DEX...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-02-09

    ... (dexamethasone) Topical Aerosol, 0.01%. In the Federal Register of June 10, 1999 (64 FR 31226), FDA announced... (see 36 FR 7982, April 28, 1971), and it was labeled for relief of the inflammatory and pruritic... August 18, 2003 (68 FR 49481), FDA announced that it was withdrawing approval of NDA 12- 731,...

  4. Low-dose dexamethasone as a treatment for women with heavy menstrual bleeding: protocol for response-adaptive randomised placebo-controlled dose-finding parallel group trial (DexFEM)

    PubMed Central

    Warner, P; Weir, C J; Hansen, C H; Douglas, A; Madhra, M; Hillier, S G; Saunders, P T K; Iredale, J P; Semple, S; Walker, B R; Critchley, H O D

    2015-01-01

    Introduction Heavy menstrual bleeding (HMB) diminishes individual quality-of-life and poses substantial societal burden. In HMB endometrium, inactivation of cortisol (by enzyme 11β hydroxysteroid dehydrogenase type 2 (11βHSD2)), may cause local endometrial glucocorticoid deficiency and hence increased angiogenesis and impaired vasoconstriction. We propose that ‘rescue’ of luteal phase endometrial glucocorticoid deficiency could reduce menstrual bleeding. Methods and analysis DexFEM is a double-blind response-adaptive parallel-group placebo-controlled trial in women with HMB (108 to be randomised), with active treatment the potent oral synthetic glucocorticoid dexamethasone, which is relatively resistant to 11βHSD2 inactivation. Participants will be aged over 18 years, with mean measured menstrual blood loss (MBL) for two screening cycles ≥50 mL. The primary outcome is reduction in MBL from screening. Secondary end points are questionnaire assessments of treatment effect and acceptability. Treatment will be for 5 days in the mid-luteal phases of three treatment menstrual cycles. Six doses of low-dose dexamethasone (ranging from 0.2 to 0.9 mg twice daily) will be compared with placebo, to ascertain optimal dose, and whether this has advantage over placebo. Statistical efficiency is maximised by allowing randomisation probabilities to ‘adapt’ at five points during enrolment phase, based on the response data available so far, to favour doses expected to provide greatest additional information on the dose–response. Bayesian Normal Dynamic Linear Modelling, with baseline MBL included as covariate, will determine optimal dose (re reduction in MBL). Secondary end points will be analysed using generalised dynamic linear models. For each dose for all end points, a 95% credible interval will be calculated for effect versus placebo. Ethics and dissemination Dexamethasone is widely used and hence well-characterised safety-wise. Ethical approval has been

  5. Melatonin attenuates dexamethasone-induced spatial memory impairment and dexamethasone-induced reduction of synaptic protein expressions in the mouse brain.

    PubMed

    Tongjaroenbuangam, Walaiporn; Ruksee, Nootchanart; Mahanam, Thanutchaporn; Govitrapong, Piyarat

    2013-11-01

    Chronic stress or prolonged exposure to high levels of glucocorticoid induces neuropathological alterations, such as dendritic atrophy of hippocampal or cortical neurons. The chronic administration of high doses of dexamethasone (DEX), a synthetic glucocorticoid receptor agonist, impairs long-term memory and motor coordination, reduces body weight and induces mortality in mice. DEX is typically administered clinically for a prolonged period. Therefore, we are interested in studying the mechanism by which chronic DEX administration affects cognitive function. In this study, we attempted to explore whether chronic DEX administration alters the process of memory formation and to determine the mechanism underlying the detrimental effect of DEX. The results showed that mice treated with DEX for 21 consecutive days had significantly impaired spatial memory in the Morris Water Maze task. Mice treated with DEX had prolonged water maze performance latencies and spent less time in the target quadrant compared to the control group. Furthermore, DEX reduced brain-derived neurotrophic factor (BDNF), N-methyl-d-aspartate (NMDA) receptor subunit (NR2A/B), calcium/calmodulin-dependent protein kinase II (CaMKII) in both the prefrontal cortex and hippocampus and synaptophysin in the prefrontal cortex. We also investigated whether melatonin, a hormone synthesized in the pineal gland, could protect against DEX-induced changes in spatial memory and synaptic plasticity. The results showed that mice pretreated with melatonin prior to the DEX treatment had shorter escape latencies and remained in the target quadrant longer compared to the group only treated with DEX. Melatonin significantly prevented a DEX-induced reduction in the expression of NR2A/B, BDNF, CaMKII and synaptophysin. The results from the present study demonstrate that melatonin pretreatment prevents cognitive impairment caused by DEX. However, the precise mechanism by which melatonin affects cognitive function requires

  6. Effects of beta 2-agonist- and dexamethasone-treatment on relaxation and regulation of beta-adrenoceptors in human bronchi and lung tissue.

    PubMed

    Hauck, R W; Harth, M; Schulz, C; Präuer, H; Böhm, M; Schömig, A

    1997-08-01

    1. Long-term treatment with beta 2-adrenoceptor agonists can lead to a decreased therapeutic efficacy of bronchodilatation in patients with obstructive pulmonary disease. In order to examine whether or not this is due to beta-adrenoceptor desensitization, human bronchial muscle relaxation was studied in isolated bronchial rings after pretreatment with beta 2-adrenoceptor agonists. Additionally, the influence of pretreatment with dexamethasone on desensitization was studied. 2. The effect of beta 2-agonist incubation alone and after coincubation with dexamethasone on density and affinity of beta-adrenoceptors was investigated by radioligand binding experiments. 3. In human isolated bronchi, isoprenaline induces a time- and concentration-dependent beta-adrenoceptor desensitization as judged from maximal reduction in potency by a factor of 7 and reduction of 73 +/- 4% in efficacy of isoprenaline to relax human bronchial smooth muscle. 4. After an incubation period of 60 min with 100 mumol l-1 terbutaline, a significant decline in its relaxing efficacy (81 +/- 8%) and potency (by a factor 5.5) occurred. 5. Incubation with 30 mumol l-1 isoprenaline for 60 min did not impair the maximal effect of a subsequent aminophylline response but led to an increase in potency (factor 4.4). 6. Coincubation of dexamethasone with isoprenaline (120 min; 30 mumol l-1) preserved the effect of isoprenaline on relaxation (129 +/- 15%). 7. In radioligand binding experiments, pretreatment of lung tissue for 60 min with isoprenaline (30 mumol l-1) resulted in a decrease in beta-adrenoceptor binding sites (Bmax) to 64 +/- 1.6% (P < 0.05), while the antagonist affinity (KD) for [3H]-CGP-12177 remained unchanged. 8. In contrast, radioligand binding studies on lung tissue pretreated with either dexamethasone (30 mumol l-1) or isoprenaline (30 mumol l-1) plus dexamethasone (30 mumol l-1) for 120 min did not lead to a significant change of Bmax (160 +/- 22.1% vs 142.3 +/- 28.7%) or KD (5.0 nmol l-1

  7. Dexamethasone in the presence of desipramine enhances MAPK/ERK1/2 signaling possibly via its interference with β-arrestin.

    PubMed

    Lucki, Anat; Klein, Ehud; Karry, Rachel; Ben-Shachar, Dorit

    2014-01-01

    Antidepressant medication is the standard treatment for major depression disorder (MDD). However, the response to these treatments is often incomplete and many patients remain refractory. In the present study, we show that the glucocorticoid receptor (GR) agonist dexamethasone (DEX) increased MAPK/ERK1/2 signaling in the presence of the noradrenergic antidepressant, desipramine (DMI), while no such effect was induced by DEX or DMI alone in human neuroblastoma SH-SY5Y cells. This enhancement was dependent on the activation of both α(2) adrenergic receptors (AR) and GR. The timing of MAPK/ERK1/2 activation as well as DEX-induced reduction in membranous α(2) AR suggests the involvement of a β-arrestin-dependent mechanism. In line with the latter, DEX increased cytosolic and decreased membranous levels of β-arrestin. Concomitantly, DEX induced a time-dependent increase in cytosolic α(2) AR-β-arrestin interaction and a decrease in β-arrestin interaction with Mdm2 E3 ubiquitin ligase. All of these effects of DEX were prevented by the GR antagonist RU486. Our data suggest an additional intracellular role for DEX, in which activation of GR interferes with the trafficking and degradation of β-arrestin-α2c-AR complex. We suggest that such an interaction in the presence of DMI can enhance MAPK/ERK1/2 signaling, a key player in neural plasticity and neurogenesis processes, which is impaired in MDD, while stimulated by antidepressants.

  8. Maternal Dexamethasone Exposure Alters Synaptic Inputs to Gonadotropin-Releasing Hormone Neurons in the Early Postnatal Rat.

    PubMed

    Lim, Wei Ling; Idris, Marshita Mohd; Kevin, Felix Suresh; Soga, Tomoko; Parhar, Ishwar S

    2016-01-01

    Maternal dexamethasone [(DEX); a glucocorticoid receptor agonist] exposure delays pubertal onset and alters reproductive behavior in the adult offspring. However, little is known whether maternal DEX exposure affects the offspring's reproductive function by disrupting the gonadotropin-releasing hormone (GnRH) neuronal function in the brain. Therefore, this study determined the exposure of maternal DEX on the GnRH neuronal spine development and synaptic cluster inputs to GnRH neurons using transgenic rats expressing enhanced green fluorescent protein (EGFP) under the control of GnRH promoter. Pregnant females were administered with DEX (0.1 mg/kg) or vehicle (VEH, water) daily during gestation day 13-20. Confocal imaging was used to examine the spine density of EGFP-GnRH neurons by three-dimensional rendering and synaptic cluster inputs to EGFP-GnRH neurons by synapsin I immunohistochemistry on postnatal day 0 (P0) males. The spine morphology and number on GnRH neurons did not change between the P0 males following maternal DEX and VEH treatment. The number of synaptic clusters within the organum vasculosum of the lamina terminalis (OVLT) was decreased by maternal DEX exposure in P0 males. Furthermore, the number and levels of synaptic cluster inputs in close apposition with GnRH neurons was decreased following maternal DEX exposure in the OVLT region of P0 males. In addition, the postsynaptic marker molecule, postsynaptic density 95, was observed in GnRH neurons following both DEX and VEH treatment. These results suggest that maternal DEX exposure alters neural afferent inputs to GnRH neurons during early postnatal stage, which could lead to reproductive dysfunction during adulthood. PMID:27630615

  9. Maternal Dexamethasone Exposure Alters Synaptic Inputs to Gonadotropin-Releasing Hormone Neurons in the Early Postnatal Rat

    PubMed Central

    Lim, Wei Ling; Idris, Marshita Mohd; Kevin, Felix Suresh; Soga, Tomoko; Parhar, Ishwar S.

    2016-01-01

    Maternal dexamethasone [(DEX); a glucocorticoid receptor agonist] exposure delays pubertal onset and alters reproductive behavior in the adult offspring. However, little is known whether maternal DEX exposure affects the offspring’s reproductive function by disrupting the gonadotropin-releasing hormone (GnRH) neuronal function in the brain. Therefore, this study determined the exposure of maternal DEX on the GnRH neuronal spine development and synaptic cluster inputs to GnRH neurons using transgenic rats expressing enhanced green fluorescent protein (EGFP) under the control of GnRH promoter. Pregnant females were administered with DEX (0.1 mg/kg) or vehicle (VEH, water) daily during gestation day 13–20. Confocal imaging was used to examine the spine density of EGFP–GnRH neurons by three-dimensional rendering and synaptic cluster inputs to EGFP–GnRH neurons by synapsin I immunohistochemistry on postnatal day 0 (P0) males. The spine morphology and number on GnRH neurons did not change between the P0 males following maternal DEX and VEH treatment. The number of synaptic clusters within the organum vasculosum of the lamina terminalis (OVLT) was decreased by maternal DEX exposure in P0 males. Furthermore, the number and levels of synaptic cluster inputs in close apposition with GnRH neurons was decreased following maternal DEX exposure in the OVLT region of P0 males. In addition, the postsynaptic marker molecule, postsynaptic density 95, was observed in GnRH neurons following both DEX and VEH treatment. These results suggest that maternal DEX exposure alters neural afferent inputs to GnRH neurons during early postnatal stage, which could lead to reproductive dysfunction during adulthood.

  10. Maternal Dexamethasone Exposure Alters Synaptic Inputs to Gonadotropin-Releasing Hormone Neurons in the Early Postnatal Rat

    PubMed Central

    Lim, Wei Ling; Idris, Marshita Mohd; Kevin, Felix Suresh; Soga, Tomoko; Parhar, Ishwar S.

    2016-01-01

    Maternal dexamethasone [(DEX); a glucocorticoid receptor agonist] exposure delays pubertal onset and alters reproductive behavior in the adult offspring. However, little is known whether maternal DEX exposure affects the offspring’s reproductive function by disrupting the gonadotropin-releasing hormone (GnRH) neuronal function in the brain. Therefore, this study determined the exposure of maternal DEX on the GnRH neuronal spine development and synaptic cluster inputs to GnRH neurons using transgenic rats expressing enhanced green fluorescent protein (EGFP) under the control of GnRH promoter. Pregnant females were administered with DEX (0.1 mg/kg) or vehicle (VEH, water) daily during gestation day 13–20. Confocal imaging was used to examine the spine density of EGFP–GnRH neurons by three-dimensional rendering and synaptic cluster inputs to EGFP–GnRH neurons by synapsin I immunohistochemistry on postnatal day 0 (P0) males. The spine morphology and number on GnRH neurons did not change between the P0 males following maternal DEX and VEH treatment. The number of synaptic clusters within the organum vasculosum of the lamina terminalis (OVLT) was decreased by maternal DEX exposure in P0 males. Furthermore, the number and levels of synaptic cluster inputs in close apposition with GnRH neurons was decreased following maternal DEX exposure in the OVLT region of P0 males. In addition, the postsynaptic marker molecule, postsynaptic density 95, was observed in GnRH neurons following both DEX and VEH treatment. These results suggest that maternal DEX exposure alters neural afferent inputs to GnRH neurons during early postnatal stage, which could lead to reproductive dysfunction during adulthood. PMID:27630615

  11. Perinatal dexamethasone-induced alterations in apoptosis within the hippocampus and paraventricular nucleus of the hypothalamus are influenced by age and sex.

    PubMed

    Zuloaga, Damian G; Carbone, David L; Quihuis, Alicia; Hiroi, Ryoko; Chong, David L; Handa, Robert J

    2012-07-01

    Exposure to high levels of glucocorticoids (GCs) during development leads to long-term changes in hypothalamic-pituitary-adrenal (HPA) axis regulation, although little is known about the neural mechanisms that underlie these alterations. In this study, we investigated the effects of late gestational (days 18-22) or postnatal (days 4-6) administration of the GC receptor agonist dexamethasone (DEX) on an apoptosis marker in two brain regions critical to HPA axis regulation, the hippocampus and the hypothalamic paraventricular nucleus (PVN). One day after the final DEX injection, male and female rats were sacrificed, and brains were processed for immunohistochemical detection of cleaved caspase-3, an apoptotic cell death indicator. DEX increased cleaved caspase-3 immunoreactivity in the CA1 hippocampal region of both sexes following prenatal but not postnatal treatment. Prenatal DEX also increased caspase-3 immunoreactivity in the CA3 region, an elevation that tended to be greater in females. In contrast, postnatal DEX resulted in a much smaller, albeit significant, induction in CA3 caspase-3 compared with prenatal treatment. Quantitative real-time PCR analysis revealed that prenatal but not postnatal DEX-induced hippocampal cleaved caspase-3 correlated with elevated mRNA of the proapoptotic gene Bad. Few caspase-3-ir cells were identified within the PVN regardless of treatment age, although postnatal but not prenatal DEX increased this number. However, the region immediately surrounding the PVN (peri-PVN) showed significant increases in caspase-3-ir cells following pre- and postnatal DEX. Together these findings indicate that developmental GC exposure increases apoptosis in HPAaxis-associated brain regions in an age- and sex-dependent manner.

  12. Iontophoresis of dexamethasone phosphate: competition with chloride ions

    PubMed Central

    Sylvestre, J.-P.; Díaz-Marín, C.; Delgado-Charro, M. B.; Guy, R. H.

    2008-01-01

    The objective was to study the competition of chloride released from a Ag/AgCl cathode on the iontophoretic delivery of dexamethasone phosphate (Dex-Phos). Iontophoresis of Dex-Phos was performed in side-by-side diffusion cells (0.78 cm2) using pig skin. A 0.3 mA constant current was applied via Ag/AgCl electrodes. The amounts of Dex-Phos and dexamethasone (Dex) were also quantified in the stratum corneum (SC), using tape stripping, after passive and iontophoretic delivery. The profiles of Dex-Phos and Dex, as a function of position in the SC, were deduced. The iontophoretic delivery of Dex-Phos from pure water was unaffected by the accumulation of Cl− released by the donor cathode when the drug’s concentration was 4.25 mM to 17 mM. At 0.85 mM, however, Cl− competition was significant and the drug flux was significantly reduced. Formulation of the drug in the presence of Cl− resulted in a non-linear dependence of flux on the molar fraction of the drug. Tape stripping experiments confirmed the enhanced delivery of Dex-Phos by iontophoresis relative to passive diffusion, with Dex-Phos concentration greater inside the barrier post-iontophoresis than that in the donor. The latter observation could explain the robustness of Dex-Phos delivery to the presence of Cl− in the donor solution. PMID:18662729

  13. RGD(F/S/V)-Dex: towards the development of novel, effective, and safe glucocorticoids

    PubMed Central

    Jiang, Xueyun; Zhao, Ming; Wang, Yuji; Zhu, Haimei; Zhao, Shurui; Wu, Jianhui; Song, Yuanbo; Peng, Shiqi

    2016-01-01

    Dexamethasone (Dex) is an effective glucocorticoid in treating inflammation and preventing rejection reaction. However, the side effects limit its clinical application. To improve its druggable profile, the conjugates of RGD-peptide-modified Dex were presented and their enhanced anti-inflammation activity, minimized osteoporotic action, and nanoscaled assembly were explored. (RGD stands for Arg-Gly-Asp. Standard single letter biochemical abbreviations for amino acids have been used throughout this paper.) In respect of the rejection reaction, the survival time of the implanted myocardium of the mice treated with 1.43 µmol/kg/d of the conjugates for 15 consecutive days was significantly longer than that of the mice treated with 2.5 µmol/kg/d of Dex, and the conjugates, but not Dex, exhibited no toxic action. At a single dose of 14.3 µmol/kg (100 times minimal effective dose, 0.143 µmol/kg), the conjugates induced no liver, kidney, or systemic toxicity. At the dose of 1.43 µmol/kg, the conjugates, but not Dex, prolonged the bleeding time of the mice, and inhibited the thrombosis of the rats. In water and rat plasma, the conjugates formed nanoparticles of 14–250 and 101–166 nm in diameter, respectively. Since the nanoparticles of ~100 nm in size cannot be entrapped by macrophages in the circulation, RGDF-Dex would particularly be worthy of development, since its nanoparticle diameter is 101 nm. PMID:27022245

  14. Dexamethasone Oral

    MedlinePlus

    ... of aspirin or other arthritis medication, limit your consumption of alcoholic beverages while taking this drug. Dexamethasone makes your stomach and intestines more susceptible to the irritating effects of alcohol, aspirin, and certain arthritis medications: this ...

  15. Biphasic influence of dexamethasone exposure on embryonic vertebrate skeleton development

    SciTech Connect

    Cheng, Xin; Chen, Jian-long; Ma, Zheng-lai; Zhang, Zhao-long; Lv, Shun; Mai, Dong-mei; Liu, Jia-jia; Chuai, Manli; Lee, Kenneth Ka Ho; Wan, Chao; Yang, Xuesong

    2014-11-15

    Dexamethasone (Dex) has anti-inflammatory and immunomodulatory properties against many conditions. There is a potential teratogenic risk, however, for pregnant women receiving Dex treatment. It has been claimed that Dex exposure during pregnancy could affect osteogenesis in the developing embryo, which still remains highly controversial. In this study, we employed chick embryos to investigate the effects of Dex exposure on skeletal development using combined in vivo and in vitro approach. First, we demonstrated that Dex (10{sup −8}–10{sup −6} μmol/egg) exposure resulted in a shortening of the developing long bones of chick embryos, and it accelerated the deposition of calcium salts. Secondly, histological analysis of chick embryo phalanxes exhibited Dex exposure inhibited the proliferation of chondrocytes, increased apoptosis of chondrocytes and osteocytes, and led to atypical arranged hypertrophic chondrocytes. The expression of genes related to skeletogenesis was also analyzed by semi-quantitative RT-PCR. The expression of ALP, Col1a2 and Col2a1 was decreased in the Dex treated phalanxes. A detectable increase was observed in Runx-2 and Mmp-13 expression. We next examined how Dex affected the different stages of skeletogenesis in vitro. Utilizing limb bud mesenchyme micromass cultures, we determined that Dex exposure exerted no effect on apoptosis but impaired chondrogenic cell proliferation. Interestingly, low dose of Dex moderately prompted nodule formation as revealed by alcian blue staining, but higher doses of Dex significantly inhibited similar chondrogenic differentiation. Dex exposure did not induce apoptosis when the chondrogenic precursors were still at the mesenchymal stage, however, cell viability was suppressed when the mesenchyme differentiated into chondrocytes. Alizarin red staining revealed that the capacity to form mineralized bone nodules was correspondingly enhanced as Dex concentrations increased. The mRNA level of Sox-9 was slightly

  16. The DEX/CRH test for major depression: a potentially useful diagnostic test.

    PubMed

    Mokhtari, Mohammadreza; Arfken, Cynthia; Boutros, Nash

    2013-07-30

    The dexamethasone/corticotropin-releasing hormone (DEX/CRH) test has been proposed as a potential diagnostic test for major depressive disorder (MDD). A previously proposed four-step approach assesses the stage of development for a biological finding into a clinically useful diagnostic test. Using this approach, we evaluated the progress of the DEX/CRH test using meta-analysis as a part of step 1. A literature review identified 15 studies of the DEX/CRH test in patients with MDD and healthy controls. Meta-analysis estimated the effect size, heterogeneity, and confidence intervals using random effects models. Studies consistent with any step of the four-step approach were identified, and their characteristics were presented. Eleven studies reported significantly higher cortisol levels with the DEX/CRH test in patients with MDD, compared with the healthy controls (step 1). Eight eligible studies were included in meta-analysis, and had an effect size of 1.34 (95% confidence interval: 0.70-1.97). Most studies were step-1 studies (comparison of patients and healthy controls), and no step-4 studies (multicenter trials) were found. This review emphasizes that despite appearing as a promising test, the DEX/CRH has not been adequately studied for the required stages of development into a clinically useful laboratory test. Particularly, additional step-3 and step-4 studies are necessary.

  17. Melatonin prevents cytosolic calcium overload, mitochondrial damage and cell death due to toxically high doses of dexamethasone-induced oxidative stress in human neuroblastoma SH-SY5Y cells.

    PubMed

    Suwanjang, Wilasinee; Abramov, Andrey Y; Charngkaew, Komgrid; Govitrapong, Piyarat; Chetsawang, Banthit

    2016-07-01

    Stressor exposure activates the hypothalamic-pituitary-adrenal (HPA) axis and causes elevations in the levels of glucocorticoids (GC) from the adrenal glands. Increasing evidence has demonstrated that prolonged exposure to high GC levels can lead to oxidative stress, calcium deregulation, mitochondrial dysfunction and apoptosis in a number of cell types. However, melatonin, via its antioxidant activity, exhibits a neuroprotective effect against oxidative stress-induced cell death. Therefore, in the present study, we explored the protective effect of melatonin in GC-induced toxicity in human neuroblastoma SH-SY5Y cells. Cellular treatment with the toxically high doses of the synthetic GC receptor agonist, dexamethasone (DEX) elicited marked decreases in the levels of glutathione and increases in ROS production, lipid peroxidation and cell death. DEX toxicity also induced increases in the levels of cytosolic calcium and mitochondrial fusion proteins (Mfn1 and Opa1) but decreases in the levels of mitochondrial fission proteins (Fis1 and Drp1). Mitochondrial damage was observed in large proportions of the DEX-treated cells. Pretreatment of the cells with melatonin substantially prevented the DEX-induced toxicity. These results suggest that melatonin might exert protective effects against oxidative stress, cytosolic calcium overload and mitochondrial damage in DEX-induced neurotoxicity. PMID:27155536

  18. Thermosensitive hydrogel containing dexamethasone micelles for preventing postsurgical adhesion in a repeated-injury model.

    PubMed

    Wu, Qinjie; Wang, Ning; He, Tao; Shang, Jinfeng; Li, Ling; Song, Linjiang; Yang, Xi; Li, Xia; Luo, Na; Zhang, Wenli; Gong, Changyang

    2015-09-01

    Tissue adhesion is a common complication after surgery. In this work, a dexamethasone loaded polymeric micelles in thermosensitive hydrogel composite (Dex hydrogel) was prepared, which combined the anti-adhesion barrier with controlled release of anti-adhesion drug. Dexamethasone (Dex) was encapsulated in polymeric micelles (Dex micelles), and then the Dex micelles were loaded into biodegradable and thermosensitive hydrogel. The obtained Dex hydrogel showed a temperature-dependent sol-gel-sol phase transition behavior. The Dex hydrogel could form a non-flowing gel in situ upon subcutaneous injection and gradually degrade in about 20 days. In addition, Dex hydrogel was assigned for anti-adhesion studies in a more rigorous recurrent adhesion animal model. Compared with normal saline (NS) and Dex micelles group, tissue adhesions in hydrogel and Dex hydrogel group were significantly alleviated. In Dex hydrogel group, the media adhesion score is 0, which was dramatically lower than that in blank hydrogel group (2.50, P < 0.001). In histopathological examination and scanning electron microscopy (SEM) analysis, an integral neo-mesothelial cell layer with microvilli on their surface was observed, which revealed that the injured parietal and visceral peritoneum were fully recovered without the concerns of adhesion formation. Our results suggested that Dex hydrogel may serve as a potential anti-adhesion candidate.

  19. Thermosensitive hydrogel containing dexamethasone micelles for preventing postsurgical adhesion in a repeated-injury model

    PubMed Central

    Wu, Qinjie; Wang, Ning; He, Tao; Shang, Jinfeng; Li, Ling; Song, Linjiang; Yang, Xi; Li, Xia; Luo, Na; Zhang, Wenli; Gong, Changyang

    2015-01-01

    Tissue adhesion is a common complication after surgery. In this work, a dexamethasone loaded polymeric micelles in thermosensitive hydrogel composite (Dex hydrogel) was prepared, which combined the anti-adhesion barrier with controlled release of anti-adhesion drug. Dexamethasone (Dex) was encapsulated in polymeric micelles (Dex micelles), and then the Dex micelles were loaded into biodegradable and thermosensitive hydrogel. The obtained Dex hydrogel showed a temperature-dependent sol-gel-sol phase transition behavior. The Dex hydrogel could form a non-flowing gel in situ upon subcutaneous injection and gradually degrade in about 20 days. In addition, Dex hydrogel was assigned for anti-adhesion studies in a more rigorous recurrent adhesion animal model. Compared with normal saline (NS) and Dex micelles group, tissue adhesions in hydrogel and Dex hydrogel group were significantly alleviated. In Dex hydrogel group, the media adhesion score is 0, which was dramatically lower than that in blank hydrogel group (2.50, P < 0.001). In histopathological examination and scanning electron microscopy (SEM) analysis, an integral neo-mesothelial cell layer with microvilli on their surface was observed, which revealed that the injured parietal and visceral peritoneum were fully recovered without the concerns of adhesion formation. Our results suggested that Dex hydrogel may serve as a potential anti-adhesion candidate. PMID:26324090

  20. Systemic effects of intratympanic dexamethasone therapy

    PubMed Central

    Novoa, Eva; Gärtner, Marcel; Henzen, Christoph

    2014-01-01

    Objective The study aimed to assess the possible systemic effects of intratympanic dexamethasone (IT-Dex) on the hypothalamic–pituitary–adrenal (HPA) axis, inflammation, and bone metabolism. Design A prospective cohort study including 30 adult patients of a tertiary referral ENT clinic treated with 9.6 mg IT-Dex over a period of 10 days was carried out. Methods Effects on plasma and salivary cortisol concentrations (basal and after low-dose (1 μg) ACTH stimulation), peripheral white blood cell count, and biomarkers for bone turnover were measured before (day 0) and after IT-Dex (day 16). Additional measurements for bone turnover were performed 5 months after therapy. Clinical information and medication with possible dexamethasone interaction were recorded. Results IT-Dex was well tolerated, and no effect was detected on the HPA axis (stimulated plasma and salivary cortisol concentration on day 0: 758±184 and 44.5±22.0 nmol/l; day 16: 718±154 and 39.8±12.4 nmol/l; P=0.58 and 0.24 respectively). Concentrations of osteocalcin (OC) and bone-specific alkaline phosphatase (BSAP) did not differ after dexamethasone (OC on days 0 and 16 respectively: 24.1±10.5 and 23.6±8.8 μg/l; BSAP on day 0, 16, and after 5 months respectively: 11.5±4.2, 10.3±3.4, and 12.6±5.06 μg/l); similarly, there was no difference in the peripheral white blood cell count (5.7×1012/l and 6.1×1012/l on days 0 and 16 respectively). Conclusions IT-Dex therapy did not interfere with endogenous cortisol secretion or bone metabolism. PMID:25055818

  1. Clinical Applications of Dexamethasone for Aged Eyes.

    PubMed

    Abadia, Beatriz; Calvo, Pilar; Ferreras, Antonio; Bartol, Fran; Verdes, Guayente; Pablo, Luis

    2016-09-01

    The risk of severe eye problems has been found to increase significantly with age, particularly between the fifth and sixth decades of life. Cataracts, dry eye, neovascular age-related macular degeneration, diabetic retinopathy and retinal vein occlusion (RVO) are very common and very different age-related ocular diseases that reduce the patient's quality of life. The rationale for using corticosteroids to treat anterior and posterior ocular segment diseases is driven by inflammation. Dexamethasone, one of the most powerful corticosteroids available, is widely used for topical or intravitreal administration. Topical dexamethasone has proven efficacy for the management of postoperative inflammation in the anterior segment after cataract surgery and symptom relief in dry-eye disease. A new sustained-release 700 µg dexamethasone intravitreal implant (DEX) was recently approved for the treatment of macular edema following RVO, diabetic macular edema, or non-infectious uveitis, and its use is increasing, especially when other therapeutic agents have failed. The most common side effects are increased intraocular pressure and cataract formation. The potency of DEX, alone or in combination with other agents, makes DEX a promising option for treating several retinal diseases. PMID:27566619

  2. Analgesia after Epidural Dexamethasone is Further Enhanced by IV Dipyrone, but Not IV Parecoxibe Following Minor Orthopedic Surgery

    PubMed Central

    Righeti, Claudia CF; Kitayama, Antonio T

    2014-01-01

    Background Epidural administration of dexamethasone has been suggested for pain control after minor orthopedic surgery. This study was conducted to assess its efficacy after such surgery, combined or not to IV dipyrone, IV parecoxibe or their combination. Methods 91 patients were randomly assigned to seven groups. Patients were submitted to spinal bupivacaine anesthesia combined to epidural administration of either 10 ml saline or 10 mg dexamethasone diluted to 10-ml volume. Patients also received 10 ml IV saline or 1 gr dipyrone and/or 40 mg parecoxibe diluted to 10 ml with saline. Control group (CG) received epidural and IV saline. Dexamethasone group (DexG) received epidural dexamethasone and IV saline. Dipyrone group (DipG) received epidural saline and IV dipyrone. Dex-Dip G received epidural dexamethasone and IV dipyrone. Parecoxibe group (ParG) received epidural saline and IV parecoxibe. Dex-ParG received epidural dexamethasone and IV parecoxibe. Finally, Dex-Dip-ParG received epidural dexamethasone and IV dipyrone plus IV parecoxibe. Results The CG expressed 4h of analgesia and sooner requested pain killer. DexG was similar to DipG or ParG or Dex-ParG (7-hours), and they requested less ketoprofen compared to the CG (P < 0.05). However, the Dex-DipG and the Dex-Dip-ParG resulted in longer time to demand pain killer (17-hours) and less ketoprofen consumption in 24-hours (P < 0.002). Adverse effects were similar among groups. Conclusions The analgesia secondary to epidural dexamethasone was enhanced by IV dipyrone, while no effects were observed by the addition of IV parecoxibe. PMID:25317284

  3. Prenatal dexamethasone exposure induces changes in nonhuman primate offspring cardiometabolic and hypothalamic-pituitary-adrenal axis function

    PubMed Central

    de Vries, Annick; Holmes, Megan C.; Heijnis, Areke; Seier, Jürgen V.; Heerden, Joritha; Louw, Johan; Wolfe-Coote, Sonia; Meaney, Michael J.; Levitt, Naomi S.; Seckl, Jonathan R.

    2007-01-01

    Prenatal stress or glucocorticoid administration has persisting “programming” effects on offspring in rodents and other model species. Multiple doses of glucocorticoids are in widespread use in obstetric practice. To examine the clinical relevance of glucocorticoid programming, we gave 50, 120, or 200 μg/kg/d of dexamethasone (dex50, dex120, or dex200) orally from mid-term to a singleton-bearing nonhuman primate, Chlorocebus aethiops (African vervet). Dexamethasone dose-dependently reduced maternal cortisol levels without effecting maternal blood pressure, glucose, electrolytes, or weight gain. Birth weight was unaffected by any dexamethasone dose, although postnatal growth was attenuated after dex120 and dex200. At 8 months of age, dex120 and dex200 offspring showed impaired glucose tolerance and hyperinsulinemia, with reduced (approximately 25%) pancreatic β cell number at 12 months. Dex120 and dex200 offspring had increased systolic and diastolic blood pressures at 12 months. Mild stress produced an exaggerated cortisol response in dex200 offspring, implying hypothalamic-pituitary-adrenal axis programming. The data are compatible with the extrapolation of the glucocorticoid programming hypothesis to primates and indicate that repeated glucocorticoid therapy and perhaps chronic stress in humans may have long-term effects. PMID:17380204

  4. Dexamethasone Enhances 1α,25-Dihydroxyvitamin D3 Effects by Increasing Vitamin D Receptor Transcription*

    PubMed Central

    Hidalgo, Alejandro A.; Deeb, Kristin K.; Pike, J. Wesley; Johnson, Candace S.; Trump, Donald L.

    2011-01-01

    Calcitriol, the active form of vitamin D, in combination with the glucocorticoid dexamethasone (Dex) has been shown to increase the antitumor effects of calcitriol in squamous cell carcinoma. In this study we found that pretreatment with Dex potentiates calcitriol effects by inhibiting cell growth and increasing vitamin D receptor (VDR) and VDR-mediated transcription. Treatment with actinomycin D inhibits Vdr mRNA synthesis, indicating that Dex regulates VDR expression at transcriptional level. Real time PCR shows that treatment with Dex increases Vdr transcripts in a time- and a dose-dependent manner, indicating that Dex directly regulates expression of Vdr. RU486, an inhibitor of glucocorticoids, inhibits Dex-induced Vdr expression. In addition, the silencing of glucocorticoid receptor (GR) abolishes the induction of Vdr by Dex, indicating that Dex increases Vdr transcripts in a GR-dependent manner. A fragment located 5.2 kb upstream of Vdr transcription start site containing two putative glucocorticoid response elements (GREs) was evaluated using a luciferase-based reporter assay. Treatment with 100 nm Dex induces transcription of luciferase driven by the fragment. Deletion of the GRE distal to transcription start site was sufficient to abolish Dex induction of luciferase. Also, chromatin immunoprecipitation reveals recruitment of GR to distal GRE with Dex treatment. We conclude that Dex increases VDR and vitamin D effects by increasing Vdr de novo transcription in a GR-dependent manner. PMID:21868377

  5. Effect of long term dexamethasone treatment on the glucocorticoid receptor

    SciTech Connect

    Silva, C.M.; DeLorenzo, T.M.; Cidlowski, J.A.

    1986-05-01

    The ability of dexamethasone(dex) to induce alkaline phosphatase activity was found to decrease with chronic hormone exposure. In order to better understand this adaptive resistance, the structure of the receptor from control cells and cells under long term dex (10/sup -6/M) treatment was analyzed. Native isoelectric focusing showed that receptor from dex treated cells focused at more basic pI than receptor from control cells. Denaturing two-dimensional gel analysis resulted in the characteristic 4-5 spots of (/sup 3/H)dexamethasone mesylate (DM) binding of receptor from control cells, but no (/sup 3/H)DM binding could be seen for receptor from dex treated cells. In order to study DNA-binding characteristics, gels were renatured, transferred to nitrocellulose and probed with (/sup 32/P)MMTV-GRE. Receptor from control cells showed 5 spots of DNA-binding at 101 kDa molecular weight and a pI range of 7.42 to 7.32. However, receptor from dex treated cells showed less intense DNA-binding which occurred only at the more basic range of pIs (7.42 to 7.39). Furthermore, no nuclear receptor sites could be measured in the dex treated cells, whereas 20,000 sites were measured in control cells. Even after being taken off hormone treatment for 12 days, cells could regenerate only 50% of their receptors. In conclusion, this system is conducive to studying the mechanism of receptor regulation.

  6. Mechanisms of Dexamethasone-Induced Disturbed Sleep and Fatigue in Paediatric Patients Receiving Treatment for ALL

    PubMed Central

    Vallance, Kelly; Liu, Wei; Mandrell, Belinda N.; Panetta, John C; Gattuso, Jami S.; Hockenberry, Marilyn; Zupanec, Sue; Yang, Lei; Yang, Jie; Hinds, Pamela S.

    2010-01-01

    Background Dexamethasone contributes to high cure rates in pediatric acute lymphoblastic leukaemia (ALL) but significantly and adversely alters sleep and fatigue. Herein we explored three mechanisms (pharmacokinetics, serum albumin, and pharmacogenetics) through which dexamethasone may cause debilitating fatigue and disrupted sleep. Methods We enrolled 100 patients on a 10-day study: 5 days of no dexamethasone (OFF DEX) followed by 5 days of dexamethasone (ON DEX) during continuation chemotherapy. Sleep variables were collected with continuous actigraphy on Days 1 through 5, both OFF DEX and ON DEX. On Days 2 and 5 of each 5-day period, parents and patients 7 years of age and older completed a sleep diary and Fatigue Scale questionnaire. Blood was collected at 0 (pre-dexamethasone), 1, 2, 4, and 8 hours after the first oral dexamethasone dose for pharmacokinetic analysis. Serum albumin concentration was retrospectively analyzed in stored samples. Patient DNA was genotyped for 99 polymorphic loci in candidate genes associated with glucocorticoid metabolism. Results Dexamethasone clearance was significantly greater in younger patients than in older ones and in lower risk patients. In multiple regression models, risk group was significantly related to pharmacokinetic parameters. We found that polymorphisms in three genes (AHSG, IL6, POLDIP3) were significantly associated with sleep measures but not fatigue. Conclusion Risk group had the most significant relationship with disrupted sleep in patients while on dexamethasone. Serum albumin levels had neither a direct relationship with sleep or fatigue variables nor an indirect relationship through systemic exposure to dexamethasone. We identified candidate genes that may help explain the adverse events of disrupted sleep in pediatric patients receiving dexamethasone. PMID:20400291

  7. Maternal treatment with dexamethasone during lactation delays male puberty and disrupts reproductive functions via hypothalamic-pituitary-gonadal axis alterations.

    PubMed

    Jeje, S O; Akindele, O O; Balogun, M E; Raji, Y

    2016-03-01

    The effects of maternal treatment with dexamethasone during lactation on pubertal timing, serum hormonal profile and sperm indices in the male offspring were assessed. Twenty lactating dams were divided into 4 groups (n=5). Group 1 was administered subcutaneously 0.02ml/100g/day normal saline at lactation days 1-21. Groups 2-4 were administered subcutaneously 100μg/kg/day dexamethasone (Dex) at lactation days 1-7, 1-14, and 1-21 respectively. Results showed that there was significant reduction in serum testosterone in the DexLD 1-7 (p<0.05), DexLD 1-14 (p<0.01) and DexLD 1-21 (p<0.001) relative to control. In addition there was a significant reduction in serum FSH and LH in the DexLD 1-7 (p<0.01), DexLD 1-14 (p<0.001) and DexLD 1-21 (p<0.001) when compared with the control. Treatment with dexamethasone during lactation significantly increased the days of preputial separation in the DexLD 1-7 (p<0.05), DexLD 1-14 (p<0.05) and DexLD 1-21 (p<0.001) relative to control. Maternal treatment with dexamethasone throughout lactation period also significantly reduced sperm counts (p<0.001), motility (p<0.01) and increased percentage abnormal sperm (p<0.001) in the offspring when compared with the control. In conclusion, maternal treatment with dexamethasone during lactation may induce delayed puberty and disrupt reproductive functions by altering activities at hypothalamic-pituitary-gonadal axis in the male offspring.

  8. Dexamethasone treatment differentially alters viral shedding and the antibody and acute phase protein response after multivalent respiratory vaccination in beef steers

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Our objective was to examine immunosuppression induced by dexamethasone (DEX) administration in cattle upon immunological responses to a multivalent respiratory vaccine containing replicating and non-replicating agents. Steers ( n = 32; 209 +/- 8 kg) seronegative to infectious bovine rhinotracheitis...

  9. Dexamethasone induced ultrastructural changes in cultured human trabecular meshwork cells.

    PubMed

    Wilson, K; McCartney, M D; Miggans, S T; Clark, A F

    1993-09-01

    Glucocorticoid-induced ocular hypertension has been demonstrated in both animals and humans. It is possible that glucocorticoid-induced changes in trabecular meshwork (TM) cells are responsible for this hypertension. In order to elaborate further the effect of glucocorticoids on the trabecular meshwork, the ultrastructural consequences of dexamethasone (DEX) treatment were examined in three different human TM cell lines. Confluent TM cells were treated with 0.1 microM of DEX for 14 days, and then processed for light, epifluorescent microscopy or transmission electron microscopy (TEM). The effect of DEX treatment on TM cell and nuclear size was quantified using computer assisted morphometrics. Morphometric analysis showed a significant increase in both TM cell and nuclear size after 14 days of DEX treatment. Epifluorescent microscopy of rhodamine-phalloidin stained, control TM cells showed the normal arrangement of stress fibers. In contrast, DEX-treated TM cells showed unusual geodesic dome-like cross-linked actin networks. Control TM cells had the normal complement and arrangement of organelles as well as electron dense inclusions and large vacuoles. DEX-treated TM cells showed stacked arrangements of smooth and rough endoplasmic reticulum, proliferation of the Golgi apparatus, pleomorphic nuclei and increased amounts of extracellular matrix material. The DEX-induced alterations observed in the present study may be an indication of the processes that are occurring in the in vivo disease process. PMID:8261790

  10. Electro-responsive macroporous polypyrrole scaffolds for triggered dexamethasone delivery.

    PubMed

    Seyfoddin, A; Chan, A; Chen, W-T; Rupenthal, I D; Waterhouse, G I N; Svirskis, D

    2015-08-01

    Corticosteroids such as dexamethasone are first line ophthalmic treatment for non-infectious posterior uveitis. Corticosteroids are often administered via intravitreal injection to treat this condition with frequent injections associated with poor treatment adherence and complications such as endophthalmitis. Current ocular implants provide sustained corticosteroid release at predetermined rates and lack the ability for dose individualisation. This study describes the successful fabrication of electrically responsive macroporous polypyrrole (PPy) thin films, and their subsequent application to triggered dexamethasone release. Colloidal crystal films composed of 370nm polymethylmethacrylate colloids were first deposited on ITO coated glass substrates, and subsequently used as sacrificial templates for the fabrication of high surface area, 3-dimensionally ordered macroporous PPy inverse opal (PPy IO) thin films. SEM, UV-Vis reflectance and cyclic voltammetry measurements established that the redox state of the PPy IO films could be controlled via electrical stimulation, which in turn influences both porosity and optical properties of the films. Incorporation of the anti-inflammatory corticosteroid, dexamethasone phosphate (DexP), in the PPy IO films during their fabrication resulted in an effective delivery platform for triggered DexP release. A sustained release profile was observed for the PPy IO-DexP films, bursts of release could be triggered by electrical stimulation. The amount of DexP released from the PPy IO-DexP films was significantly higher than that released from the conventional non-porous PPy-DexP films of comparable mass. Results suggest that electrically responsive PPy IO structures are highly suitable for on-demand drug delivery applications. This technology may enable physicians to fine-tune the required dose according to disease state and patients' needs to enhance the safety and efficacy of corticosteroid treatment. PMID:26141345

  11. Folate ameliorates dexamethasone-induced fetal and placental growth restriction potentially via improvement of trophoblast migration.

    PubMed

    Zhou, Linfang; Zhang, Ai; Wang, Kai; Zhou, Qian; Duan, Tao

    2015-01-01

    Overexposure to prenatal dexamethasone (Dex) leads to small placental and fetal size and the alteration of fetal programming. Folate plays important roles in processes associated with successful pregnancy, including angiogenesis and trophoblast invasion. Placental folate transport is altered with prenatal Dex administration. The purpose of this study was to investigate the protective role of maternal folate administration in placentas exposed to Dex. In vitro, four groups of C57BL/6J pregnant mice were utilized: 1) normal drinking water+Saline injection group (NN); 2) normal drinking water+Dex injection group (ND); 3) drinking water with folate+Saline injection group (FN); and 4) drinking water with folate+Dex injection group (FD). In vivo, four treatment groups of the human extravillous trophoblast HTR-8/SVneo cells were classified: 1) control (NN); 2) Dex treatment (ND); 3) folate treatment (FN); and 4) folate and Dex treatment (FD). The results showed the maternal folate increases the placental size, birth weight, and expression of matrix metalloproteinases 9 (MMP9) in a mice model of Dex overexposure. In human extravillous trophoblast HTR8/SVneo, folate ameliorated the Dex-induced supress of cell migration and improved the expression/activity of MMP2 and MMP9. In conclusion, folate might be a potential therapy intervention to reduce the adverse effects of prenatal Dex exposure partially via improved trophoblast migration.

  12. Lenalidomide and high-dose dexamethasone compared with dexamethasone as initial therapy for multiple myeloma: a randomized Southwest Oncology Group trial (S0232)

    PubMed Central

    Crowley, John; Hussein, Mohamad A.; Bolejack, Vanessa; Moore, Dennis F.; Whittenberger, Brock F.; Abidi, Muneer H.; Durie, Brian G. M.; Barlogie, Bart

    2010-01-01

    The Southwest Oncology Group conducted a randomized trial comparing lenalidomide (LEN) plus dexamethasone (DEX; n = 97) to placebo (PLC) plus DEX (n = 95) in newly diagnosed myeloma. Three 35-day induction cycles applied DEX 40 mg/day on days 1 to 4, 9 to 12, and 17 to 20 together with LEN 25 mg/day for 28 days or PLC. Monthly maintenance used DEX 40 mg/day on days 1 to 4 and 15 to 18 along with LEN 25 mg/day for 21 days or PLC. Crossover from PLC-DEX to LEN-DEX was encouraged on progression. One-year progression-free survival, overall response rate, and very good partial response rate were superior with LEN-DEX (78% vs 52%, P = .002; 78% vs 48%, P < .001; 63% vs 16%, P < .001), whereas 1-year overall survival was similar (94% vs 88%; P = .25). Toxicities were more pronounced with LEN-DEX (neutropenia grade 3 or 4: 21% vs 5%, P < .001; thromboembolic events despite aspirin prophylaxis: 23.5% [initial LEN-DEX or crossover] vs 5%; P < .001). This trial was registered at www.clinicaltrials.gov as #NCT00064038. PMID:20876454

  13. Early handling modulates outcome of neonatal dexamethasone exposure.

    PubMed

    Claessens, Sanne E F; Daskalakis, Nikolaos P; Oitzl, Melly S; de Kloet, E Ronald

    2012-09-01

    Synthetic glucocorticoids such as dexamethasone (DEX) are used to prevent or treat respiratory disorders in prematurely born infants. Besides the short-term benefit on lung development, numerous human and animal studies have reported adverse neurodevelopmental side effects. In contrast, maternal care is known to exert a positive influence on neurodevelopmental outcome in rodents. The aim of the current study was therefore to investigate whether neonatal handling (days 1-21), known to induce maternal care, might serve as an intervention strategy modulating the adverse effects of DEX treatment (days 1-3). For this purpose we have measured the outcome of these early-life manipulations on development as well as adult endocrine and behavioral phenotype of male rats. Maternal care was observed during the first week of life and indeed enhanced in response to handling. Eye opening was accelerated and body weight reduced in DEX-treated animals. In adulthood, we report that handling ameliorated impaired spatial learning observed in DEX treated non-handled animals in the T-maze. Additionally, handling reduced susceptibility to the impact of DEX treatment in the water maze. Although DEX treatment and handling both resulted in enhanced negative feedback of the stress-induced corticosterone response and both reduced startle reactivity, the acquisition of fear was only reduced by handling, without effect of DEX. Interestingly, handling had a beneficial effect on pre-pulse inhibition, which was diminished after DEX treatment. In conclusion, these findings indicate that handling of the neonate enhances maternal care and attenuates specific DEX-induced alterations in the adult behavioral phenotype.

  14. Dexamethasone impairs hypoxia-inducible factor-1 function

    SciTech Connect

    Wagner, A.E.; Huck, G.; Stiehl, D.P.; Jelkmann, W.; Hellwig-Buergel, T.

    2008-07-25

    Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription-factor composed of {alpha}- and {beta}-subunits. HIF-1 is not only necessary for the cellular adaptation to hypoxia, but it is also involved in inflammatory processes and wound healing. Glucocorticoids (GC) are therapeutically used to suppress inflammatory responses. Herein, we investigated whether GC modulate HIF-1 function using GC receptor (GR) possessing (HepG2) and GR deficient (Hep3B) human hepatoma cell cultures as model systems. Dexamethasone (DEX) treatment increased HIF-1{alpha} levels in the cytosol of HepG2 cells, while nuclear HIF-1{alpha} levels and HIF-1 DNA-binding was reduced. In addition, DEX dose-dependently lowered the hypoxia-induced luciferase activity in a reporter gene system. DEX suppressed the hypoxic stimulation of the expression of the HIF-1 target gene VEGF (vascular endothelial growth factor) in HepG2 cultures. DEX did not reduce hypoxically induced luciferase activity in HRB5 cells, a Hep3B derivative lacking GR. Transient expression of the GR in HRB5 cells restored the susceptibility to DEX. Our study discloses the inhibitory action of GC on HIF-1 dependent gene expression, which may be important with respect to the impaired wound healing in DEX-treated patients.

  15. Dexamethasone-induced cell death is restricted to specific molecular subgroups of multiple myeloma

    PubMed Central

    Kervoëlen, Charlotte; Ménoret, Emmanuelle; Gomez-Bougie, Patricia; Bataille, Régis; Godon, Catherine; Marionneau-Lambot, Séverine; Moreau, Philippe; Pellat-Deceunynck, Catherine; Amiot, Martine

    2015-01-01

    Due to its cytotoxic effect in lymphoid cells, dexamethasone is widely used in the treatment of multiple myeloma (MM). However, only a subset of myeloma patients responds to high-dose dexamethasone. Despite the undeniable anti-myeloma benefits of dexamethasone, significant adverse effects have been reported. We re-evaluate the anti-tumor effect of dexamethasone according to the molecular heterogeneity of MM. We demonstrated that the pro-death effect of dexamethasone is related to the genetic heterogeneity of MM because sensitive cell lines were restricted to MAF and MMSET signature subgroups, whereas all CCND1 cell lines (n = 10) were resistant to dexamethasone. We demonstrated that the glucocorticoid receptor expression was an important limiting factor for dexamethasone-induced cell death and we found a correlation between glucocorticoid receptor levels and the induction of glucocorticoid-induced leucine zipper (GILZ) under dexamethasone treatment. By silencing GILZ, we next demonstrated that GILZ is necessary for Dex induced apoptosis while triggering an imbalance between anti- and pro-apoptotic Bcl-2 proteins. Finally, the heterogeneity of the dexamethasone response was further confirmed in vivo using myeloma xenograft models. Our findings suggested that the effect of dexamethasone should be re-evaluated within molecular subgroups of myeloma patients to improve its efficacy and reduce its adverse effects. PMID:26323097

  16. Neonatal dexamethasone accelerates spreading depression in the rat, and antioxidant vitamins counteract this effect.

    PubMed

    Lopes-de-Morais, Andréia Albuquerque Cunha; Mendes-da-Silva, Rosângela Figueiredo; dos-Santos, Eryka Maria; Guedes, Rubem Carlos Araújo

    2014-12-01

    The use of dexamethasone (Dex) to treat chronic lung disease in preterm infants may produce adverse effects in the developing brain. Here, we evaluated the effects of neonatal Dex on the propagation of cortical spreading depression (CSD), and tested the action of vitamins C and E against the effect of Dex. Five groups of Wistar rats received, respectively: [1] no treatment (Naïve); [2] Vehicle (V); [3] tapering doses of Dex (Dex; 0.5mg/kg, 0.3mg/kg, and 0.1mg/kg) on postnatal day (PND) 1-3; [4] Dex plus 200mg/kg vitamin C and 100mg/kg vitamin E (DexCE); [5] only vitamins C and E (CE). Vehicle and vitamins were administered on PND 1-6. CSD was recorded after the pups reached maturity (PND 60-70). The Dex-treated group presented with higher CSD velocities (mean values ± SD, in mm/min: 4.14 ± 0.22, n=10) compared with the control groups (Naïve: 3.52 ± 0.13, n=8; V: 3.57 ± 0.18, n=10; CE: 3.51 ± 0.24, n=10; p<0.05 for all). Vitamins C and E antagonized this effect (DexCE group; CSD velocity: 3.43 ± 0.12, n=9). No intergroup difference was observed concerning P-wave amplitude and duration. In all groups, after the cortex underwent CSD, the electrocorticogram (ECoG) amplitude increased approximately 50% compared with the baseline amplitude for the same animal (CSD-induced ECoG potentiation); however, no intergroup difference was observed. Data suggest that coadministration of antioxidant vitamins with Dex may be a helpful therapeutic strategy to reduce brain adverse effects of dexamethasone.

  17. Effects of illicit dexamethasone upon hepatic drug metabolizing enzymes and related transcription factors mRNAs and their potential use as biomarkers in cattle.

    PubMed

    Giantin, Mery; Lopparelli, Rosa M; Zancanella, Vanessa; Martin, Pascal G; Polizzi, Arnaud; Gallina, Guglielmo; Gottardo, Flaviana; Montesissa, Clara; Ravarotto, Licia; Pineau, Thierry; Dacasto, Mauro

    2010-01-27

    In cattle fattening, the illicit use of growth promoters (GPs) represents a major problem. The synthetic corticosteroid dexamethasone (DEX) is the GP mostly used, alone or in combination with other steroids or beta-agonists. Recently, GPs were shown to disrupt some cattle cytochromes P450 (CYPs) at the post-transcriptional level; therefore, the effects of two illicit protocols containing DEX (alone or together with 17beta-estradiol, 17betaE) upon main cattle liver drug metabolizing enzymes (DMEs) mRNAs and related transcription factors were investigated by quantitative real time RT-PCR. Eleven genes, out of the 18 considered, were significantly modulated by GPs. Corticosteroid-responsive genes did not respond univocally, whereas retinoic X receptor alpha (RXRalpha) and estrogen receptor alpha (ERalpha) were upregulated depending on the illicit protocol used. Nowadays, an increasing interest has been noticed toward the detection of biomarkers of response (BMRs) to be used in the screening of GPs misuse in cattle farming. In the present study, CYP2B6-like, CYP2E1, glutathione S-transferase A1- and sulfotransferase A1-like (GSTA1- and SULT1A1-like) mRNAs were significantly modulated regardless of the GP, the illicit protocol, and the animal breed, representing promising BMRs. The usefulness of these BMRs needs to be characterized more in depth.

  18. Selective Non-Steroidal Glucocorticoid Receptor Agonists Attenuate Inflammation but Do Not Impair Intestinal Epithelial Cell Restitution In Vitro

    PubMed Central

    Reuter, Kerstin C.; Loitsch, Stefan M.; Dignass, Axel U.; Steinhilber, Dieter; Stein, Jürgen

    2012-01-01

    Introduction Despite the excellent anti-inflammatory and immunosuppressive action of glucocorticoids (GCs), their use for the treatment of inflammatory bowel disease (IBD) still carries significant risks in terms of frequently occurring severe side effects, such as the impairment of intestinal tissue repair. The recently-introduced selective glucocorticoid receptor (GR) agonists (SEGRAs) offer anti-inflammatory action comparable to that of common GCs, but with a reduced side effect profile. Methods The in vitro effects of the non-steroidal SEGRAs Compound A (CpdA) and ZK216348, were investigated in intestinal epithelial cells and compared to those of Dexamethasone (Dex). GR translocation was shown by immunfluorescence and Western blot analysis. Trans-repressive effects were studied by means of NF-κB/p65 activity and IL-8 levels, trans-activation potency by reporter gene assay. Flow cytometry was used to assess apoptosis of cells exposed to SEGRAs. The effects on IEC-6 and HaCaT cell restitution were determined using an in vitro wound healing model, cell proliferation by BrdU assay. In addition, influences on the TGF-β- or EGF/ERK1/2/MAPK-pathway were evaluated by reporter gene assay, Western blot and qPCR analysis. Results Dex, CpdA and ZK216348 were found to be functional GR agonists. In terms of trans-repression, CpdA and ZK216348 effectively inhibited NF-κB activity and IL-8 secretion, but showed less trans-activation potency. Furthermore, unlike SEGRAs, Dex caused a dose-dependent inhibition of cell restitution with no effect on cell proliferation. These differences in epithelial restitution were TGF-β-independent but Dex inhibited the EGF/ERK1/2/MAPK-pathway important for intestinal epithelial wound healing by induction of MKP-1 and Annexin-1 which was not affected by CpdA or ZK216348. Conclusion Collectively, our results indicate that, while their anti-inflammatory activity is comparable to Dex, SEGRAs show fewer side effects with respect to wound healing

  19. Early Dexamethasone Treatment Induces Placental Apoptosis in Sheep

    PubMed Central

    Meng, Wenbin; Shang, Hongkai; Li, Shaofu; Sloboda, Deborah M.; Ehrlich, Loreen; Lange, Karolin; Xu, Huaisheng; Henrich, Wolfgang; Dudenhausen, Joachim W.; Plagemann, Andreas; Newnham, John P.; Challis, John R. G.

    2015-01-01

    Glucocorticoid treatment given in late pregnancy in sheep resulted in altered placental development and function. An imbalance of placental survival and apoptotic factors resulting in an increased rate of apoptosis may be involved. We have now investigated the effects of dexamethasone (DEX) in early pregnancy on binucleate cells (BNCs), placental apoptosis, and fetal sex as a determinant of these responses. Pregnant ewes carrying singleton fetuses (n = 105) were randomized to control (n = 56, 2 mL saline/ewe) or DEX treatment (n = 49, intramuscular injections of 0.14 mg/kg ewe weight per 12 hours over 48 hours) at 40 to 41 days of gestation (dG). Placentomes were collected at 50, 100, 125, and 140 dG. At 100 dG, DEX in females reduced BNC numbers, placental antiapoptotic (proliferating cell nuclear antigen), and increased proapoptotic factors (Bax, p53), associated with a temporarily decrease in fetal growth. At 125 dG, BNC numbers and apoptotic markers were restored to normal. In males, ovine placental lactogen-protein levels after DEX were increased at 50 dG, but at 100 and 140 dG significantly decreased compared to controls. In contrast to females, these changes were independent of altered BNC numbers or apoptotic markers. Early DEX was associated with sex-specific, transient alterations in BNC numbers, which may contribute to changes in placental and fetal development. Furthermore, in females, altered placental apoptosis markers may be involved. PMID:25063551

  20. Postnatal High-Fat Diet Increases Liver Steatosis and Apoptosis Threatened by Prenatal Dexamethasone through the Oxidative Effect.

    PubMed

    Huang, Ying-Hsien; Chen, Chih-Jen; Tang, Kuo-Shu; Sheen, Jiunn-Ming; Tiao, Mao-Meng; Tain, You-Lin; Chen, Chih-Cheng; Chu, En-Wei; Li, Shih-Wen; Yu, Hong-Ren; Huang, Li-Tung

    2016-01-01

    The objective of this study was to investigate cellular apoptosis in prenatal glucocorticoid overexposure and a postnatal high fat diet in rats. Pregnant Sprague-Dawley rats at gestational days 14 to 21 were administered saline (vehicle) or dexamethasone and weaned onto either a normal fat diet or a high fat diet for 180 days; in total four experimental groups were designated, i.e., vehicle treated group (VEH), dexamethasone treated group (DEX), vehicle treated plus high-fat diet (VHF), and dexamethasone treated plus high-fat diet (DHF). Chronic effects of prenatal liver programming were assessed at postnatal day 180. The apoptotic pathways involved proteins were analyzed by Western blotting for their expressions. Apoptosis and liver steatosis were also examined by histology. We found that liver steatosis and apoptosis were increased in the DHF, DEX, and VHF treated groups, and that the DHF treated group was increased at higher levels than the DEX and VHF treated groups. The expression of leptin was decreased more in the DHF treated group than in the DEX and VHF treated groups. Decreased peroxisome proliferator-activated receptor-gamma coactivator 1α, phosphoinositide-3-kinase, manganese superoxide dismutase and increased malondialdehyde expression levels were seen in DHF treated group relative to the DEX treated group. The DHF treated group exhibited higher levels of oxidative stress, apoptosis and liver steatosis than the DEX treated group. These results indicate that the environment of high-fat diet plays an important role in the development of liver injury after prenatal stress.

  1. OSU53 Rescues Human OB-6 Osteoblastic Cells from Dexamethasone through Activating AMPK Signaling.

    PubMed

    Xu, Dawei; Zhao, Wei; Zhu, Xinhui; Fan, Jianbo; Cui, Shengyu; Sun, Yuyu; Chen, Xiang; Liu, Wei; Cui, Zhi-Ming

    2016-01-01

    Excessive dexamethasone (Dex) application causes osteoblast cell death, which could lead to osteoporosis or osteonecrosis. AMP-activated protein kinase (AMPK) activation is shown to protect osteoblasts/osteoblastic cells from Dex. In this report, we tested the potential effect of OSU53, a novel AMPK activator, in Dex-treated osteoblastic cells. We show that OSU53 activated AMPK signaling in human OB-6 osteoblastic cells. Further, Dex-induced osteoblastic OB-6 cell death and apoptosis were largely attenuated with pre-treatment with OSU53. OSU53 was more efficient than other known AMPK activators (A-769662 and Compound 13) in protecting OB-6 cells against Dex. AMPK activation is required for OSU53-induced actions in OB-6 cells. AMPKα shRNA knockdown or dominant-negative mutation (dn-AMPKα T172A) almost completely blocked OSU53-induced AMPK activation and OB-6 cell protection against Dex. Further studies showed that OSU53 increased NADPH (nicotinamide adenine dinucleotide phosphate) activity and alleviated Dex-induced oxidative stress in OB-6 cells. Such effects by OSU53 were again almost abolished with AMPKα shRNA or dn-AMPKα in OB-6 cells. Together, these results demonstrate that OSU53 protects osteoblastic cells from Dex possibly via activating AMPK-dependent signaling. PMID:27632213

  2. Resistance of LPS-activated bone marrow derived macrophages to apoptosis mediated by dexamethasone

    PubMed Central

    Haim, Yasmin Ohana; Unger, Naamit Deshet; Souroujon, Miriam C.; Mittelman, Moshe; Neumann, Drorit

    2014-01-01

    Glucocorticoids (GC) display pleiotropic effects on the immune system. Macrophages are a major target for GC action. Here we show that dexamethasone (DEX), a synthetic GC, decreased viability of naïve bone marrow-derived macrophages (BMDM), involving an apoptotic mechanism. Administration of DEX together with lipopolysaccharide (LPS) protected BMDM against DEX-mediated cell death, suggesting that activated BMDM respond to DEX differently than naïve BMDM. An insight to the molecular basis of LPS actions was provided by a 7 fold increase in mRNA levels of glucocorticoid receptor beta (GRβ), a GR dominant-negative splice variant which inhibits GRα's transcriptional activity. LPS did not inhibit all DEX-mediated effects on BMDM; DEX significantly reduced the percentage of BMDM expressing high levels of the cell surface markers F4/80 and CD11b and led to a decrease in macrophage inflammatory protein 1 alpha (MIP1-α) mRNA and protein levels. These two DEX-mediated effects were not prevented by LPS. Our finding that LPS did not reduce the DEX-induced elevation of glucocorticoid-induced leucine zipper (GILZ), a mediator of GCs anti-inflammatory actions, may provide an underlying mechanism. These findings enable a better understanding of clinical states, such as sepsis, in which macrophages are activated by endotoxins and treatment by GCs is considered. PMID:24608810

  3. OSU53 Rescues Human OB-6 Osteoblastic Cells from Dexamethasone through Activating AMPK Signaling

    PubMed Central

    Xu, Dawei; Zhao, Wei; Zhu, Xinhui; Fan, Jianbo; Cui, Shengyu; Sun, Yuyu; Chen, Xiang; Liu, Wei; Cui, Zhi-ming

    2016-01-01

    Excessive dexamethasone (Dex) application causes osteoblast cell death, which could lead to osteoporosis or osteonecrosis. AMP-activated protein kinase (AMPK) activation is shown to protect osteoblasts/osteoblastic cells from Dex. In this report, we tested the potential effect of OSU53, a novel AMPK activator, in Dex-treated osteoblastic cells. We show that OSU53 activated AMPK signaling in human OB-6 osteoblastic cells. Further, Dex-induced osteoblastic OB-6 cell death and apoptosis were largely attenuated with pre-treatment with OSU53. OSU53 was more efficient than other known AMPK activators (A-769662 and Compound 13) in protecting OB-6 cells against Dex. AMPK activation is required for OSU53-induced actions in OB-6 cells. AMPKα shRNA knockdown or dominant-negative mutation (dn-AMPKα T172A) almost completely blocked OSU53-induced AMPK activation and OB-6 cell protection against Dex. Further studies showed that OSU53 increased NADPH (nicotinamide adenine dinucleotide phosphate) activity and alleviated Dex-induced oxidative stress in OB-6 cells. Such effects by OSU53 were again almost abolished with AMPKα shRNA or dn-AMPKα in OB-6 cells. Together, these results demonstrate that OSU53 protects osteoblastic cells from Dex possibly via activating AMPK-dependent signaling. PMID:27632213

  4. Dexamethasone: intravitreal implant.

    PubMed

    2011-01-01

    Macular oedema is one of the complications of retinal vein occlusion. About half of the patients recover spontaneously within 3 to 6 months. There is currently no drug that improves outcome. An intravitreal implant delivering 0.7 mg of dexamethasone has been authorised for the treatment of macular oedema in this setting. Clinical assessment is based on two double-blind randomised trials including a total of 1267 patients, comparing treatment with intravitreal implants delivering about 0.7 mg or 0.35 mg of dexamethasone, versus a sham procedure. Despite a more rapid initial improvement with dexamethasone, the number of patients whose reading ability improved at 6 months did not significantly differ between the groups. A retrospective subgroup analysis raised the possibility that dexamethasone implants may be beneficial in patients with central retinal vein occlusion. The adverse effects of dexamethasone intravitreal implants are the same as those of intraocular steroid injections, including elevated intraocular pressure (25% of patients), cataracts (27%), conjunctival haemorrhage (20%), and ocular pain. In practice, dexamethasone intravitreal implants do not have a positive harm-benefit balance in most patients with macular oedema following retinal vein occlusion. More rapid recovery after central vein occlusion remains to be confirmed. Pending such studies, it is better to avoid using dexamethasone implants. Patients should instead receive ophthalmologic monitoring to detect and manage possible complications, and any risk factors should be treated.

  5. Controlled Release of Dexamethasone From an Intravitreal Delivery System Using Porous Silicon Dioxide

    PubMed Central

    Hou, Huiyuan; Wang, Chengyun; Nan, Kaihui; Freeman, William R.; Sailor, Michael J.; Cheng, Lingyun

    2016-01-01

    Purpose The current study aims to evaluate a porous silicon-based drug delivery system meant for sustained delivery of dexamethasone (Dex) to the vitreous and retina. Methods Dexamethasone was grafted covalently into the pore walls of fully oxidized porous silicon particles (pSiO2-COO-Dex), which then was evaluated for the pharmacological effect of the payload on cultured ARPE19 cells before intravitreal injection. The Dex release profile was investigated in a custom designed dynamic dissolution chamber to mimic the turnover of vitreous fluid in rabbit eyes. Ocular safety, in vivo release, and pharmacodynamics were evaluated in rabbit eyes, and the human VEGF-induced rabbit retinal vascular permeability model. Results Loading efficiency of Dex was 69 ± 9 μg per 1 mg of the pSiO2-COO-Dex particles. Dynamic in vitro release demonstrated a sustained mode when compared to free Dex, with the drug half-life extended by 5 times. The released Dex was unaltered and biologically active. In vivo drug release in rabbit eyes revealed a mode similar to the release seen in vitro, with a vitreous half-life of 11 days. At 2 and 4 weeks after a single intravitreal injection of pSiO2-COO-Dex particles (mean 2.71 ± 0.47 mg), intravitreal 500 ng of VEGF did not induce significant retinal vessel dilation or fluorescein leakage, while these events were observed in the eyes injected with empty pSiO2 particles or with free Dex. The retinal vessel score from fluorescein angiography for the control eyes was double the score for the eyes injected with pSiO2-COO-Dex. No adverse reaction was observed for the eyes injected with drug-loaded pSi particles during the course of the study. Conclusions The porous silicon-based Dex delivery system (pSiO2-COO-Dex) can be administered safely into vitreous without toxicity. Dex release from the porous silicon particles was sustained for 2 months and was effective against VEGF-induced retinal vessel reaction. PMID:26882530

  6. Anti-CD163-dexamethasone protects against apoptosis after ischemia/reperfusion injuries in the rat liver

    PubMed Central

    Møller, Lin Nanna Okholm; Knudsen, Anders Riegels; Andersen, Kasper Jarlhelt; Nyengaard, Jens Randel; Hamilton-Dutoit, Stephen; Okholm Møller, Elise Marie; Svendsen, Pia; Møller, Holger Jon; Moestrup, Søren Kragh; Graversen, Jonas Heilskov; Mortensen, Frank Viborg

    2015-01-01

    Aim The Pringle maneuver is a way to reduce blood loss during liver surgery. However, this may result in ischemia/reperfusion injury in the development of which Kupffer cells play a central role. Corticosteroids are known to have anti-inflammatory effects. Our aim was to investigate whether a conjugate of dexamethasone and antibody against the CD163 macrophage cell surface receptor could reduce ischemia/reperfusion injury in the rat liver. Methods Thirty-six male Wistar rats were used for the experiments. Animals were randomly divided into four groups of eight receiving anti-CD163-dexamethasone, high dose dexamethasone, low dose dexamethasone or placebo intravenously 18 h before laparotomy with subsequent 60 min of liver ischemia. After reperfusion for 24 h the animals had their liver removed. Bloods were drawn 30 min and 24 h post ischemia induction. Liver cell apoptosis and necrosis were analyzed by stereological quantification. Results After 24 h' reperfusion, the fraction of cell in non-necrotic tissues exhibiting apoptotic profiles was significantly lower in the high dose dexamethasone (p = 0.03) and anti-CD163-dex (p = 0.03) groups compared with the low dose dexamethasone and placebo groups. There was no difference in necrotic cell volume between groups. After 30 min of reperfusion, levels of haptoglobin were significantly higher in the anti-CD163-dex and high dose dexamethasone groups. Alanine aminotransferase and alkaline phosphatase were significantly higher in the high dose dexamethasone group compared to controls after 24 h' reperfusion. Conclusions We show that pharmacological preconditioning with anti-CD163-dex and high dose dexamethasone reduces the number of apoptotic cells following ischemia/reperfusion injury. PMID:26566435

  7. Dexamethasone Increases αvβ3 Integrin Expression and Affinity through a Calcineurin/NFAT Pathway

    PubMed Central

    Faralli, Jennifer A.; Gagen, Debjani; Filla, Mark S.; Crotti, Tania N.; Peters, Donna M.

    2013-01-01

    The purpose of this study was to determine how dexamethasone (DEX) regulates the expression and activity of αvβ3 integrin. FACS analysis showed that DEX treatment induced expression of an activated αvβ3 integrin. Its expression remained high as long as DEX was present and continued following DEX removal. FACS analysis showed that the upregulation of αvβ3 integrin was the result of an increase in the expression of the β3 integrin subunit. By real time qPCR, DEX treatment induced a 6.2-fold increase (p<0.04) in β3 integrin mRNA by day 2 compared to control and remained elevated for 6 days of treatment and then an additional 10 days once the DEX was removed. The increase in β3 integrin mRNA levels required only 1 day of DEX treatment to increase levels for 4 days in the absence of DEX. In contrast, DEX did not alter β1 integrin mRNA or protein levels. The DEX-induced upregulation of β3 integrin mRNA was partly due to an increase in its half-life to 60.7 h from 22.5 h in control cultures (p<0.05) and could be inhibited by RU486 and cycloheximide, suggesting that DEX-induced de novo protein synthesis of an activation factor was needed. The calcineurin inhibitors cyclosporin A (CsA) and FK506 inhibited the DEX induced increase in β3 integrin mRNA. In summary, the DEX-induced increase in β3 integrin is a secondary glucocorticoid response that results in prolonged expression of αvβ3 integrin and the upregulation of the β3 integrin subunit through the calcineurin/NFAT pathway. PMID:24100160

  8. The in vitro fungicidal activity of human macrophages against Penicillium marneffei is suppressed by dexamethasone.

    PubMed

    Ma, Tuan; Chen, Renqiong; Li, Xiqing; Lu, Changming; Xi, Liyan

    2015-09-01

    Penicillium marneffei (P. marneffei) is a pathogenic fungus that can persist in macrophages and cause a life-threatening systemic mycosis in immunocompromised hosts. To elucidate the mechanisms underlying this opportunistic fungal infection, we established the co-culture system of P. marneffei conidia and human monocyte-derived macrophages (MDM) for investigating the interactions between them. And, we impaired the immune state of MDM by the addition of dexamethasone (DEX). Compared with immunocompetent MDM without DEX treatment in response to P. marneffei, DEX could damage MDM function in initiating the innate immune response through decreasing TNF-α production and the proportion of P. marneffei conidia in mature phagolysosomes, while the red pigment secretion by P. marneffei conidia was promoted by DEX following MDM lysis. Our data provide the evidence that DEX-treated MDM have a low fungicidal activity against P. marneffei that causes penicilliosis in immunocompromised hosts.

  9. Dexamethasone suppression test

    MedlinePlus

    DST; ACTH suppression test; Cortisol suppression test ... During this test, you will receive dexamethasone. This is a strong man-made (synthetic) glucocorticoid medication. Afterward, your blood is drawn ...

  10. Dexamethasone-loaded Block Copolymer Nanoparticles Induce Leukemia Cell Death and Enhances Therapeutic Efficacy: A Novel Application in Pediatric Nanomedicine

    PubMed Central

    Krishnan, Vinu; Xu, Xian; Barwe, Sonali P.; Yang, Xiaowei; Czymmek, Kirk; Waldman, Scott A.; Mason, Robert W.; Jia, Xinqiao; Rajasekaran, Ayyappan K.

    2014-01-01

    Nanotechnology approaches have tremendous potential for enhancing treatment efficacy with lower doses of chemotherapeutics. Nanoparticle-based drug delivery approaches are poorly developed for childhood leukemia. Dexamethasone (Dex) is one of the most common chemotherapeutic drugs used in the treatment of childhood leukemia. In this study, we encapsulated Dex in polymeric nanoparticles and validated their anti-leukemic potential in vitro and in vivo. Nanoparticles (NPs) with an average diameter of 110 nm were assembled from amphiphilic block copolymers poly (ethylene glycol) (PEG) and poly (ε-caprolactone) (PCL) bearing pendant cyclic ketals. The blank nanoparticles were non-toxic to cultured cells in vitro and to mice in vivo. Encapsulation of Dex into the nanoparticles (Dex-NP) did not compromise the bioactivity of the drug. Dex-NPs induced glucocorticoid phosphorylation and showed cytotoxicity similar to the free Dex in leukemic cells. Studies using nanoparticles labeled with fluorescent dyes revealed leukemic cell surface binding and internalization. In vivo biodistribution studies showed NP accumulation in the liver and spleen with subsequent clearance of the particles with time. In a pre-clinical model of leukemia, Dex-NPs significantly improved the quality of life and survival of mice compared to the free drug. To our knowledge, this is the first report showing the efficacy of polymeric nanoparticles to deliver Dex to potentially treat childhood leukemia and reveals that low dose of Dex should be sufficient for inducing cell death and improve survival. PMID:23194373

  11. Effects of vitamin D and yeast extract supplementation on turkey mortality and clostridial dermatitis incidence in a dexamethasone immunosuppresssion model

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Clostridial dermatitis is a production disease of commercial turkeys that is chararacterized by sudden mortality in market-aged male birds and lesions that include fluid and air bubbles under the skin of the thigh, breast, and tail area. We have developed a model for CD using dexamethasone (Dex) inj...

  12. Effect of dexamethasone on fetal hepatic glutamine-glutamate exchange.

    PubMed

    Timmerman, M; Teng, C; Wilkening, R B; Fennessey, P; Battaglia, F C; Meschia, G

    2000-05-01

    Intravenous infusion of dexamethasone (Dex) in the fetal lamb causes a two- to threefold increase in plasma glutamine and other glucogenic amino acids and a decrease of plasma glutamate to approximately one-third of normal. To explore the underlying mechanisms, hepatic amino acid uptake and conversion of L-[1-(13)C]glutamine to L-[1-(13)C]glutamate and (13)CO(2) were measured in six sheep fetuses before and in the last 2 h of a 26-h Dex infusion. Dex decreased hepatic glutamine and alanine uptakes (P < 0.01) and hepatic glutamate output (P < 0.001). Hepatic outputs of the glutamate (R(Glu,Gln)) and CO(2) formed from plasma glutamine decreased to 21 (P < 0.001) and 53% (P = 0.009) of control, respectively. R(Glu,Gln), expressed as a fraction of both outputs, decreased (P < 0.001) from 0.36 +/- 0.02 to 0.18 +/- 0.04. Hepatic glucose output remained virtually zero throughout the experiment. We conclude that Dex decreases fetal hepatic glutamate output by increasing the routing of glutamate carbon into the citric acid cycle and by decreasing the hepatic uptake of glucogenic amino acids. PMID:10780940

  13. Evaluation of spatial memory and locomotor activity during hypercortisolism induced by the administration of dexamethasone in adult male rats.

    PubMed

    Yılmaz, Tevfik; Gedikli, Öznur; Yildirim, Mehmet

    2015-01-21

    In neurosurgery practice glucocorticoids are commonly used. Steroids may have central nervous system side effects affecting whole body, including steroid-induced mental agitation and psychosis. In experimental and clinical studies conducted by using dexamethasone (DEX), it has been reported that DEX adversely affects learning and memory skills. Unfortunately, there are yet no clinically accepted clinical approaches to prevent DEX-induced cognitive dysfunction. In this experimental study it was aimed to investigate the effect of chronic DEX administration on learning-memory and locomotor behaviors in adult male Sprague Dawley rats. In addition, it was also aimed to explore the potential favorable contribution of melatonin (MEL) and vitamin C (Vit C) having antioxidant and neuroprotective properties to the effects of DEX on learning-memory and locomotor behaviors. For this purpose, rats were injected 10mg/kg DEX intraperitoneally, both alone and in combination with MEL (40 mg/kg) and Vit C (100mg/kg), for 9 days, and the animals were tested using the radial arm maze and open field apparatus. The test results revealed that DEX caused a significant decrease in spatial memory and locomotor activities and MEL and Vit C failed to reverse losses in these activities. Furthermore, DEX led to a gradual weight loss that reached 30% of the initial weight at 9th day of the injection. DEX administration causes a generalized loss of behavioral activity of rats. Experimental studies devised to investigate effects of DEX should take into account this DEX-induced generalized behavioral loss when assessing the effects of DEX on learning and memory skills. This article is part of a Special Issue entitled SI: Brain and Memory.

  14. HPAC info-dex 2 -- Locating a product

    SciTech Connect

    Not Available

    1994-06-01

    Products for mechanical systems are listed in more than 1,200 categories, and under each heading are the names of the manufactures supplying that product. Cross references make it easy to find the products you need. The headings are arranged by the governing noun; for example, Butterfly Valves'' will be found under Valves, Butterfly''. Companies shown in boldface type have page number references directing you to their advertised product information in HPAC Info-dex 6, starting on page 112.

  15. Modulation of the epithelial barrier by dexamethasone and prolactin in cultured Madin-Darby canine kidney (MDCK) cells.

    PubMed

    Peixoto, E B M I; Collares-Buzato, C B

    2006-02-01

    Glucocorticoids and prolactin (PRL) have a direct effect on the formation and maintenance of tight junctions (TJs) in cultured endothelial and mammary gland epithelial cells. In this work, we investigated the effect of a synthetic glucocorticoid dexamethasone (DEX) and PRL on the paracellular barrier function in MDCK renal epithelial cells. DEX (4 microM)+PRL (2 microg/ml) and DEX alone increased significantly the transepithelial electrical resistance after chronic treatment (4 days) of confluent MDCK monolayers or after 24 h treatment of subconfluent monolayers. Immunoblotting and immunocytochemistry revealed no changes in the expression and distribution of TJ-associated proteins occludin, ZO-1 and claudin-1 in confluent monolayers after hormone addition. However, a marked increase in junctional content for occludin and ZO-1 with no changes in their total expression was observed in subconfluent MDCK monolayers 24 h exposed to DEX or DEX+PRL. No change in cell proliferation/growth was detected at subconfluent conditions following hormone treatment. An increase in the total number of viable cells was observed only in confluent MDCK monolayers after exposure to DEX+PRL suggesting that the main effect of these hormones on already established barrier may be associated with the inhibition of cell death. In conclusion, our data suggest that these hormones (specially dexamethasone) have an effect on TJ structure and function only during the formation of MDCK epithelial barrier by probably modulating the localization, stability or assembly of TJ proteins to membrane sites of intercellular contact.

  16. Dexamethasone loaded core-shell SF/PEO nanofibers via green electrospinning reduced endothelial cells inflammatory damage.

    PubMed

    Chen, Weiming; Li, Dawei; Ei-Shanshory, Ahmed; El-Newehy, Mohamed; Ei-Hamshary, Hany A; Al-Deyab, Salem S; He, Chuanglong; Mo, Xiumei

    2015-02-01

    Silk fibroin (SF)/PEO nanofibers prepared by green electrospinning is safe, non-toxic and environment friendly, it is a potential drug delivery carrier for tissue engineering. In this study, a core-shell nanofibers named as Dex@SF/PEO were obtained by green electrospinning with SF/PEO as the shell and dexamethasone (Dex) in the core. The nanofiber morphology and core-shell structure were studied by Scanning Electron Microscope (SEM) and Transmission Electron Microscope (TEM). The Dex release behavior from the nanofibers was tested by High Performance liquid (HPLC) method. The protective effect of drug loaded nanofibers mats on Porcine hip artery endothelial cells (PIECs) against LPS-induced inflammatory damage were determined by MTT assay. TEM result showed the distinct core-shell structure of nanofibers. In vitro drug release studies demonstrated that dexamethasone can sustain release over 192 h and core-shell nanofibers showed more slow release of Dex compared with the blending electrospinning nanofibers. Anti-inflammatory activity in vitro showed that released Dex can reduce the PIECs inflammatory damage and apoptosis which induced by lipopolysaccharide (LPS). Dex@SF/PEO nanofibers are safe and non-toxic because of no harmful organic solvents used in the preparation, it is a promising environment friendly drug carrier for tissue engineering.

  17. Acute effects of neonatal dexamethasone treatment on proliferation and astrocyte immunoreactivity in hippocampus and corpus callosum: towards a rescue strategy.

    PubMed

    Claessens, Sanne E F; Belanoff, Joseph K; Kanatsou, Sofia; Lucassen, Paul J; Champagne, Danielle L; de Kloet, E Ronald

    2012-10-30

    Dexamethasone (DEX), a synthetic glucocorticoid, has been used to treat respiratory distress syndrome in prematurely born infants. Despite the important short-term benefit on lung function, there is growing concern about the long-term outcome of this treatment, since follow-up studies of prematurely born infants have shown lasting adverse neurodevelopmental effects. Since the mechanism underlying these neurodevelopmental impairments is largely unknown, the aim of the present study was (i) to investigate the acute effects of neonatal DEX treatment on the developing brain; and (ii) to block specifically the effects of DEX on the brain by central administration of the glucocorticoid receptor (GR) antagonist mifepristone. Long Evans rat pups were injected subcutaneously with tapering doses of DEX or saline (SAL) on postnatal days (pnd) 1, 2 and 3. Separate groups received intracerebroventricular injections with mifepristone prior to DEX treatment. On pnd 4 and 10, pups were sacrificed and brains collected for analysis of cell proliferation (Ki-67) and astrogliosis (GFAP). We report that neonatal DEX treatment reduced hippocampal cell proliferation on pnd 4, an effect that was normalized by pnd 10. Although on pnd 4, GFAP expression was not affected, DEX treatment caused a significant reduction in the number and density of astrocytes in hippocampus and corpus callosum on pnd 10, which was normalized by mifepristone pre-treatment. These acute alterations in the neonate brain might underlie later functional impairments reported in DEX-treated animals and humans and further illustrate the impact of early GR activation on brain development.

  18. Effects of dexamethasone and HA1077 on actin cytoskeleton and β-catenin in cultured human trabecular meshwork cells

    PubMed Central

    Peng, Jie; Feng, Xiao-Yun; Ye, Zi-Meng; Luo, Qian; Cheng, Yi-Lian; Wu, Zheng-Zheng; Lei, Chun-Tao; Gong, Bo

    2016-01-01

    AIM To investigate the effects of dexamethasone (DEX) and 1-(5-isoquinolinesulfonyl)-homopiperazine (HA1077) on actin cytoskeleton and β-catenin in cultured human trabecular meshwork (HTM) cells. METHODS The HTM cells were separated from human eyeball and cultured in vitro. They were divided into control group, DEX (1×10−6 mol/L) group, HA1077 (3×10−5 mol/L) group, and DEX (1×10−6 mol/L) and HA1077 (3×10−5 mol/L) group. Actin cytoskeleton and β-catenin in HTM cells of the four groups were examined by immunofluorescence and Western blot analyses. RESULTS In DEX group, there were reorganization of actin cytoskeleton and formation of cross linked actin networks (CLANs), which were partially reversed in DEX and HA1077 group. DEX treatment also induced an increased expression of β-catenin, which was obviously reduced in DEX and HA1077 group. Meanwhile, the cultured HTM cells in HA1077 group had lower expression of β-catenin than that in the control group. CONCLUSION Our results show that HA1077 can reverse the changes of actin organization and expression of β-catenin induced by DEX in cultured HTM cells, suggesting that HA1077 may play an important role in increasing outflow and reducing intraocular pressure. PMID:27803851

  19. Biomembranes from slaughterhouse blood erythrocytes as prolonged release systems for dexamethasone sodium phosphate.

    PubMed

    Drvenica, Ivana T; Bukara, Katarina M; Ilić, Vesna Lj; Mišić, Danijela M; Vasić, Borislav Z; Gajić, Radoš B; Đorđević, Verica B; Veljović, Đorđe N; Belić, Aleksandar; Bugarski, Branko M

    2016-07-01

    The present study investigated preparation of bovine and porcine erythrocyte membranes from slaughterhouse blood as bio-derived materials for delivery of dexamethasone-sodium phosphate (DexP). The obtained biomembranes, i.e., ghosts were characterized in vitro in terms of morphological properties, loading parameters, and release behavior. For the last two, an UHPLC/-HESI-MS/MS based analytical procedure for absolute drug identification and quantification was developed. The results revealed that loading of DexP into both type of ghosts was directly proportional to the increase of drug concentration in the incubation medium, while incubation at 37°C had statistically significant effect on loaded amount of DexP (P < 0.05). The encapsulation efficiency was about fivefold higher in porcine compared to bovine ghosts. Insight into ghosts' surface morphology by field emission-scanning electron microscopy and atomic force microscopy confirmed that besides inevitable effects of osmosis, DexP inclusion itself had no observable additional effect on the morphology of the ghosts carriers. DexP release profiles were dependent on erythrocyte ghost type and amount of residual hemoglobin. However, sustained DexP release was achieved and shown over 3 days from porcine ghosts and 5 days from bovine erythrocyte ghosts. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1046-1055, 2016. PMID:27254304

  20. Hepatoprotective effects of parsley, basil, and chicory aqueous extracts against dexamethasone-induced in experimental rats

    PubMed Central

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

    2016-01-01

    Aim: The objective of this study is to investigate the hypoglycemic, hypolipidemic, and hepatoprotective effects of the aqueous extract of parsley, basil, and chicory whole plant in normal and dexamethasone (Dex) rats. Materials and Methods: 50 female albino rats were used in this study and divided into 5 groups (for each 10). Group (1) fed basal diet and maintained as negative control group. Group (2) received Dex in a dose of (0.1 mg/kg b. wt.). Groups 3, 4, and 5 were treated with Dex along with three different plant extracts of parsley, basil, and chicory (2 g/kg b. wt.), (400 mg/kg b. wt.), and (100 mg/kg b. wt.), respectively. Results: All these groups were treated given three times per week for 8 consecutive weeks. Dex-induced alterations in the levels of serum glucose, triglyceride, cholesterol, low-density lipoprotein-cholesterol levels and cardiovascular indices and serum alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase activities, liver thiobarbituric acid (TBARS) levels increased, while high-density lipoprotein-cholesterol, total protein, albumin, and liver glutathione (GSH) levels decreased. On the other hand, plant extracts succeeded to modulate these observed abnormalities resulting from Dex as indicated by the reduction of glucose, cholesterol, TBARS, and the pronounced improvement of the investigated biochemical and antioxidant parameters. Conclusions: It was concluded that probably, due to its antioxidant property, parsley, basil, and chicory extracts have hepatoprotective effects in Dex-induced in rats. PMID:27069727

  1. Effects of dexamethasone before and after puberty on the daily corticosterone rhythm.

    PubMed

    Ramaley, J A

    1975-01-01

    Female Sprague-Dawley-derived rats were injected at 25 days of age (prepubertal) or 60 days of age (adult) with 1 mug dexamethasone/100 g b.w. either before the beginning of the daily rise in serum corticosterone (at 10.00 or 12.00 h in adults and 10.00 h in prepubertal rats) or after the daily rise had begun (at 14.00 h in adults, and 12.00 or 14.00 h in perpubertal rats). Blood samples were collected by decapitation at 16.00, 20.00 and 24.00 h on that day and 04.00, 08.00 and 16.00 h the following day. In adults, dexamethasone (DEX) given at 10.00 shifted the corticosterone (B) peak to 04.00. In prepubertal rats, DEX given before the B rise did not shift the subsequent peak and the patterns of B did not diverge from controls. DEX given at 12.00 or 14.00 shifted the peak to 24.00 h. At 08.00 the next day, B was depressed in adults but normal in prepubertal rats. At 16.00 h, both age groups showed depressed B in comparison to controls. Prepubertal rats appear to respond differently to dexamethasone than do adults. PMID:1143619

  2. Dexamethasone retrodialysis attenuates microglial response to implanted probes in vivo.

    PubMed

    Kozai, Takashi D Y; Jaquins-Gerstl, Andrea S; Vazquez, Alberto L; Michael, Adrian C; Cui, X Tracy

    2016-05-01

    Intracortical neural probes enable researchers to measure electrical and chemical signals in the brain. However, penetration injury from probe insertion into living brain tissue leads to an inflammatory tissue response. In turn, microglia are activated, which leads to encapsulation of the probe and release of pro-inflammatory cytokines. This inflammatory tissue response alters the electrical and chemical microenvironment surrounding the implanted probe, which may in turn interfere with signal acquisition. Dexamethasone (Dex), a potent anti-inflammatory steroid, can be used to prevent and diminish tissue disruptions caused by probe implantation. Herein, we report retrodialysis administration of dexamethasone while using in vivo two-photon microscopy to observe real-time microglial reaction to the implanted probe. Microdialysis probes under artificial cerebrospinal fluid (aCSF) perfusion with or without Dex were implanted into the cortex of transgenic mice that express GFP in microglia under the CX3CR1 promoter and imaged for 6 h. Acute morphological changes in microglia were evident around the microdialysis probe. The radius of microglia activation was 177.1 μm with aCSF control compared to 93.0 μm with Dex perfusion. T-stage morphology and microglia directionality indices were also used to quantify the microglial response to implanted probes as a function of distance. Dexamethasone had a profound effect on the microglia morphology and reduced the acute activation of these cells. PMID:26923363

  3. Pharmacogenetic interaction between dexamethasone and Cd36-deficient segment of spontaneously hypertensive rat chromosome 4 affects triacylglycerol and cholesterol distribution into lipoprotein fractions.

    PubMed

    Krupková, Michaela; Sedová, Lucie; Liska, Frantisek; Krenová, Drahomíra; Kren, Vladimír; Seda, Ondrej

    2010-04-16

    Dexamethasone (DEX) is known to induce diabetes and dyslipidemia. We have compared fasting triacylglycerol and cholesterol concentrations across 20 lipoprotein fractions and glucose tolerance in control (standard diet) and DEX-treated 7-month-old males of two rat strains, Brown Norway (BN) and congenic BN.SHR-(Il6-Cd36)/Cub (BN.SHR4). These two inbred strains differ in a defined segment of chromosome 4, originally transferred from the spontaneously hypertensive rat (SHR) including the mutant Cd36 gene, a known target of DEX. Compared to BN, the standard-diet-fed BN.SHR4 showed higher cholesterol and triacylglycerol concentrations across many lipoprotein fractions, particularly in small VLDL and LDL particles. Total cholesterol was decreased by DEX by more than 21% in BN.SHR4 contrasting with the tendency to increase in BN (strain*DEX interaction p = 0.0017). Similar pattern was observed for triacylglycerol concentrations in LDL. The LDL particle size was significantly reduced by DEX in both strains. Also, while control BN and BN.SHR4 displayed comparable glycaemic profiles during oral glucose tolerance test, we observed a markedly blunted DEX induction of glucose intolerance in BN.SHR4 compared to BN. In summary, we report a pharmacogenetic interaction between limited genomic segment with mutated Cd36 gene and dexamethasone-induced glucose intolerance and triacylglycerol and cholesterol redistribution into lipoprotein fractions.

  4. A single dose of dexamethasone encapsulated in polyethylene glycol-coated polylactic acid nanoparticles attenuates cisplatin-induced hearing loss following round window membrane administration.

    PubMed

    Sun, Changling; Wang, Xueling; Zheng, Zhaozhu; Chen, Dongye; Wang, Xiaoqin; Shi, Fuxin; Yu, Dehong; Wu, Hao

    2015-01-01

    This study aimed to investigate the sustained drug release properties and hearing protection effect of polyethylene glycol-coated polylactic acid (PEG-PLA) stealth nanoparticles loaded with dexamethasone (DEX). DEX was fabricated into PEG-PLA nanoparticles using an emulsion and evaporation technique, as previously reported. The DEX-loaded PEG-PLA nanoparticles (DEX-NPs) had a hydrodynamic diameter of 130±4.78 nm, and a zeta potential of -26.13±3.28 mV. The in vitro release of DEX from DEX-NPs lasted 24 days in phosphate buffered saline (pH 7.4), 5 days in artificial perilymph (pH 7.4), and 1 day in rat plasma. Coumarin 6-labeled NPs placed onto the round window membrane (RWM) of guinea pigs penetrated RWM quickly and accumulated to the organs of Corti, stria vascularis, and spiral ganglion cells after 1 hour of administration. The DEX-NPs locally applied onto the RWM of guinea pigs by a single-dose administration continuously released DEX in 48 hours, which was significantly longer than the free DEX that was cleared out within 12 hours after administration at the same dose. Further functional studies showed that locally administrated single-dose DEX-NPs effectively preserved outer hair cells in guinea pigs after cisplatin insult and thus significantly attenuated hearing loss at 4 kHz and 8 kHz frequencies when compared to the control of free DEX formulation. Histological analyses indicated that the administration of DEX-NPs did not induce local inflammatory responses. Therefore, prolonged delivery of DEX by PEG-PLA nanoparticles through local RWM diffusion (administration) significantly protected the hair cells and auditory function in guinea pigs from cisplatin toxicity, as determined at both histological and functional levels, suggesting the potential therapeutic benefits in clinical applications.

  5. 76 FR 21034 - Dex One, et al.; Amended Certification Regarding Eligibility To Apply for Worker Adjustment...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-14

    ...-75,172E). The notice was published in the Federal Register on March 10, 2011 (76 FR 13228). At the... for Worker Adjustment Assistance TA-W-75,172 Dex One, Formerly Known as RH Donnelly and/or Dex Media..., FL TA-W-75,172A Dex One, Formerly Known as RH Donnelly and/or Dex Media LLC, East Division,...

  6. Risk factors for neutropenia with lenalidomide plus dexamethasone therapy for multiple myeloma.

    PubMed

    Mitani, Y; Usami, E; Kimura, M; Nakao, T; Okada, K; Matsuoka, T; Kokuryou, T; Yoshimura, T; Yamakawa, M

    2016-06-01

    Neutropenia may develop as an adverse event in patients with multiple myeloma receiving lenalidomide (LEN) plus dexamethasone (DEX) therapy. In the present study, we examined the risk factors associated with grade 3/4 neutropenia during the first cycle of LEN plus DEX therapy. We observed that hemoglobin level (≤ 8.5 g/dl) was a significant risk factor for grade 3/4 neutropenia during the first cycle of therapy (odds ratio: 19.40; 95% confidence interval: 2.68-141.00; p < 0.01). thus, our findings suggest that determining the hemoglobin level could be useful in the risk management for neutropenia in patients receiving LEN plus DEX therapy. PMID:27455556

  7. Dexamethasone pretreatment attenuates lung and kidney injury in cholestatic rats induced by hepatic ischemia/reperfusion.

    PubMed

    Zhou, Liangyi; Yao, Xiangqing; Chen, Yanling

    2012-02-01

    Hepatic ischemia followed by reperfusion (IR) results in mild to severe organ injury, in which tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) seem to be involved. Thus, we aim to assess the influence of hepatic ischemia/reperfusion injury on remote organs in addition to cholestasis and consider the possible efficacy of steroid pretreatment in reducing the injury. A common bile duct ligation model was done on 24 male Sprague-Dawley rats. After 7 days, the rats were divided randomly into control group, IR group, and dexamethasone (DEX) group. The IR group showed significant increases in serum alanine aminotransferase, aspartate aminotransferase, and creatinine levels compared with the control and DEX groups. By ELISA techniques, higher levels of TNF-α and IL-1β in lung and kidney tissues were measured in the IR group than in the control and DEX groups, these were verified by immunohistochemistry. The lung histology of the IR group rats showed neutrophil infiltration, interstitial edema, and alveolar wall thickening. Kidney histology of the IR group rats showed vacuolization of the proximal tubular epithelial cells and tubular dilatation with granular eosinophilic casts. Better morphological aspects were observed in the DEX-pretreated animals. Minimal lesions were observed in the control. The results suggest that hepatic ischemia/reperfusion injury in cholestatic rats induced lung and kidney injuries. Pretreatment with dexamethasone reduced the IR-induced injury in addition to cholestasis.

  8. P-Selectin Targeted Dexamethasone-Loaded Lipid Nanoemulsions: A Novel Therapy to Reduce Vascular Inflammation

    PubMed Central

    Simion, Viorel; Constantinescu, Cristina Ana; Stan, Daniela; Deleanu, Mariana; Tucureanu, Monica Madalina; Butoi, Elena; Manduteanu, Ileana; Simionescu, Maya

    2016-01-01

    Inflammation is a common process associated with numerous vascular pathologies. We hypothesized that targeting the inflamed endothelium by coupling a peptide with high affinity for P-selectin to the surface of dexamethasone-loaded lipid nanoemulsions will highly increase their specific binding to activated endothelial cells (EC) and reduce the cell activation. We developed and characterized dexamethasone-loaded lipid nanoemulsions directed towards P-selectin (PLN-Dex) and monitored their anti-inflammatory effects in vitro using cultured EC (EA.hy926 cells) and in vivo using a mouse model of acute inflammation [lipopolysaccharides (LPS) intravenously administered in C57BL/6 mice]. We found that PLN-Dex bound specifically to the surface of activated EC are efficiently internalized by EC and reduced the expression of proinflammatory genes, thus preventing the monocyte adhesion and transmigration to/through activated EC. Given intravenously in mice with acute inflammation, PLN-Dex accumulated at a significant high level in the lungs (compared to nontargeted nanoemulsions) and significantly reduced mRNA expression level of key proinflammatory cytokines such as IL-1β, IL-6, and MCP-1. In conclusion, the newly developed nanoformulation, PLN-Dex, is functional in vitro and in vivo, reducing selectively the endothelium activation and the consequent monocyte infiltration and diminishing significantly the lungs' inflammation, in a mouse model of acute inflammation. PMID:27703301

  9. Dexamethasone-loaded reconstitutable charged polymeric (PLGA)n -b-bPEI micelles for enhanced nuclear delivery of gene therapeutics.

    PubMed

    Mishra, Deepa; Kang, Han Chang; Cho, Hana; Bae, You Han

    2014-06-01

    This study investigates the potential of dexamethasone (Dex) to enhance the nuclear accumulation and subsequent gene expression of plasmid DNA (pDNA) delivered using a charged polymeric micelle-based gene delivery system. (PLGA)n -b-bPEI25kDa block copolymers are synthesized and used to prepare Dex-loaded cationic micelles (DexCM). After preparing DexCM/pDNA complexes, bPEI1.8kDa is coated on the complexes using a Layer-by-Layer (LbL) technique to construct DexCM/pDNA/bPEI1.8kDa complexes (i.e., LbL-DexCM polyplexes) that are 100-180 nm in diameter and have a zeta potential of 30-40 mV. In MCF7 cells, LbL-DexCM polyplexes cause 3-13-fold higher transfection efficiencies compared to LbL-CM polyplexes and show negligible cytotoxicity. LbL-DexCM3 polyplexes induce much higher nuclear delivery of pDNA compared to LbL-CM3 polyplexes. These results suggest that Dex-loaded polyplexes could be used in gene and drug delivery applications to increase nuclear accumulation of therapeutic payloads, further leading to a decrease in the dose of the drug and gene necessary to achieve equivalent therapeutic effects.

  10. Panobinostat plus bortezomib and dexamethasone in previously treated multiple myeloma: outcomes by prior treatment.

    PubMed

    Richardson, Paul G; Hungria, Vânia T M; Yoon, Sung-Soo; Beksac, Meral; Dimopoulos, Meletios Athanasios; Elghandour, Ashraf; Jedrzejczak, Wieslaw W; Guenther, Andreas; Nakorn, Thanyaphong Na; Siritanaratkul, Noppadol; Schlossman, Robert L; Hou, Jian; Moreau, Philippe; Lonial, Sagar; Lee, Jae Hoon; Einsele, Hermann; Sopala, Monika; Bengoudifa, Bourras-Rezki; Corrado, Claudia; Binlich, Florence; San-Miguel, Jesús F

    2016-02-11

    Panobinostat is a potent pan-deacetylase inhibitor that affects the growth and survival of multiple myeloma (MM) cells through alteration of epigenetic mechanisms and protein metabolism. Panobinostat plus bortezomib and dexamethasone (PAN-BTZ-Dex) led to a significant increase in progression-free survival (PFS) vs placebo plus bortezomib and dexamethasone (Pbo-BTZ-Dex) in patients with relapsed or relapsed and refractory MM in the phase 3 PANORAMA 1 trial. This subgroup analysis evaluated outcomes in patients in the PANORAMA 1 trial based on prior treatment: a prior immunomodulatory drug (IMiD; n = 485), prior bortezomib plus an IMiD (n = 193), and ≥2 prior regimens including bortezomib and an IMiD (n = 147). Median PFS with PAN-BTZ-Dex vs Pbo-BTZ-Dex across subgroups was as follows: prior IMiD (12.3 vs 7.4 months; hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.43-0.68), prior bortezomib plus IMiD (10.6 vs 5.8 months; HR, 0.52; 95% CI, 0.36-0.76), and ≥2 prior regimens including bortezomib and an IMiD (12.5 vs 4.7 months; HR, 0.47; 95% CI, 0.31-0.72). Common grade 3/4 adverse events and laboratory abnormalities in patients who received PAN-BTZ-Dex across the prior treatment groups included thrombocytopenia, lymphopenia, neutropenia, diarrhea, and asthenia/fatigue. Incidence of on-treatment deaths among patients who received prior bortezomib and an IMiD (regardless of number of prior regimens) was similar between treatment arms. This analysis demonstrated a clear PFS benefit of 7.8 months with PAN-BTZ-Dex among patients who received ≥2 prior regimens including bortezomib and an IMiD, a population with limited treatment options and poorer prognosis. This trial was registered at www.clinicaltrials.gov as #NCT01023308.

  11. Salvage therapy with bortezomib and dexamethasone in elderly patients with relapsed/refractory multiple myeloma.

    PubMed

    Castelli, Roberto; Pantaleo, Giuseppe; Gallipoli, Paolo; Gidaro, Antonio; Arquati, Massimo; Wu, Maddalena A; Lambertenghi Deliliers, Giorgio

    2015-11-01

    Bortezomib-dexamethasone (bort-dex) is effective for relapsed/refractory (R/R) multiple myeloma, but few data are available for elderly patients. The aim of this study was to evaluate efficacy and toxicity of bort-dex in elderly R/R MM patients. We evaluated 81 R/R MM patients treated with bort-dex. Eight of them had light-chain disease. The median age of the patients was 73 years (range 65-89 years). All patients were R/R MM patients and had been treated with melphalan and prednisone with or without thalidomide or bortezomib in the first line or with lenalidomide and dexamethasone in the second line. The median number of previous lines was 2. Thirty-nine (48%) patients received bortezomib intravenously and 42 (52%) patients received bortezomib subcutaneously. The median number of bort-dex cycles was 6 (range 1-11). Fifty-three (65.4%) patients achieved at least a partial response, including eight (11%) patients with complete response and nine (12.5%) patients with very good partial responses. The median duration of response, time to next therapy and treatment-free intervals were 8, 11 and 5 months. Duration of response was significantly longer for patients achieving complete response/very good partial response than for those achieving partial response (7.3 vs. 3.8 months, P=0.03). After a median follow-up of 24 months, 78 patients showed disease progression and 70 died. The median time to progression, progression-free survival and overall survival were 8.9, 8.7 and 22 months, respectively. Peripheral neuropathy occurred in 38 (47%) patients. Our data highlight that bort-dex is effective and tolerable in fit elderly patients, thus justifying the efforts for deeper responses. However, awareness of short-lived responses to bort-dex should lead to a thorough evaluation of the need for maintenance.

  12. Covalent incorporation and controlled release of active dexamethasone from injectable polyethylene glycol hydrogels.

    PubMed

    Bezuidenhout, Deon; Oosthuysen, Anel; Davies, Neil; Ahrenstedt, Lage; Dobner, Stephan; Roberts, Peter; Zilla, Peter

    2013-05-01

    Dexamethasone (Dex) is used in a wide range of applications, but may have undesirable systemic side effects. A number of techniques have thus been developed to deliver the substance locally. In this study, dexamethasone was acrylated, pegylated, and tethered to hydrolytically degradable (acrylate based) and nondegradable (vinyl sulfone based) polyethylene glycol hydrogels by nucleophilic addition. Hydrogel swelling, drug elution and drug activity were followed over an extended period in vitro. Nondegradable gels were stable for more than a year, while degradable gels showed increasing swelling ratios due to degradation that resulted in disintegration after ~12 days. Near-linear (zero order) release could be achieved in some cases with the degradable gels, while release from the nondegradable gels approximated first order initial release kinetics. Significantly delayed release was observed in all cases where the Dex was linked to the gels, when compared with controls where the drug was merely physically incorporated. Eluates from the gels containing the tethered drug showed high levels of activity for extended time periods, while the activity of the eluates from gels containing nonbound dexamethasone decreased rapidly within the first few days. Dexamethasone can thus be incorporated using nucleophilic addition chemistry to produce gels that are capable of sustained release of the active drug. The methodology is applicable to a variety of drugs that contain hydroxyl groups.

  13. Protective Effects of Clenbuterol against Dexamethasone-Induced Masseter Muscle Atrophy and Myosin Heavy Chain Transition

    PubMed Central

    Umeki, Daisuke; Ohnuki, Yoshiki; Mototani, Yasumasa; Shiozawa, Kouichi; Suita, Kenji; Fujita, Takayuki; Nakamura, Yoshiki; Saeki, Yasutake; Okumura, Satoshi

    2015-01-01

    Background Glucocorticoid has a direct catabolic effect on skeletal muscle, leading to muscle atrophy, but no effective pharmacotherapy is available. We reported that clenbuterol (CB) induced masseter muscle hypertrophy and slow-to-fast myosin heavy chain (MHC) isoform transition through direct muscle β2-adrenergic receptor stimulation. Thus, we hypothesized that CB would antagonize glucocorticoid (dexamethasone; DEX)-induced muscle atrophy and fast-to-slow MHC isoform transition. Methodology We examined the effect of CB on DEX-induced masseter muscle atrophy by measuring masseter muscle weight, fiber diameter, cross-sectional area, and myosin heavy chain (MHC) composition. To elucidate the mechanisms involved, we used immunoblotting to study the effects of CB on muscle hypertrophic signaling (insulin growth factor 1 (IGF1) expression, Akt/mammalian target of rapamycin (mTOR) pathway, and calcineurin pathway) and atrophic signaling (Akt/Forkhead box-O (FOXO) pathway and myostatin expression) in masseter muscle of rats treated with DEX and/or CB. Results and Conclusion Masseter muscle weight in the DEX-treated group was significantly lower than that in the Control group, as expected, but co-treatment with CB suppressed the DEX-induced masseter muscle atrophy, concomitantly with inhibition of fast-to-slow MHC isoforms transition. Activation of the Akt/mTOR pathway in masseter muscle of the DEX-treated group was significantly inhibited compared to that of the Control group, and CB suppressed this inhibition. DEX also suppressed expression of IGF1 (positive regulator of muscle growth), and CB attenuated this inhibition. Myostatin protein expression was unchanged. CB had no effect on activation of the Akt/FOXO pathway. These results indicate that CB antagonizes DEX-induced muscle atrophy and fast-to-slow MHC isoform transition via modulation of Akt/mTOR activity and IGF1 expression. CB might be a useful pharmacological agent for treatment of glucocorticoid

  14. Metabolic hormones regulate basal and growth hormone-dependent igf2 mRNA level in primary cultured coho salmon hepatocytes: effects of insulin, glucagon, dexamethasone, and triiodothyronine.

    PubMed

    Pierce, A L; Dickey, J T; Felli, L; Swanson, P; Dickhoff, W W

    2010-03-01

    Igf1 and Igf2 stimulate growth and development of vertebrates. Circulating Igfs are produced by the liver. In mammals, Igf1 mediates the postnatal growth-promoting effects of growth hormone (Gh), whereas Igf2 stimulates fetal and placental growth. Hepatic Igf2 production is not regulated by Gh in mammals. Little is known about the regulation of hepatic Igf2 production in nonmammalian vertebrates. We examined the regulation of igf2 mRNA level by metabolic hormones in primary cultured coho salmon hepatocytes. Gh, insulin, the glucocorticoid agonist dexamethasone (Dex), and glucagon increased igf2 mRNA levels, whereas triiodothyronine (T(3)) decreased igf2 mRNA levels. Gh stimulated igf2 mRNA at physiological concentrations (0.25x10(-9) M and above). Insulin strongly enhanced Gh stimulation of igf2 at low physiological concentrations (10(-11) M and above), and increased basal igf2 (10(-8) M and above). Dex stimulated basal igf2 at concentrations comparable to those of stressed circulating cortisol (10(-8) M and above). Glucagon stimulated basal and Gh-stimulated igf2 at supraphysiological concentrations (10(-7) M and above), whereas T(3) suppressed basal and Gh-stimulated igf2 at the single concentration tested (10(-7) M). These results show that igf2 mRNA level is highly regulated in salmon hepatocytes, suggesting that liver-derived Igf2 plays a significant role in salmon growth physiology. The synergistic regulation of igf2 by insulin and Gh in salmon hepatocytes is similar to the regulation of hepatic Igf1 production in mammals.

  15. Anhedonia, suicide ideation and dexamethasone nonsuppression in depressed patients.

    PubMed

    Oei, T I; Verhoeven, W M; Westenberg, H G; Zwart, F M; van Ree, J M

    1990-01-01

    In the search for a valid analysis of a number of operationalised symptoms common to depressive behaviour, a study was performed comprising 46 patients showing depressive symptoms, according to operationalised criteria and as part of which all agreed to undergo the following tests: (a) psychiatric: Present State Examination; (b) psychological: Hamilton Rating Scale, Montgomery-Asberg Rating Scale, State-Trait Anxiety Inventory, Beck Suicide Ideation Scale, Chapman Anhedonia Scale, Mood Scale, Sleep Quality Scale, Activities Scale, Social Support Scale, Questionnaire on Recently Experienced Events and the Paykel Life Events Interview; and (c) biochemical: Dexamethasone Suppression (DEX) Test. After gathering different depressive subgroups, based on operationalised symptoms, a dichotomy was made in the distributions of the (an)hedonia, suicide ideation and DEX-(non) suppression scores. This study may indicate that anhedonia, suicide ideation and DEX-nonsuppression are the opening to the identification of a subgroup of depressed patients. This symptom complex could not definitely be identified on the basis of existing DSM-III diagnostic entities, because of the known fact that this method of classification is not appropriate for our purposes in revealing pathophysiological processes. It is suggested, therefore, that these symptoms might prove to be the anchor-point from which to reach a better insight into the aetiology and pathogenesis (i.e. the final common pathway) of depression.

  16. Dexamethasone suppresses the growth of human non-small cell lung cancer via inducing estrogen sulfotransferase and inactivating estrogen

    PubMed Central

    Wang, Li-jie; Li, Jian; Hao, Fang-ran; Yuan, Yin; Li, Jing-yun; Lu, Wei; Zhou, Tian-yan

    2016-01-01

    Aim: Dexamethasone (DEX) is a widely used synthetic glucocorticoid, which has shown anti-cancer efficacy and anti-estrogenic activity. In this study we explored the possibility that DEX might be used as an endocrine therapeutic agent to treat human non-small cell lung cancer (NSCLC). Methods: The viability and proliferation of human NSCLC cell lines A549 and H1299 were assessed in vitro. Anti-tumor action was also evaluated in A549 xenograft nude mice treated with DEX (2 or 4 mg·kg−1·d−1, ig) or the positive control tamoxifen (50 mg·kg−1·d−1, ig) for 32 d. The expression of estrogen sulfotransferase (EST) in tumor cells and tissues was examined. The intratumoral estrogen levels and uterine estrogen responses were measured. Results: DEX displayed mild cytotoxicity to the NSCLC cells (IC50 >500 μmol/L) compared to tamoxifen (IC50 <50 μmol/L), but it was able to inhibit the cell proliferation at low micromolar ranges. Furthermore, DEX (0.1–10 μmol/L) dose-dependently up-regulated EST expression in the cells, and inhibited the cell migration in vitro. Triclosan, a sulfation inhibitor, was able to diminish DEX-caused inhibition on the cell viability. In A549 xenograft nude mice, DEX or tamoxifen administration remarkably suppressed the tumor growth. Moreover, DEX administration dose-dependently increased EST expression in tumor tissues, and reduced intratumoral estrogen levels as well as the volumes and weights of uterine. Conclusion: DEX suppresses the growth of A549 xenograft tumors via inducing EST and decreasing estradiol levels in tumor tissues, suggesting that DEX may be used as anti-estrogenic agent for the treatment of NSCLC. PMID:27133297

  17. Electrospinning of Bioactive Dex-PAA Hydrogel Fibers

    NASA Astrophysics Data System (ADS)

    Louie, Katherine Boyook

    In this work, a novel method is developed for making nano- and micro-fibrous hydrogels capable of preventing the rejection of implanted materials. This is achieved by either (1) mimicking the native cellular environment, to exert fine control over the cellular response or (2) acting as a protective barrier, to camouflage the foreign nature of a material and evade recognition by the immune system. Comprehensive characterization and in vitro studies described here provide a foundation for developing substrates for use in clinical applications. Hydrogel dextran and poly(acrylic acid) (PAA) fibers are formed via electrospinning, in sizes ranging from nanometers to microns in diameter. While "as-electrospun" fibers are continuous in length, sonication is used to fragment fibers into short fiber "bristles" and generate nano- and micro- fibrous surface coatings over a wide range of topographies. Dex-PAA fibrous surfaces are chemically modified, and then optimized and characterized for non-fouling and ECM-mimetic properties. The non-fouling nature of fibers is verified, and cell culture studies show differential responses dependent upon chemical, topographical and mechanical properties. Dex-PAA fibers are advantageously unique in that (1) a fine degree of control is possible over three significant parameters critical for modifying cellular response: topography, chemistry and mechanical properties, over a range emulating that of native cellular environments, (2) the innate nature of the material is non-fouling, providing an inert background for adding back specific bioactive functionality, and (3) the fibers can be applied as a surface coating or comprise the scaffold itself. This is the first reported work of dex-PAA hydrogel fibers formed via electrospinning and thermal cross-linking, and unique to this method, no toxic solvents or cross-linking agents are needed to create hydrogels or for surface attachment. This is also the first reported work of using sonication to

  18. Postnatal High-Fat Diet Increases Liver Steatosis and Apoptosis Threatened by Prenatal Dexamethasone through the Oxidative Effect

    PubMed Central

    Huang, Ying-Hsien; Chen, Chih-Jen; Tang, Kuo-Shu; Sheen, Jiunn-Ming; Tiao, Mao-Meng; Tain, You-Lin; Chen, Chih-Cheng; Chu, En-Wei; Li, Shih-Wen; Yu, Hong-Ren; Huang, Li-Tung

    2016-01-01

    The objective of this study was to investigate cellular apoptosis in prenatal glucocorticoid overexposure and a postnatal high fat diet in rats. Pregnant Sprague-Dawley rats at gestational days 14 to 21 were administered saline (vehicle) or dexamethasone and weaned onto either a normal fat diet or a high fat diet for 180 days; in total four experimental groups were designated, i.e., vehicle treated group (VEH), dexamethasone treated group (DEX), vehicle treated plus high-fat diet (VHF), and dexamethasone treated plus high-fat diet (DHF). Chronic effects of prenatal liver programming were assessed at postnatal day 180. The apoptotic pathways involved proteins were analyzed by Western blotting for their expressions. Apoptosis and liver steatosis were also examined by histology. We found that liver steatosis and apoptosis were increased in the DHF, DEX, and VHF treated groups, and that the DHF treated group was increased at higher levels than the DEX and VHF treated groups. The expression of leptin was decreased more in the DHF treated group than in the DEX and VHF treated groups. Decreased peroxisome proliferator-activated receptor-gamma coactivator 1α, phosphoinositide-3-kinase, manganese superoxide dismutase and increased malondialdehyde expression levels were seen in DHF treated group relative to the DEX treated group. The DHF treated group exhibited higher levels of oxidative stress, apoptosis and liver steatosis than the DEX treated group. These results indicate that the environment of high-fat diet plays an important role in the development of liver injury after prenatal stress. PMID:26978357

  19. Long-term dexamethasone treatment alters the histomorphology of acinar cells in rat parotid and submandibular glands.

    PubMed

    Bighetti, Bruna B; d Assis, Gerson F; Vieira, Danilo C; Violato, Natalia M; Cestari, Tania M; Taga, Rumio; Bosqueiro, José R; Rafacho, Alex

    2014-10-01

    Glucocorticoids (GCs) induce insulin resistance (IR), a condition known to alter oral homeostasis. This study investigated the effects of long-term dexamethasone administration on morphofunctional aspects of salivary glands. Male Wistar rats received daily injections of dexamethasone [0.1 mg/kg body weight (b.w.), intraperitoneally] for 10 days (DEX), whereas control rats received saline. Subsequently, glycaemia, insulinaemia, insulin secretion and salivary flow were analysed. The parotid and submandibular glands were collected for histomorphometric evaluation and Western blot experiments. The DEX rats were found to be normoglycaemic, hyperinsulinaemic, insulin resistant and glucose intolerant (P < 0.05). DEX rat islets secreted more insulin in response to glucose (P < 0.05). DEX rats had significant reductions in the masses of the parotid (29%) and submandibular (16%) glands (P < 0.05) that was associated with reduced salivary flux rate. The hypotrophy in both glands observed in the DEX group was associated with marked reduction in the volume of the acinar cells in these glands of 50% and 26% respectively (P < 0.05). The total number of acinar cells was increased in the submandibular glands of the DEX rats (P < 0.05) but not in the parotid glands. The levels of proteins related to insulin and survival signalling in both glands did not differ between the groups. In conclusion, the long-term administration of dexamethasone caused IR, which was associated with significant reductions in both mass and flux rate of the salivary glands. The parotid and submandibular glands exhibited reduced acinar cell volume; however, the submandibular glands displayed acinar hyperplasia, indicating a gland-specific response to GCs. Our data emphasize that GC-based therapies and insulin-resistant states have a negative impact on salivary gland homeostasis.

  20. Long-term dexamethasone treatment alters the histomorphology of acinar cells in rat parotid and submandibular glands

    PubMed Central

    Bighetti, Bruna B; Assis, Gerson F d; Vieira, Danilo C; Violato, Natalia M; Cestari, Tania M; Taga, Rumio; Bosqueiro, José R; Rafacho, Alex

    2014-01-01

    Glucocorticoids (GCs) induce insulin resistance (IR), a condition known to alter oral homeostasis. This study investigated the effects of long-term dexamethasone administration on morphofunctional aspects of salivary glands. Male Wistar rats received daily injections of dexamethasone [0.1 mg/kg body weight (b.w.), intraperitoneally] for 10 days (DEX), whereas control rats received saline. Subsequently, glycaemia, insulinaemia, insulin secretion and salivary flow were analysed. The parotid and submandibular glands were collected for histomorphometric evaluation and Western blot experiments. The DEX rats were found to be normoglycaemic, hyperinsulinaemic, insulin resistant and glucose intolerant (P < 0.05). DEX rat islets secreted more insulin in response to glucose (P < 0.05). DEX rats had significant reductions in the masses of the parotid (29%) and submandibular (16%) glands (P < 0.05) that was associated with reduced salivary flux rate. The hypotrophy in both glands observed in the DEX group was associated with marked reduction in the volume of the acinar cells in these glands of 50% and 26% respectively (P < 0.05). The total number of acinar cells was increased in the submandibular glands of the DEX rats (P < 0.05) but not in the parotid glands. The levels of proteins related to insulin and survival signalling in both glands did not differ between the groups. In conclusion, the long-term administration of dexamethasone caused IR, which was associated with significant reductions in both mass and flux rate of the salivary glands. The parotid and submandibular glands exhibited reduced acinar cell volume; however, the submandibular glands displayed acinar hyperplasia, indicating a gland-specific response to GCs. Our data emphasize that GC-based therapies and insulin-resistant states have a negative impact on salivary gland homeostasis. PMID:25186305

  1. The role of adjunctive dexamethasone in the treatment of bacterial meningitis: an updated systematic meta-analysis

    PubMed Central

    Shao, Mei; Xu, Peng; Liu, Jun; Liu, Wenyun; Wu, Xiujie

    2016-01-01

    Background Bacterial meningitis is a serious infection in children and adults worldwide, with considerable morbidity, mortality, and severe neurological sequelae. Dexamethasone is often used before antibiotics in cases of this disease, and improves outcomes. Objective Although several studies have identified the role of adjunctive dexamethasone therapy in the treatment of bacterial meningitis, the results are still inconclusive. The aim of this study was to systematically evaluate the therapeutic and adverse effect of adjunctive dexa-methasone in patients with bacterial meningitis. Materials and methods Relevant randomized, double-blind, placebo-controlled trials of dexamethasone in bacterial meningitis published between 2000 and 2016 were retrieved from the common electronic databases. The odds ratio (OR) and risk ratio (RR) with their 95% confidence interval (CI) were employed to calculate the effect. Results A total of ten articles including 2,459 bacterial meningitis patients (1,245 in the dex-amethasone group and 1,214 in the placebo group) were included in this meta-analysis. Our result found that dexamethasone was not associated with a significant reduction in follow-up mortality (292 of 1,245 on dexamethasone versus 314 of 1,214 on placebo; OR =0.91, 95% CI =0.80–1.03, P=0.14) and severe neurological sequelae (22.4% versus 24.1%, OR =0.84, 95% CI =0.54–1.29, P=0.42). However, dexamethasone seemed to reduce hearing loss among survivors (21.2% versus 26.1%; OR =0.76, 95% CI =0.59–0.98, P=0.03). No significant difference was found between these two groups in adverse events. Conclusion Our results suggested that adjunctive dexamethasone might not be beneficial in the treatment of bacterial meningitis. Future studies with more data are needed to further prove the role of dexamethasone in bacterial meningitis. PMID:27478366

  2. Dexamethasone inhibits corticosterone deposition in feathers of greenfinches.

    PubMed

    Hõrak, Peeter; Männiste, Marju; Meitern, Richard; Sild, Elin; Saks, Lauri; Sepp, Tuul

    2013-09-15

    Corticosterone (CORT) content of feathers is a potent source of information about activation of hypothalamus-pituitary-adrenal (HPA) axis during feather growth, which is used for assessment of well-being and stress history of individuals and populations in avian studies. However, little is known about factors affecting deposition of CORT into feathers and how feather CORT covaries with other markers of stress imposed upon individuals during feather growth. We addressed these questions by measuring CORT levels in feathers of wild-caught greenfinches (Carduelis chloris) brought into captivity. One tail feather was removed from all the birds upon arrival to the laboratory and the CORT levels of replacement feathers, grown in captivity were recorded. The birds were subjected to treatments of immune activation (by injection of phytohaemagglutinin) and synthetic glucocorticoid (dexamethasone, DEX) administration. Only DEX injection affected feather CORT levels. DEX-injected birds deposited on average 37% less of CORT in their feathers than saline-injected birds. Despite significant effects of DEX and immune activation treatments on differential leukocyte counts, we did not find any correlations between CORT and leukocyte hemoconcentrations or heterophil/lymphocyte ratios (a haematological index of stress), measured at three stages of feather growth. Our findings provide novel evidence that feather CORT levels are sensitive to manipulation of hormonal balance of birds, thereby supporting the diagnostic value of feather CORT measurements. However, we did not find any evidence about covariation between feather CORT and other markers of stress perceived during the period of feather growth. This calls for further research on information content of feather CORT, preferably in experiments manipulating more diverse array of psychological, immunological and abiotic stressors.

  3. Pregnancy outcomes following the administration of high doses of dexamethasone in early pregnancy

    PubMed Central

    Kayvan Jafari, Sabah; Nezafat Firizi, Maryam; Abbaspour, Ali Reza; Ghafoori Gharib, Fahime; Ghobadi, Yusef; Gholizadeh, Samira

    2016-01-01

    Objective In the present study, we aimed to evaluate the effects of high doses of dexamethasone (DEX) in early pregnancy on pregnancy outcomes. Methods Pregnant BALB/c mice were treated with high-dose DEX in the experimental group or saline in the control group on gestational days (GDs) 0.5 to 4.5. Pregnant mice were sacrificed on GDs 7.5, 13.5, or 18.5 and their peripheral blood, placentas, fetuses, and uterine tissue were collected. Decidual and placenta cell supernatants were examined to evaluate the effect of DEX on the proliferation of mononuclear cells, the quantity of uterine macrophages and uterine natural killer (uNK) cells, and levels of progesterone and 17β-estradiol, as determined by an 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide assay, immunohistochemistry, and enzyme-linked immunosorbent assay, respectively. We also were measured fetal and placental growth parameters on GD 18.5. Results We found that high doses of DEX were associated with an increased abortion rate, enhancement of the immunosuppressive effect of the decidua, alterations in placental growth parameters, decreased progesterone and 17β-estradiol levels, and a reduced frequency of macrophages and uNK cells. Conclusion Our data suggest that the high-dose administration of DEX during early pregnancy negatively affected pregnancy outcomes. PMID:27104153

  4. Characterization of Porous, Dexamethasone-Releasing Polyurethane Coatings for Glucose Sensors

    PubMed Central

    Vallejo-Heligon, Suzana G.; Klitzman, Bruce; Reichert, William M.

    2014-01-01

    Commercially available implantable needle-type glucose sensors for diabetes management are robust analytically but can be unreliable clinically primarily due to tissue-sensor interactions. Here, we present the physical, drug release, and bioactivity characterization of tubular, porous dexamethasone (Dex) releasing polyurethane coatings designed to attenuate local inflammation in the tissue-sensor interface. Porous polyurethane coatings were produced by the salt-leaching/gas-foaming method. Scanning electron microscopy (SEM) and Micro-computed tomography (Micro-CT) showed a controlled porosity and coating thickness. In vitro drug release from coatings monitored over two weeks presented an initial fast release followed by a slower release. Total release from coatings was highly dependent on initial drug loading amount. Functional in vitro testing of glucose sensors deployed with porous coatings against glucose standards demonstrated that highly porous coatings minimally affected signal strength and response rate. Bioactivity of the released drug was determined by monitoring Dex-mediated, dose-dependent apoptosis of human peripheral blood derived monocytes in culture. Acute animal studies were used to determine the appropriate Dex payload for the implanted porous coatings. Pilot short-term animal studies showed that Dex released from porous coatings implanted in rat subcutis attenuated the initial inflammatory response to sensor implantation. These results suggest that deploying sensors with the porous, Dex-releasing coatings is a promising strategy to improve glucose sensor performance. PMID:25065548

  5. Evaluation of behavioral problems after prenatal dexamethasone treatment in Swedish adolescents at risk of CAH.

    PubMed

    Wallensteen, Lena; Zimmermann, Marius; Sandberg, Malin Thomsen; Gezelius, Anton; Nordenström, Anna; Hirvikoski, Tatja; Lajic, Svetlana

    2016-09-01

    Prenatal dexamethasone (DEX) treatment in congenital adrenal hyperplasia (CAH) is effective in reducing virilization in affected girls, but other lasting effects are largely unknown. Here, we explore potential side effects of the treatment that will eventually help to make risk benefit analyses of the treatment. Therefore, we investigated the long-term effects of such prenatal DEX treatment on behavioral problems and temperament in children aged 7-17years. Standardized parent-completed questionnaires were used to evaluate adaptive functioning, behavioral and emotional problems (using CBCL), social anxiety (SPAI-C-P), and temperament (EAS). Self-reports were used to assess the children's own perception of social anxiety (SASC-R). The study compared 34 DEX-treated children and adolescents who were treated during the first trimester of fetal life and do not have CAH with 66 untreated controls from the Swedish population. No statistically significant differences were found between groups, suggesting that healthy children who were treated with DEX during early fetal life seem to be well adjusted without major behavioral or emotional problems as assessed by their parents. Moreover, self-reported social anxiety was not increased in DEX-exposed children and adolescents. In fact, the control group scored higher on items assessing anxiety in new, social situations. Nevertheless, for some of these comparisons, non-significant moderate to large effect sizes were observed, implying that the null findings should be interpreted with caution and require studies on larger, internationally combined cohorts. PMID:27373757

  6. Effect of vitamin B12 on cleft palate induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin and dexamethasone in mice.

    PubMed

    Zhao, Shu-Fan; Chai, Mao-Zhou; Wu, Min; He, Yong-Hong; Meng, Tian; Shi, Bing

    2014-03-01

    The purpose of this study was to investigate the effect of vitamin B12 on palatal development by co-administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and dexamethasone (DEX). We examined the morphological and histological features of the palatal shelf and expression levels of key signaling molecules (transforming growth factor-β3 (TGF-β3) and TGF-β type I receptor (activin receptor-like kinase 5, ALK5)) during palatogenesis among a control group (Group A), TCDD+DEX exposed group (Group B), and TCDD+DEX+vitamin B12 exposed group (Group C). While we failed to find that vitamin B12 decreased the incidence of cleft palate induced by TCDD+DEX treatment, the expression levels of key signaling molecules (TGF-β3 and ALK5) during palatogenesis were significantly modulated. In TCDD+DEX exposed and TCDD+DEX+vitamin B12 exposed groups, palatal shelves could not contact in the midline due to their small sizes. Our results suggest that vitamin B12 may inhibit the expression of some cleft palate inducers such as TGF-β3 and ALK5 in DEX+TCDD exposed mice, which may be beneficial against palatogenesis to some degree, even though we were unable to observe a protective role of vitamin B12 in morphological and histological alterations of palatal shelves induced by DEX and TCDD.

  7. Retinoic acid and dexamethasone affect RAR-beta and surfactant protein C mRNA in the MLE lung cell line.

    PubMed

    Grummer, M A; Zachman, R D

    1998-01-01

    Lung development and surfactant biosynthesis are affected by retinoic acid (RA) and dexamethasone (Dex). Using a mouse lung epithelial cell line, we are exploring RA-Dex interactions through the study of RA and Dex effects on RA receptor (RAR) and surfactant protein (SP) C mRNA expression. RA increased expression of RAR-beta (5.5 times) and SP-C (2 times) mRNA, with maximal effects at 24 h and at 10(-6) M. The RA induction was not inhibited by cycloheximide, suggesting RA affects transcription. With added actinomycin D, RA did not affect the disappearance rate of RAR-beta mRNA, but SP-C mRNA degradation was slowed, indicating an effect on SP-C mRNA stability. Dex decreased RAR-beta and SP-C expression to 75 and 70% of control values, respectively, with greatest effects at 48 h and at 10(-7) M. There was no effect of Dex on either RAR-beta or SP-C mRNA disappearance with actinomycin D. However, cycloheximide prevented the effect of Dex. Despite Dex, RA increased both RAR-beta and SP-C mRNA. This work suggests that RA and Dex affect RAR-beta and SP-C genes by different mechanisms. PMID:9458794

  8. Prenatal exposure to dexamethasone alters Leydig cell steroidogenic capacity in immature and adult rats.

    PubMed

    Page, K C; Sottas, C M; Hardy, M P

    2001-01-01

    This study examines the effects of prenatal exposure to dexamethasone (DEX) on postnatal testosterone production in male rats. Pregnant female rats were treated on gestation days 14-19 with DEX (100 microg/kg body weight per day; n = 9) or vehicle (n = 9). Results show that 35-day-old male offspring from DEX-treated pregnant females (n = 42) had decreased levels of serum testosterone (45.6% lower, P < .05) compared with control offspring (n = 43), although serum luteinizing hormone (LH) levels were not significantly altered. These findings suggest that a direct programming of developing gonadal cells occurs in response to high levels of maternal glucocorticoid. Indeed, testosterone production was significantly reduced in Leydig cells isolated from immature offspring of DEX-treated pregnant females compared with controls (48.3%, P < .001), and LH stimulation of these cells did not compensate for the lowered steroidogenic capacity. The hypothalamic-pituitary-adrenal axis was also affected, because significant reductions in both serum adrenocorticotropic hormone (ACTH; 26.2%, P < .001) and corticosterone (CORT; 32.3%, P < .001) were measured in DEX-exposed immature male offspring. In contrast, adult male offspring from DEX-treated dams had significantly higher levels of serum ACTH (39.2%, P <. 001) and CORT (37.8%, P < .001). These same animals had higher serum testosterone (31.6%, P < or = .05) and a significant reduction in serum LH (30.8%, P < .001). Moreover, Leydig cells isolated from these adult offspring exhibited an increased capacity for testosterone biosynthesis under basal (38.6%, P < .001) and LH-stimulated conditions (33.5%, P < .001). In summary, sustained changes in steroidogenic capacity were observed in male rats exposed to high levels of glucocorticoid during prenatal development. More specifically, DEX exposure in utero perturbed Leydig cell testosterone production in both pubertal and adult rats.

  9. Long-lasting effects of dexamethasone on immune cells and wound healing in the zebrafish.

    PubMed

    Sharif, Faiza; Steenbergen, Peter J; Metz, Juriaan R; Champagne, Danielle L

    2015-01-01

    This study assessed the lasting impact of dexamethasone (DEX) exposure during early development on tissue repair capacity at later life stages (5, 14, and 24 days post fertilization [dpf]) in zebrafish larvae. Using the caudal fin amputation model, we show that prior exposure to DEX significantly delays but does not prevent wound healing at all life stages studied. DEX-induced impairments on wound healing were fully restored to normal levels with longer post amputation recovery time. Further analyses revealed that DEX mainly exerted its detrimental effects in the early phase (0-5 hours) of wound-healing process. Specifically, we observed the following events: (1) massive amount of cell death both by necrosis and apoptosis; (2) significant reduction in the number as well as misplacement of macrophages at the wound site; (3) aberrant migration and misplacement of neutrophils and macrophages at the wound site. These events were accompanied by significant (likely compensatory) changes in the expression of genes involved in tissue patterning, including up-regulation of FKBP5 6 hours post DEX exposure and that of Wnt3a and RARγ at 24 hours post amputation. Taken together, this study provides evidence that DEX exposure during early sensitive periods of development appears to cause permanent alterations in the cellular/molecular immune processes that are involved in the early phase of wound healing in zebrafish. These findings are consistent with previous studies showing that antenatal course of DEX is associated with immediate and lasting alterations of the immune system in rodent models and humans. Therefore, the current findings support the use of the larval zebrafish model to study the impact of stress and stress hormone exposure in immature organisms on health risks in later life.

  10. Repeated paroxetine treatment reverses anhedonia induced in rats by chronic mild stress or dexamethasone.

    PubMed

    Casarotto, P C; Andreatini, R

    2007-11-01

    The present study was designed to assess the effect of dexamethasone, a synthetic glucocorticoid receptor agonist, in the sucrose preference test in rats. Rats treated acutely with dexamethasone (5-10 mg/kg) showed a significant decrease in sucrose preference (anhedonia) in comparison to vehicle treated rats, although 1 mg/kg dexamethasone did not alter the sucrose preference. Daily paroxetine treatment (10 g/kg, i.p., 14 days) reversed the anhedonic effect of acute dexamethasone (5 mg/kg), while causing no increased sucrose preference in rats that received dexamethasone vehicle. The paroxetine vehicle treated rats showed anhedonia even 14 days after acute dexamethasone administration. Paroxetine (10 mk/kg, i.p. for 28 days) also reversed anhedonia induced by chronic mild stress (8 weeks). In conclusion, acute dexamethasone induced an enduring anhedonic state that was reversed by repeated paroxetine treatment. Thus, the present study adds new data to the evidence supporting an important role for glucocorticoid in depression.

  11. Target gene expression signatures in neutrophils and lymphocytes from cattle administered with dexamethasone at growth promoting purposes.

    PubMed

    Lopparelli, R M; Giantin, M; Pozza, G; Stefani, A L; Ravarotto, L; Montesissa, C; Dacasto, M

    2012-08-01

    The glucocorticoid dexamethasone (DEX), when used as a growth promoter, cause morphological and functional alterations in cattle lymphoid organs and cells. In the present experiment, the transcriptional effects of an illicit DEX protocol upon six target genes were investigated in cattle neutrophils (NEU) and lymphocytes (LFC). Blood samples were taken before (T(0)) and 2, 3, 10, 19, 31 and 43 days from the beginning of DEX administration (T(1)-T(6)). Leukocytes were counted and cells isolated by gradient centrifugation; then, glutathione peroxidase 1 and 3 (GPX1 and GPX3), glucocorticoid receptor alpha (GRα), l-selectin, nuclear factor κB, subunit p65 (NFκB) and tumor necrosis factor alpha (TNFα) mRNA amounts were measured through a quantitative Real Time RT-PCR approach. A significant change vs controls in NEU/LFC ratio was noticed from T(3) forward. Compared to T(0), DEX significantly increased to a variable extent all candidate gene mRNAs abundances in NEU; in contrast, only l-selectin, GRα and GPX1 were significantly up-regulated in LFC. Present results suggest that illicit DEX affects transcription in cattle immune cells, that might be considered as a promising surrogate tissue for the screening of DEX abuse in cattle farming.

  12. Quantitative approach to lectin-based glycoprofiling of thymic tissues in the control- and the dexamethasone-treated mice.

    PubMed

    Balcan, Erdal

    2016-06-01

    Dexamethasone (DEX) is the most commonly used synthetic glucocorticoid in treatment of various inflammatory conditions. Here we focused on evaluating the effect of DEX on apoptosis and glycan profile in the mouse thymic tissues. Histological examinations revealed that the DEX treatment cause severe alterations in thymus, such as disruption of thymic capsule, impaired epithelial cell-thymocyte contacts, cellular loss and increased apoptosis. The identification of thymic glycans in the control- and the DEX-treated mice was carried out by using a panel of five plant lectins, Maackia amurensis agglutinin (MAA), peanut agglutinin (PNA), Sambucus nigra agglutinin (SNA), Concanavalin A (ConA) and wheat germ agglutinin (WGA). Lectin histochemistry results showed that glycosylation pattern of thymus changes upon DEX treatment. For further detailed quantitative analyses of the binding intensities for each lectin, histochemical data were scored as high positive (HP), mild positive (MP) and low positive (LP) and differences among signaling densities were investigated. The staining patterns of thymic regions observed with lectin histochemistry suggest that DEX can affect the thymic glycan profile as well as thymocyte apoptosis. These results are consistent with the opinion that not only sialic acid, but also other sugar motifs may be responsible for thymocyte development. PMID:27067421

  13. Live cell imaging of actin dynamics in dexamethasone-treated porcine trabecular meshwork cells.

    PubMed

    Fujimoto, Tomokazu; Inoue, Toshihiro; Inoue-Mochita, Miyuki; Tanihara, Hidenobu

    2016-04-01

    The regulation of the actin cytoskeleton in trabecular meshwork (TM) cells is important for controlling outflow of the aqueous humor. In some reports, dexamethasone (DEX) increased the aqueous humor outflow resistance and induced unusual actin structures, such as cross-linked actin networks (CLAN), in TM cells. However, the functions and dynamics of CLAN in TM cells are not completely known, partly because actin stress fibers have been observed only in fixed cells. We conducted live-cell imaging of the actin dynamics in TM cells with or without DEX treatment. An actin-green fluorescent protein (GFP) fusion construct with a modified insect virus was transfected into porcine TM cells. Time-lapse imaging of live TM cells treated with 25 μM Y-27632 and 100 nM DEX was performed using an inverted fluorescence microscope. Fluorescent images were recorded every 15 s for 30 min after Y-27632 treatment or every 30 min for 72 h after DEX treatment. The GFP-actin was expressed in 22.7 ± 10.9% of the transfected TM cells. In live TM cells, many actin stress fibers were observed before the Y-27632 treatment. Y-27632 changed the cell shape and decreased stress fibers in a time-dependent manner. In fixed cells, CLAN-like structures were seen in 26.5 ± 1.7% of the actin-GFP expressed PTM cells treated with DEX for 72 h. In live imaging, there was 28% CLAN-like structure formation at 72 h after DEX treatment, and the lifetime of CLAN-like structures increased after DEX treatment. The DEX-treated cells with CLAN-like structures showed less migration than DEX-treated cells without CLAN-like structures. Furthermore, the control cells (without DEX treatment) with CLAN-like structures also showed less migration than the control cells without CLAN-like structures. These results suggested that CLAN-like structure formation was correlated with cell migration in TM cells. Live cell imaging of the actin cytoskeleton provides valuable information on the actin dynamics in TM

  14. Lipoprotein lipase activity in rat cardiomyocytes is stimulated by insulin and dexamethasone.

    PubMed Central

    Ewart, H S; Carroll, R; Severson, D L

    1997-01-01

    Lipoprotein lipase (LPL) activity was studied in rat cardiomyocytes after overnight culture (16 h) in the presence of insulin (100 nM) and/or dexamethasone (100 nM). Insulin in combination with dexamethasone (INS/DEX) increased heparin-releasable LPL activity by 71% over the control level (566+/-85 versus 331+/-48 nmol/h.mg cell protein). This was accompanied by a 61% increase in total cellular LPL activity (914+/-89 versus 567+/-64 nmol/h.mg cell protein). The increase in LPL activity occurred at sub-nanomolar concentrations of the hormones, but neither hormone was effective alone. LPL protein mass, quantified by ELISA, was the same in both control and INS/DEX-treated cells (27.7 versus 28.6 ng/mg cell protein, respectively), thus LPL specific activity in cardiomyocytes was increased by INS/DEX treatment (0.113 versus 0.069 mU/ng LPL protein). These findings emphasize the importance of hormonal interactions in the regulation of LPL in heart tissue. PMID:9359413

  15. Delivery of dexamethasone from bioactive nanofiber matrices stimulates odontogenesis of human dental pulp cells through integrin/BMP/mTOR signaling pathways.

    PubMed

    Lim, Hyun-Chang; Nam, Ok Hyung; Kim, Mi-Joo; El-Fiqi, Ahmed; Yun, Hyung-Mun; Lee, Yoo-Mi; Jin, Guang-Zhen; Lee, Hae-Hyoung; Kim, Hae-Won; Kim, Eun-Cheol

    2016-01-01

    Therapeutically relevant design of scaffolds is of special importance in the repair and regeneration of tissues including dentin and pulp. Here we exploit nanofiber matrices that incorporate bioactive glass nanoparticles (BGNs) and deliver the odontogenic drug dexamethasone (DEX) to stimulate the odontogenic differentiation of human dental pulp cells (HDPCs). DEX molecules were first loaded onto the BGN, and then the DEX-BGN complex was incorporated within the biopolymer nanofiber matrix through electrospinning. The release of DEX continued over a month, showing a slow releasing profile. HDPCs cultured on the DEX-releasing BGN matrices were viable, proliferating well up to 14 days. The odontogenic differentiation, as assessed by alkaline phosphatase activity, mRNA expression of genes, and mineralization, was significantly stimulated on the matrices incorporating BGN and further on those releasing DEX. The DEX-releasing BGN matrices highly upregulated the expression of the integrin subsets α1, α5, and β3 as well as integrin downstream signaling molecules, including focal adhesion kinase (FAK), Paxillin, and RhoA, and activated bone morphogenetic protein mRNA and phosphorylation of Smad1/5/8. Furthermore, the DEX-releasing BGN-matrices stimulated Akt and mammalian target of rapamycin (mTOR), which was proven by the inhibition study. Collectively, the designed therapeutic nanofiber matrices that incorporate BGN and deliver DEX were demonstrated to promote odontogenesis of HDPCs, and the integrins, bone morphogenetic protein, and mTOR signaling pathways are proposed to be the possible molecular mechanisms. While further in vivo studies are still needed, the DEX-releasing bioactive scaffolds are considered as a potential therapeutic nanomatrix for regenerative endodontics and tissue engineering. PMID:27354790

  16. Dynamic regulation of PDX-1 and FoxO1 expression by FoxA2 in dexamethasone-induced pancreatic β-cells dysfunction.

    PubMed

    Chen, Fang; Zhu, Yunxia; Tang, Xinyi; Sun, Yidan; Jia, Weiping; Sun, Yujie; Han, Xiao

    2011-05-01

    Transcription factors forkhead box (Fox)O1 and pancreatic and duodenal homeobox-1 (PDX-1) are involved in dexamethasone (DEX)-induced dysfunction in pancreatic β-cells. However, the molecular mechanism underlying the regulation of FoxO1 and PDX-1 expression in β-cells treated with DEX is not fully understood. In this study, we found that DEX markedly increased FoxO1 mRNA and protein expression, whereas it decreased PDX-1 mRNA and protein expression in a dose- and time-dependent manner. Further study showed that FoxA2 was involved in regulation of FoxO1 and PDX-1 expression in DEX-induced pancreatic β-cells dysfunction. Interestingly, we demonstrated for the first time that FoxA2 could bind to the FoxO1 gene promoter and positively regulate FoxO1 expression. Moreover, we found that DEX increased the activity of FoxA2 binding to the FoxO1 promoter but decreased the activity of FoxA2 binding to the PDX-1 promoter of RINm5F cells. Knockdown of FoxA2 by RNA interference inhibited FoxO1 expression and restored PDX-1 expression in pancreatic β-cells treated with DEX. However, DEX had no effect on the expression of FoxA2. Together, the results of the present study demonstrated that FoxA2 could dynamically regulate FoxO1 and PDX-1 expression in pancreatic β-cells treated with DEX, which provides new important information on the transcriptional regulation of FoxO1 and PDX-1 in DEX-induced pancreatic β-cells. Inhibition of FoxA2 can effectively protect β-cells against DEX-induced dysfunction.

  17. Delivery of dexamethasone from bioactive nanofiber matrices stimulates odontogenesis of human dental pulp cells through integrin/BMP/mTOR signaling pathways.

    PubMed

    Lim, Hyun-Chang; Nam, Ok Hyung; Kim, Mi-Joo; El-Fiqi, Ahmed; Yun, Hyung-Mun; Lee, Yoo-Mi; Jin, Guang-Zhen; Lee, Hae-Hyoung; Kim, Hae-Won; Kim, Eun-Cheol

    2016-01-01

    Therapeutically relevant design of scaffolds is of special importance in the repair and regeneration of tissues including dentin and pulp. Here we exploit nanofiber matrices that incorporate bioactive glass nanoparticles (BGNs) and deliver the odontogenic drug dexamethasone (DEX) to stimulate the odontogenic differentiation of human dental pulp cells (HDPCs). DEX molecules were first loaded onto the BGN, and then the DEX-BGN complex was incorporated within the biopolymer nanofiber matrix through electrospinning. The release of DEX continued over a month, showing a slow releasing profile. HDPCs cultured on the DEX-releasing BGN matrices were viable, proliferating well up to 14 days. The odontogenic differentiation, as assessed by alkaline phosphatase activity, mRNA expression of genes, and mineralization, was significantly stimulated on the matrices incorporating BGN and further on those releasing DEX. The DEX-releasing BGN matrices highly upregulated the expression of the integrin subsets α1, α5, and β3 as well as integrin downstream signaling molecules, including focal adhesion kinase (FAK), Paxillin, and RhoA, and activated bone morphogenetic protein mRNA and phosphorylation of Smad1/5/8. Furthermore, the DEX-releasing BGN-matrices stimulated Akt and mammalian target of rapamycin (mTOR), which was proven by the inhibition study. Collectively, the designed therapeutic nanofiber matrices that incorporate BGN and deliver DEX were demonstrated to promote odontogenesis of HDPCs, and the integrins, bone morphogenetic protein, and mTOR signaling pathways are proposed to be the possible molecular mechanisms. While further in vivo studies are still needed, the DEX-releasing bioactive scaffolds are considered as a potential therapeutic nanomatrix for regenerative endodontics and tissue engineering.

  18. Delivery of dexamethasone from bioactive nanofiber matrices stimulates odontogenesis of human dental pulp cells through integrin/BMP/mTOR signaling pathways

    PubMed Central

    Lim, Hyun-Chang; Nam, Ok Hyung; Kim, Mi-joo; El-Fiqi, Ahmed; Yun, Hyung-Mun; Lee, Yoo-Mi; Jin, Guang-Zhen; Lee, Hae-Hyoung; Kim, Hae-Won; Kim, Eun-Cheol

    2016-01-01

    Therapeutically relevant design of scaffolds is of special importance in the repair and regeneration of tissues including dentin and pulp. Here we exploit nanofiber matrices that incorporate bioactive glass nanoparticles (BGNs) and deliver the odontogenic drug dexamethasone (DEX) to stimulate the odontogenic differentiation of human dental pulp cells (HDPCs). DEX molecules were first loaded onto the BGN, and then the DEX-BGN complex was incorporated within the biopolymer nanofiber matrix through electrospinning. The release of DEX continued over a month, showing a slow releasing profile. HDPCs cultured on the DEX-releasing BGN matrices were viable, proliferating well up to 14 days. The odontogenic differentiation, as assessed by alkaline phosphatase activity, mRNA expression of genes, and mineralization, was significantly stimulated on the matrices incorporating BGN and further on those releasing DEX. The DEX-releasing BGN matrices highly upregulated the expression of the integrin subsets α1, α5, and β3 as well as integrin downstream signaling molecules, including focal adhesion kinase (FAK), Paxillin, and RhoA, and activated bone morphogenetic protein mRNA and phosphorylation of Smad1/5/8. Furthermore, the DEX-releasing BGN-matrices stimulated Akt and mammalian target of rapamycin (mTOR), which was proven by the inhibition study. Collectively, the designed therapeutic nanofiber matrices that incorporate BGN and deliver DEX were demonstrated to promote odontogenesis of HDPCs, and the integrins, bone morphogenetic protein, and mTOR signaling pathways are proposed to be the possible molecular mechanisms. While further in vivo studies are still needed, the DEX-releasing bioactive scaffolds are considered as a potential therapeutic nanomatrix for regenerative endodontics and tissue engineering. PMID:27354790

  19. SARI, a novel target gene of glucocorticoid receptor, plays an important role in dexamethasone-mediated killing of B lymphoma cells.

    PubMed

    Huang, Yinghui; Zhou, Jie; Huang, Yan; He, Jintao; Wang, Yuting; Yang, Chaohui; Liu, Dongbo; Zhang, Li; He, Fengtian

    2016-04-01

    Dexamethasone (Dex) has been commonly used in lymphoma and leukemia treatment, but the detailed mechanisms are not fully understood. Suppressor of AP-1 regulated by interferon (SARI) has tumor-selective growth inhibitory effect. However, it's unclear whether SARI is involved in the Dex-mediated lymphoma growth suppression. In this study, we found that Dex-treated B lymphoma tissues had a higher level of SARI. Dex repressed the growth of B lymphoma cells and upregulated SARI expression by activating glucocorticoid receptor (GR) in vitro and in vivo. Silencing of SARI attenuated the Dex-mediated growth suppression of B lymphoma cells and inhibition of AP-1 activity. Reporter assays revealed that activation of GR enhanced the transcriptional activity of SARI promoter. EMSA and ChIP assays showed that GR directly bound to the ER9 element in SARI promoter region. These results for the first time demonstrated that SARI is a novel target gene of GR, and the upregulation of SARI plays an important role in Dex's killing effect on B lymphoma cells, suggesting that SARI may serve as a novel target and a potential indicator of Dex sensitivity in B lymphoma treatment. PMID:26808579

  20. Dexamethasone electrically controlled release from polypyrrole-coated nanostructured electrodes.

    PubMed

    Leprince, Lucas; Dogimont, Audrey; Magnin, Delphine; Demoustier-Champagne, Sophie

    2010-03-01

    One of the key challenges to engineering neural interfaces is to reduce their immune response toward implanted electrodes. One potential approach to minimize or eliminate this undesired early inflammatory tissue reaction and to maintain signal transmission quality over time is the delivery of anti-inflammatory biomolecules in the vicinity of the implant. Here, we report on a facile and reproducible method for the fabrication of high surface area nanostructured electrodes coated with an electroactive polymer, polypyrrole (PPy) that can be used to precisely release drug by applying an electrical stimuli. The method consists of the electropolymerization of PPy incorporated with drug, dexamethasone (DEX), onto a brush of metallic nanopillars, obtained by electrodeposition of the metal within the nanopores of gold-coated polycarbonate template. The study of the release of DEX triggered by electrochemical stimuli indicates that the system is a true electrically controlled release system. Moreover, it appears that the presence of metallic nanowires onto the electrode surface improves the adherence between the polymer and the electrode and increases the electroactivity of the PPy coating.

  1. Dexamethasone intravitreal implant for the treatment of noninfectious uveitis.

    PubMed

    Hunter, Rebecca S; Lobo, Ann-Marie

    2011-01-01

    Uveitis can be a sight-threatening eye disease with significant morbidity. Corticosteroids remain the mainstay of treatment of uveitis and provide an effective treatment against ocular inflammation. However, the various modes available for corticosteroid drug delivery can carry significant ocular and systemic side effects which can limit their use in the treatment of uveitis. In an effort to avoid the damage to ocular structures that can ensue with recurrent episodes of ocular inflammation, the side effects associated with systemic steroids, and the need for repeated administration of both topical and locally injected corticosteroids, sustained-release intraocular corticosteroid implants have been developed. The dexamethasone (DEX) drug delivery system (Ozurdex(®); Allergan Inc, Irvine, CA), is a biodegradable intravitreal implant. This implant has been shown to be effective in the treatment of macular edema and noninfectious posterior uveitis and has been approved by the FDA for these entities. This review will highlight the current methods available for corticosteroid delivery to the eye with a particular emphasis on the DEX intravitreal implant and the evidence currently available for its use in noninfectious uveitis.

  2. Differentiation potential of SHEDs using biomimetic periosteum containing dexamethasone.

    PubMed

    Su, Wen-Ta; Chiou, Wei-Ling; Yu, Ho-Hsu; Huang, Te-Yang

    2016-01-01

    Mimicking the architecture of the natural environment in vivo is an effective strategy for tissue engineering. The periosteum has an important function in bone regeneration. However, the harvesting of autogenous periosteum has the disadvantages of donor site morbidity and limited donor sources. This study uses an innovative artificial periosteum that forms dexamethasone (DEX)-containing polyvinyl alcohol (PVA) nanofiber obtained from skin fibrous scaffold. The aim was to evaluate the effect on bone healing of osteogenic differentiation in stems originating from human exfoliated deciduous teeth (SHEDs) in vitro. The microstructure of fabricated periosteum was observed through SEM, and results showed the apparent homogenous distribution of porous structures. DEX was also found to be continuously released into the culture medium from the periosteum for 28 days. MTT results further revealed that fabricated periosteum was cytocompatible and non-toxic to SHEDs. After 21 days of induced culture, the expression of alkaline phosphatase activity and calcium mineralization notably increased. Osteogenic results showed high early and late osteoblast gene expression by RT-PCR analysis, such as collagen type I, Runx2, OPN, and OCN. The osteoblastic protein expression of BMP-2 and OCN was clearly observed as well under fluorescence microscopy. The results, which could be applied to bone regeneration, demonstrated that skin fibrous scaffold provided an osteoinductive environment for stem cells to differentiate and that PVA nanofiber was a suitable reservoir for osteogenic factors with controlled release profile. PMID:26478401

  3. Effect of dexamethasone and oxygen exposure on neonatal rat lung retinoic acid receptor proteins.

    PubMed

    McMenamy, K R; Anderson, M J; Zachman, R D

    1994-10-01

    Retinol deficiency in animal models results in histopathologic airway changes that appear similar to those found in human premature infants with bronchopulmonary dysplasia (BPD). Dexamethasone (DEX), a steroid now often used in the treatment of BPD, might potentially affect lung vitamin A homeostasis since it alters serum and liver retinoid stores in certain models. Our objective was to determine the effect of DEX on neonatal rat lung retinoid status and the binding of retinoic acid (RA) to cytosolic and nuclear receptor proteins. We examined this effect both in room air and when the animals breathed 95% oxygen (O2). Twenty-four 1-day-old rat pups received either 1 microgram/g DEX subcutaneously, an equal volume of normal saline (NS) subcutaneously at 0 (start experiment time), 24, and 48 hours, or no injection at all, and were sacrificed at 72 hours. Twelve rats in each treatment group were housed in room air and 12 in each group were exposed to > 95% O2 for the 3 day period. Lung and liver were analyzed for retinyl palmitate (RP). Nuclear retinoic acid receptor (RAR) and cellular retinoic acid binding protein (CRABP) were measured by specific binding assays. DEX decreased liver RP by 33-55% and rat pup lung RP by over 60%; it also decreased lung RAR binding (mean dpm/microgram protein +/- SEM) in both room air and oxygen groups: Air (11.2 +/- 1.0) vs. Air/DEX (4.6 +/- 1.3, n = 6; P < 0.01), and O2 (18.2 +/- 0.6) vs. O2/DEX (3.2 +/- 0.6, n = 6; P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7838622

  4. Effect of dexamethasone and ACC on bacteria-induced mucin expression in human airway mucosa.

    PubMed

    Hauber, Hans-Peter; Goldmann, Torsten; Vollmer, Ekkehard; Wollenberg, Barbara; Zabel, Peter

    2007-11-01

    Gram-negative bacteria can stimulate mucin production, but excessive mucus supports bacterial infection and consequently leads to airway obstruction. Therefore, the effect of dexamethasone (DEX) and the antioxidant acetyl-cysteine (ACC) on bacteria-induced mucus expression was investigated. Explanted human airway mucosa and mucoepidermoid cells (Calu-3) were stimulated with lipopolysaccharide (LPS) or PAM3 (a synthetic lipoprotein). DEX or ACC were added to either LPS- or PAM3-stimulated airway mucosa or Calu-3 cells. Mucin mRNA expression (MUC5AC) and total mucus glycoconjugates (mucin protein) were quantified using real-time PCR and periodic acid Schiff staining. LPS and PAM3 significantly increased mucin expression in airway mucosa and Calu-3 cells (P < 0.05). DEX alone had no significant effect on mucin expression in airway mucosa or Calu-3 cells (P > 0.05). In contrast, DEX significantly reduced LPS- and PAM3-induced mucin expression in explanted mucosal tissue and mucin expression in Calu-3 cells (P < 0.05). In explanted human airway mucosa ACC alone significantly increased mucin expression (P < 0.05). In contrast, ACC significantly decreased LPS- and PAM3-induced mucin expression (P < 0.05). In Calu-3 cells ACC alone had no significant effect on mucin expression (P > 0.05). ACC decreased LPS- and PAM3-induced mucin expression, but this effect was not significant (P > 0.05). These data suggest that DEX can effectively reduce bacteria-induced mucin expression in the airways. ACC alone may increase mucin expression in noninfected mucosa, but it decreased bacteria-induced mucin expression. Further studies are warranted to evaluate whether the effect of DEX or ACC is clinically relevant. PMID:17600317

  5. Regulation of islet beta-cell pyruvate metabolism: interactions of prolactin, glucose, and dexamethasone.

    PubMed

    Arumugam, Ramamani; Horowitz, Eric; Noland, Robert C; Lu, Danhong; Fleenor, Donald; Freemark, Michael

    2010-07-01

    Prolactin (PRL) induces beta-cell proliferation and glucose-stimulated insulin secretion (GSIS) and counteracts the effects of glucocorticoids on insulin production. The mechanisms by which PRL up-regulates GSIS are unknown. We used rat islets and insulinoma (INS-1) cells to explore the interactions of PRL, glucose, and dexamethasone (DEX) in the regulation of beta-cell pyruvate carboxylase (PC), pyruvate dehydrogenase (PDH), and the pyruvate dehydrogenase kinases (PDKs), which catalyze the phosphorylation and inactivation of PDH. PRL increased GSIS by 37% (P < 0.001) in rat islets. Glucose at supraphysiological concentrations (11 mm) increased PC mRNA in islets; in contrast, PRL suppressed PC mRNA levels in islets and INS-1 cells, whereas DEX was without effect. Neither PRL nor DEX altered PC protein or activity levels. In INS-1 cells, PRL increased PDH activity 1.4- to 2-fold (P < 0.05-0.001) at glucose concentrations ranging from 2.5-11 mm. DEX reduced PDH activity; this effect was reversed by PRL. PDK1, -2, -3, and -4 mRNAs were detected in both islets and insulinoma cells, but the latter expressed trivial amounts of PDK4. PRL reduced PDK2 mRNA and protein levels in rat islets and INS-1 cells and PDK4 mRNA in islets; DEX increased PDK2 mRNA in islets and INS-1 cells; this effect was reversed by PRL. Our findings suggest that PRL induction of GSIS is mediated by increases in beta-cell PDH activity; this is facilitated by suppression of PDKs. PRL counteracts the effects of DEX on PDH and PDK expression, suggesting novel roles for the lactogens in the defense against diabetes. PMID:20484462

  6. Effect of dexamethasone and ACC on bacteria-induced mucin expression in human airway mucosa.

    PubMed

    Hauber, Hans-Peter; Goldmann, Torsten; Vollmer, Ekkehard; Wollenberg, Barbara; Zabel, Peter

    2007-11-01

    Gram-negative bacteria can stimulate mucin production, but excessive mucus supports bacterial infection and consequently leads to airway obstruction. Therefore, the effect of dexamethasone (DEX) and the antioxidant acetyl-cysteine (ACC) on bacteria-induced mucus expression was investigated. Explanted human airway mucosa and mucoepidermoid cells (Calu-3) were stimulated with lipopolysaccharide (LPS) or PAM3 (a synthetic lipoprotein). DEX or ACC were added to either LPS- or PAM3-stimulated airway mucosa or Calu-3 cells. Mucin mRNA expression (MUC5AC) and total mucus glycoconjugates (mucin protein) were quantified using real-time PCR and periodic acid Schiff staining. LPS and PAM3 significantly increased mucin expression in airway mucosa and Calu-3 cells (P < 0.05). DEX alone had no significant effect on mucin expression in airway mucosa or Calu-3 cells (P > 0.05). In contrast, DEX significantly reduced LPS- and PAM3-induced mucin expression in explanted mucosal tissue and mucin expression in Calu-3 cells (P < 0.05). In explanted human airway mucosa ACC alone significantly increased mucin expression (P < 0.05). In contrast, ACC significantly decreased LPS- and PAM3-induced mucin expression (P < 0.05). In Calu-3 cells ACC alone had no significant effect on mucin expression (P > 0.05). ACC decreased LPS- and PAM3-induced mucin expression, but this effect was not significant (P > 0.05). These data suggest that DEX can effectively reduce bacteria-induced mucin expression in the airways. ACC alone may increase mucin expression in noninfected mucosa, but it decreased bacteria-induced mucin expression. Further studies are warranted to evaluate whether the effect of DEX or ACC is clinically relevant.

  7. Dissociation between systemic and pulmonary anti‐inflammatory effects of dexamethasone in humans

    PubMed Central

    Bartko, Johann; Stiebellehner, Leopold; Derhaschnig, Ulla; Schoergenhofer, Christian; Schwameis, Michael; Prosch, Helmut

    2016-01-01

    Aims The local pulmonary inflammatory response has a different temporal and qualitative profile compared with the systemic inflammatory response. Although glucocorticoids substantially downregulate the systemic release of acute‐phase mediators, it is not clear whether they have comparable inhibitory effects in the human lung compartment. Therefore, we compared the anti‐inflammatory effects of a pure glucocorticoid agonist, dexamethasone, on bronchoalveolar lavage and blood cytokine concentrations in response to bronchially instilled endotoxin. Methods In this randomized, double‐blind and placebo‐controlled trial, 24 volunteers received dexamethasone or placebo and had endotoxin instilled into a lung segment and saline instilled into a contralateral segment, followed by bronchoalveolar lavage. Results Bronchially instilled endotoxin induced a local and systemic inflammatory response. Dexamethasone strongly blunted the systemic interleukin (IL) 6 and C‐reactive protein release. In sharp contrast, dexamethasone left the local release of acute‐phase mediators in the lungs virtually unchanged: bronchoalveolar lavage levels of IL‐6 were only 18% lower and levels of IL‐8 were even higher with dexamethasone compared with placebo, although the differences between treatments were not statistically significant (P = 0.07 and P = 0.08, respectively). However, dexamethasone had inhibitory effects on pulmonary protein extravasation and neutrophil migration. Conclusions The present study demonstrated a remarkable dissociation between the systemic anti‐inflammatory effects of glucocorticoids and its protective effects on capillary leak on the one hand and surprisingly low anti‐inflammatory effects in the lungs on the other. PMID:26647918

  8. Liposomal delivery of dexamethasone attenuates prostate cancer bone metastatic tumor growth In Vivo

    PubMed Central

    Buijs, Jeroen T.; van der Horst, Geertje; Cheung, Henry; van der Mark, Maaike; van Bloois, Louis; Rizzo, Larissa Y.; Lammers, Twan; Pelger, Rob C.; Storm, Gert; van der Pluijm, Gabri; Metselaar, Josbert M.

    2015-01-01

    Background The inflammatory tumor microenvironment, and more specifically the tumor‐associated macrophages, plays an essential role in the development and progression of prostate cancer towards metastatic bone disease. Tumors are often characterized by a leaky vasculature, which ‐ combined with the prolonged circulation kinetics of liposomes ‐ leads to efficient tumor localization of these drug carriers, via the so‐called enhanced permeability and retention (EPR) ‐effect. In this study, we evaluated the utility of targeted, liposomal drug delivery of the glucocorticoid dexamethasone in a model of prostate cancer bone metastases. Methods Tumor‐bearing Balb‐c nu/nu mice were treated intravenously with 0.2–1.0–5.0 mg/kg/week free‐ and liposomal DEX for 3–4 weeks and tumor growth was monitored by bioluminescent imaging. Results Intravenously administered liposomes localize efficiently to bone metastases in vivo and treatment of established bone metastases with (liposomal) dexamethasone resulted in a significant inhibition of tumor growth up to 26 days after initiation of treatment. Furthermore, 1.0 mg/kg liposomal dexamethasone significantly outperformed 1.0 mg/kg free dexamethasone, and was found to be well‐tolerated at clinically‐relevant dosages that display potent anti‐tumor efficacy. Conclusions Liposomal delivery of the glucocorticoid dexamethasone inhibits the growth of malignant bone lesions. We believe that liposomal encapsulation of dexamethasone offers a promising new treatment option for advanced, metastatic prostate cancer which supports further clinical evaluation. Prostate 75: 815–824, 2015. © 2015 The Authors. The Prostate, published by Wiley Periodicals, Inc. PMID:25663076

  9. Neuroprotective effects of quercetin, rutin and okra (Abelmoschus esculentus Linn.) in dexamethasone-treated mice.

    PubMed

    Tongjaroenbuangam, Walaiporn; Ruksee, Nootchanart; Chantiratikul, Piyanete; Pakdeenarong, Noppakun; Kongbuntad, Watee; Govitrapong, Piyarat

    2011-10-01

    The administration of dexamethasone, a synthetic glucocorticoid receptor agonist, causes neuronal death in the CA3 layer of the hippocampus, which has been associated with learning and memory impairments. This study aimed to examine the ability of okra (Abelmoschus esculentus Linn.) extract and its derivatives (quercetin and rutin) to protect neuronal function and improve learning and memory deficits in mice subjected to dexamethasone treatment. Learning and memory functions in mice were examined using the Morris water maze test. The results showed that the mice treated with dexamethasone had prolonged water maze performance latencies and shorter time spent in the target quadrant while mice pretreated with quercetin, rutin or okra extract prior to dexamethasone treatment showed shorter latencies and longer time spent in target quadrant. Morphological changes in pyramidal neurons were observed in the dexamethasone treated group. The number of CA3 hippocampal neurons was significantly lower while pretreated with quercetin, rutin or okra attenuated this change. Prolonged treatment with dexamethasone altered NMDA receptor expression in the hippocampus. Pretreatment with quercetin, rutin or okra extract prevented the reduction in NMDA receptor expression. Dentate gyrus (DG) cell proliferation was examined using the 5-bromo-2-deoxyuridine (BrdU) immunohistochemistry technique. The number of BrdU-immunopositive cells was significantly reduced in dexamethasone-treated mice compared to control mice. Pretreatment with okra extract, either quercetin or rutin was found to restore BrdU-immunoreactivity in the dentate gyrus. These findings suggest that quercetin, rutin and okra extract treatments reversed cognitive deficits, including impaired dentate gyrus (DG) cell proliferation, and protected against morphological changes in the CA3 region in dexamethasone-treated mice. The precise mechanism of the neuroprotective effect of these plant extracts should be further investigated.

  10. Prenatal exposure to dexamethasone disturbs sex-determining gene expression and fetal testosterone production in male embryos.

    PubMed

    Yun, Hyo Jung; Lee, Ji-Yeon; Kim, Myoung Hee

    2016-02-26

    Prenatal stress is known to cause intrauterine fetal growth retardation, and is also associated with various long-term effects in the form of metabolic and neurodevelopmental diseases in adults. Many of the diseases associated with prenatal stress exhibit a sex bias. Perturbations and vulnerability to prenatal stress are often more profound in males, but the mechanisms responsible for this relationship are not clear. We have previously shown that administration of the synthetic glucocorticoid, dexamethasone (Dex), at embryonic days 7.5, 8.5, and 9.5, induces embryonic growth restriction in a sex-dependent manner in a mouse model. Here we examined the effect of prenatal exposure to Dex on gonadal development. During male gonadal development, sex-determining genes, such as Sry, Sox9, and other downstream genes, were found to be dysregulated in response to prenatal Dex, whereas the genes for the ovarian pathway were affected to a lesser degree in females. In addition, fetal testosterone concentrations were decreased by prenatal exposure to Dex, in parallel with reduced numbers of 3β-hydroxysteroid dehydrogenase (3β-HSD)-positive cells in the embryonic testis. These results show that prenatal exposure to Dex differentially influences male versus female on the gene expression and hormone production during sex determination. We believe these studies provide valuable insights into possible mechanisms responsible for sex-specific responses to prenatal stress.

  11. Dexamethasone co-medication in cancer patients undergoing chemotherapy causes substantial immunomodulatory effects with implications for chemo-immunotherapy strategies

    PubMed Central

    Cook, Alistair M.; McDonnell, Alison M.; Lake, Richard A.; Nowak, Anna K.

    2016-01-01

    ABSTRACT The glucocorticoid (GC) steroid dexamethasone (Dex) is used as a supportive care co-medication for cancer patients undergoing standard care pemetrexed/platinum doublet chemotherapy. As trials for new cancer immunotherapy treatments increase in prevalence, it is important to track the immunological changes induced by co-medications commonly used in the clinic, but not specifically included in trial design or in pre-clinical models. Here, we document a number of Dex -induced immunological effects, including a large-scale lymphodepletive effect particularly affecting CD4+ T cells but also CD8+ T cells. The proportion of regulatory T cells within the CD4+ compartment did not change after Dex was administered, however a significant increase in proliferation and activation of regulatory T cells was observed. We also noted Dex -induced proportional changes in dendritic cell (DC) subtypes. We discuss these immunological effects in the context of chemoimmunotherapy strategies, and suggest a number of considerations to be taken into account when designing future studies where Dex and other GCs may be in use. PMID:27141331

  12. Maternal dexamethasone exposure inhibits the gonadotropin-releasing hormone neuronal movement in the preoptic area of rat offspring.

    PubMed

    Lim, Wei Ling; Soga, Tomoko; Parhar, Ishwar S

    2014-01-01

    Migration and final positioning of gonadotropin-releasing hormone (GnRH) neurons in the preoptic area (POA) is critical for reproduction. It is known that maternal dexamethasone (DEX) exposure impairs reproductive function and behaviour in the offspring. However, it is still not known whether maternal DEX exposure affects the postnatal GnRH neurons in the offspring. This study determined the neuronal movement of enhanced green fluorescent protein (EGFP)-tagged GnRH neurons in slice culture of postnatal day 0 (P0), P5 and P50-60 transgenic male rats. Effect of maternal DEX treatment on EGFP-GnRH neuronal movement and F-actin distribution on GnRH neurons at P0 stage were studied. Time-lapse analysis of P0 and P5 EGFP-GnRH neurons displayed active cellular movement within the POA compared to young adult P50-60 stages, suggesting possible fine-tuning movement for positioning of early postnatal GnRH neurons. The DEX-treated EGFP-GnRH neurons demonstrated decreased motility in the POA and reduced F-actin distribution in the GnRH neurons at 60 h culture compared to the vehicle-treated. These results suggest that the P0 GnRH neuronal movement in the POA is altered by maternal DEX exposure, which possibly disrupts the fine-tuning process for positioning and development of early postnatal GnRH neurons in the brain, potentially linked to reproductive dysfunction in adulthood.

  13. Prenatal exposure to dexamethasone disturbs sex-determining gene expression and fetal testosterone production in male embryos.

    PubMed

    Yun, Hyo Jung; Lee, Ji-Yeon; Kim, Myoung Hee

    2016-02-26

    Prenatal stress is known to cause intrauterine fetal growth retardation, and is also associated with various long-term effects in the form of metabolic and neurodevelopmental diseases in adults. Many of the diseases associated with prenatal stress exhibit a sex bias. Perturbations and vulnerability to prenatal stress are often more profound in males, but the mechanisms responsible for this relationship are not clear. We have previously shown that administration of the synthetic glucocorticoid, dexamethasone (Dex), at embryonic days 7.5, 8.5, and 9.5, induces embryonic growth restriction in a sex-dependent manner in a mouse model. Here we examined the effect of prenatal exposure to Dex on gonadal development. During male gonadal development, sex-determining genes, such as Sry, Sox9, and other downstream genes, were found to be dysregulated in response to prenatal Dex, whereas the genes for the ovarian pathway were affected to a lesser degree in females. In addition, fetal testosterone concentrations were decreased by prenatal exposure to Dex, in parallel with reduced numbers of 3β-hydroxysteroid dehydrogenase (3β-HSD)-positive cells in the embryonic testis. These results show that prenatal exposure to Dex differentially influences male versus female on the gene expression and hormone production during sex determination. We believe these studies provide valuable insights into possible mechanisms responsible for sex-specific responses to prenatal stress. PMID:26827828

  14. Dexamethasone Induces Connective Tissue Growth Factor Expression in Renal Tubular Epithelial Cells in a Mouse Strain-Specific Manner

    PubMed Central

    Okada, Hirokazu; Kikuta, Tomohiro; Inoue, Tsutomu; Kanno, Yoshihiko; Ban, Shinichi; Sugaya, Takeshi; Takigawa, Masaharu; Suzuki, Hiromichi

    2006-01-01

    Connective tissue growth factor (CTGF), a downstream mediator of transforming growth factor-β1, mediates mesangial cell/fibroblast proliferation and extracellular matrix production by renal cells. Here, we show that renal tubular epithelial cells from patients with minimal change nephritic syndrome produced CTGF after glucocorticoid treatment. In addition, the glucocorticoid dexamethasone (DEX) increased CTGF mRNA levels in the kidneys of C57B6 but not SJL mice and produced intermediate CTGF mRNA levels in the kidneys of F1 (C57B6 × SJL) mice, midway between the levels found for parental strains. DEX also increased CTGF mRNA levels in cultured tubular epithelial cells derived from C57B6 (mProx24) but not SJL (MCT) mice via transcriptional up-regulation of CTGF mRNA. Transient transfection experiments using luciferase reporter constructs bearing CTGF promoter fragments revealed that the −897- to −628-bp fragment contained DEX-responsive positive regulatory elements, which were active in mProx24 but not MCT cells. Long-term DEX treatment resulted in fibronectin deposition in the kidneys of C57B6 but not SJL mice, and this effect was inhibited by co-administration of CTGF anti-sense oligodeoxynucleotides. Thus, glucocorticoid-induced renal fibrogenesis seems to be influenced by genetic background, with the critical DEX-responsive elements in the −897- to −628-bp region of the CTGF promoter. PMID:16507889

  15. Antitussive activity of sigma-1 receptor agonists in the guinea-pig.

    PubMed

    Brown, Claire; Fezoui, Malika; Selig, William M; Schwartz, Carl E; Ellis, James L

    2004-01-01

    1. Current antitussive medications have limited efficacy and often contain the opiate-like agent dextromethorphan (DEX). The mechanism whereby DEX inhibits cough is ill defined. DEX displays affinity at both NMDA and sigma receptors, suggesting that the antitussive activity may involve central or peripheral activity at either of these receptors. This study examined and compared the antitussive activity of DEX and various putative sigma receptor agonists in the guinea-pig citric-acid cough model. 2. Intraperitoneal (i.p.) administration of DEX (30 mg kg(-1)) and the sigma-1 agonists SKF-10,047 (1-5 mg kg(-1)), Pre-084 (5 mg kg(-1)), and carbetapentane (1-5 mg kg(-1)) inhibited citric-acid-induced cough in guinea-pigs. Intraperitoneal administration of a sigma-1 antagonist, BD 1047 (1-5 mg kg(-1)), reversed the inhibition of cough elicited by SKF-10,047. In addition, two structurally dissimilar sigma agonists SKF-10,047 (1 mg ml(-1)) and Pre-084 (1 mg ml(-1)) inhibited cough when administered by aerosol. 3. Aerosolized BD 1047 (1 mg ml(-1), 30 min) prevented the antitussive action of SKF-10,047 (5 mg kg(-1)) or DEX (30 mg kg(-1)) given by i.p. administration and, likewise, i.p. administration of BD 1047 (5 mg kg(-1)) prevented the antitussive action of SKF-10,047 given by aerosol (1 mg ml(-1)). 4. These results therefore support the argument that antitussive effects of DEX may be mediated via sigma receptors, since both systemic and aerosol administration of sigma-1 receptor agonists inhibit citric-acid-induced cough in guinea-pigs. While significant systemic exposure is possible with aerosol administration, the very low doses administered (estimated <0.3 mg kg(-1)) suggest that there may be a peripheral component to the antitussive effect.

  16. Multicomponent Implant Releasing Dexamethasone

    NASA Astrophysics Data System (ADS)

    Nikkola, L.; Vapalahti, K.; Ashammakhi, N.

    2008-02-01

    Several inflammatory conditions are usually treated with corticosteroids. There are various problems like side effects with traditional applications of steroids, e.g. topical, or systemic routes. Local drug delivery systems have been studied and developed to gain more efficient administration with fewer side effects. Earlier, we reported on developing Dexamethasone (DX) releasing biodegradable fibers. However, their drug release properties were not satisfactory in terms of onset of drug release. Thus, we assessed the development of multicomponent (MC) implant to enhance earlier drug release from such biodegradable fibers. Poly (lactide-co-glycolide) (PLGA) and 2 wt-% and 8 wt-% DX were compounded and extruded with twin-screw extruder to form of fibers. Some of the fibers were sterilized to obtain a change in drug release properties. Four different fiber classes were studied: 2 wt-%, 8 wt-%, sterilized 2 wt-%, and sterilized 8 wt-%. 3×4 different DX-releasing fibers were then heat-pressed to form one multicomponent rod. Half of the rods where sterilized. Drug release was measured from initial fibers and multicomponent rods using a UV/VIS spectrometer. Shear strength and changes in viscosity were also measured. Drug release studies showed that drug release commenced earlier from multicomponent rods than from component fibers. Drug release from multicomponent rods lasted from day 30 to day 70. The release period of sterilized rods extended from day 23 to day 57. When compared to the original component fibers, the drug release from MC rods commenced earlier. The initial shear strength of MC rods was 135 MPa and decreased to 105 MPa during four weeks of immersion in phosphate buffer solution. Accordingly, heat pressing has a positive effect on drug release. After four weeks in hydrolysis, no disintegration was observed.

  17. Panobinostat plus bortezomib and dexamethasone in previously treated multiple myeloma: outcomes by prior treatment

    PubMed Central

    Hungria, Vânia T. M.; Yoon, Sung-Soo; Beksac, Meral; Dimopoulos, Meletios Athanasios; Elghandour, Ashraf; Jedrzejczak, Wieslaw W.; Guenther, Andreas; Nakorn, Thanyaphong Na; Siritanaratkul, Noppadol; Schlossman, Robert L.; Hou, Jian; Moreau, Philippe; Lonial, Sagar; Lee, Jae Hoon; Einsele, Hermann; Sopala, Monika; Bengoudifa, Bourras-Rezki; Corrado, Claudia; Binlich, Florence; San-Miguel, Jesús F.

    2016-01-01

    Panobinostat is a potent pan-deacetylase inhibitor that affects the growth and survival of multiple myeloma (MM) cells through alteration of epigenetic mechanisms and protein metabolism. Panobinostat plus bortezomib and dexamethasone (PAN-BTZ-Dex) led to a significant increase in progression-free survival (PFS) vs placebo plus bortezomib and dexamethasone (Pbo-BTZ-Dex) in patients with relapsed or relapsed and refractory MM in the phase 3 PANORAMA 1 trial. This subgroup analysis evaluated outcomes in patients in the PANORAMA 1 trial based on prior treatment: a prior immunomodulatory drug (IMiD; n = 485), prior bortezomib plus an IMiD (n = 193), and ≥2 prior regimens including bortezomib and an IMiD (n = 147). Median PFS with PAN-BTZ-Dex vs Pbo-BTZ-Dex across subgroups was as follows: prior IMiD (12.3 vs 7.4 months; hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.43-0.68), prior bortezomib plus IMiD (10.6 vs 5.8 months; HR, 0.52; 95% CI, 0.36-0.76), and ≥2 prior regimens including bortezomib and an IMiD (12.5 vs 4.7 months; HR, 0.47; 95% CI, 0.31-0.72). Common grade 3/4 adverse events and laboratory abnormalities in patients who received PAN-BTZ-Dex across the prior treatment groups included thrombocytopenia, lymphopenia, neutropenia, diarrhea, and asthenia/fatigue. Incidence of on-treatment deaths among patients who received prior bortezomib and an IMiD (regardless of number of prior regimens) was similar between treatment arms. This analysis demonstrated a clear PFS benefit of 7.8 months with PAN-BTZ-Dex among patients who received ≥2 prior regimens including bortezomib and an IMiD, a population with limited treatment options and poorer prognosis. This trial was registered at www.clinicaltrials.gov as #NCT01023308. PMID:26631116

  18. Panobinostat plus bortezomib and dexamethasone in previously treated multiple myeloma: outcomes by prior treatment.

    PubMed

    Richardson, Paul G; Hungria, Vânia T M; Yoon, Sung-Soo; Beksac, Meral; Dimopoulos, Meletios Athanasios; Elghandour, Ashraf; Jedrzejczak, Wieslaw W; Guenther, Andreas; Nakorn, Thanyaphong Na; Siritanaratkul, Noppadol; Schlossman, Robert L; Hou, Jian; Moreau, Philippe; Lonial, Sagar; Lee, Jae Hoon; Einsele, Hermann; Sopala, Monika; Bengoudifa, Bourras-Rezki; Corrado, Claudia; Binlich, Florence; San-Miguel, Jesús F

    2016-02-11

    Panobinostat is a potent pan-deacetylase inhibitor that affects the growth and survival of multiple myeloma (MM) cells through alteration of epigenetic mechanisms and protein metabolism. Panobinostat plus bortezomib and dexamethasone (PAN-BTZ-Dex) led to a significant increase in progression-free survival (PFS) vs placebo plus bortezomib and dexamethasone (Pbo-BTZ-Dex) in patients with relapsed or relapsed and refractory MM in the phase 3 PANORAMA 1 trial. This subgroup analysis evaluated outcomes in patients in the PANORAMA 1 trial based on prior treatment: a prior immunomodulatory drug (IMiD; n = 485), prior bortezomib plus an IMiD (n = 193), and ≥2 prior regimens including bortezomib and an IMiD (n = 147). Median PFS with PAN-BTZ-Dex vs Pbo-BTZ-Dex across subgroups was as follows: prior IMiD (12.3 vs 7.4 months; hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.43-0.68), prior bortezomib plus IMiD (10.6 vs 5.8 months; HR, 0.52; 95% CI, 0.36-0.76), and ≥2 prior regimens including bortezomib and an IMiD (12.5 vs 4.7 months; HR, 0.47; 95% CI, 0.31-0.72). Common grade 3/4 adverse events and laboratory abnormalities in patients who received PAN-BTZ-Dex across the prior treatment groups included thrombocytopenia, lymphopenia, neutropenia, diarrhea, and asthenia/fatigue. Incidence of on-treatment deaths among patients who received prior bortezomib and an IMiD (regardless of number of prior regimens) was similar between treatment arms. This analysis demonstrated a clear PFS benefit of 7.8 months with PAN-BTZ-Dex among patients who received ≥2 prior regimens including bortezomib and an IMiD, a population with limited treatment options and poorer prognosis. This trial was registered at www.clinicaltrials.gov as #NCT01023308. PMID:26631116

  19. Effects of prenatal dexamethasone treatment on physical growth, pituitary-adrenal hormones, and performance of motor, motivational, and cognitive tasks in juvenile and adolescent common marmoset monkeys.

    PubMed

    Hauser, Jonas; Knapman, Alana; Zürcher, Nicole R; Pilloud, Sonia; Maier, Claudia; Diaz-Heijtz, Rochellys; Forssberg, Hans; Dettling, Andrea; Feldon, Joram; Pryce, Christopher R

    2008-12-01

    Synthetic glucocorticoids such as dexamethasone (DEX) are commonly used to prevent respiratory distress syndrome in preterm infants, but there is emerging evidence of subsequent neurobehavioral abnormalities (e.g. problems with inattention/hyperactivity). In the present study, we exposed pregnant common marmosets (Callithrix jacchus, primates) to daily repeated DEX (5 mg/kg by mouth) during either early (d 42-48) or late (d 90-96) pregnancy (gestation period of 144 days). Relative to control, and with a longitudinal design, we investigated DEX effects in offspring in terms of physical growth, plasma ACTH and cortisol titers, social and maintenance behaviors, skilled motor reaching, motivation for palatable reward, and learning between infancy and adolescence. Early DEX resulted in reduced sociability in infants and increased motivation for palatable reward in adolescents. Late DEX resulted in a mild transient increase in knee-heel length in infants and enhanced reversal learning of stimulus-reward association in adolescents. There was no effect of either early or late DEX on basal plasma ACTH or cortisol titers. Both treatments resulted in impaired skilled motor reaching in juveniles, which attenuated in early DEX but persisted in late DEX across test sessions. The increased palatable-reward motivation and decreased social motivation observed in early DEX subjects provide experimental support for the clinical reports that prenatal glucocorticoid treatment impairs social development and predisposes to metabolic syndrome. These novel primate findings indicate that fetal glucocorticoid overexposure can lead to abnormal development of motor, affective, and cognitive behaviors. Importantly, the outcome is highly dependent upon the timing of glucocorticoid overexposure.

  20. Glucuronidation of thyroxine in primary monolayer cultures of rat hepatocytes: in vitro induction of UDP-glucuronosyltranferases by methylcholanthrene, clofibrate, and dexamethasone alone and in combination.

    PubMed

    Jemnitz, K; Veres, Z; Monostory, K; Vereczkey, L

    2000-01-01

    Induction of UDP-glucuronosyltransferases (UGTs) toward thyroxine (T4) and p-nitrophenol (pNP) by 3-methylcholanthrene (MC), dexamethasone (DEX), clofibrate (Cl), and MC combined with DEX or Cl was studied in rat hepatocyte culture. We have developed a sensitive method for the measurement of glucuronide conjugates of the two substrates based on HPLC analysis of culture medium. MC, Cl, or DEX increased the activity of T4 UGT. Combination of MC and Cl showed additive effect, enzyme activity was enhanced compared with either MC or Cl treatment alone (617, 441, and 217% of the control, respectively). Combination of MC and DEX did not result in higher T4 UGT activity than MC treatment alone. Both MC and DEX enhanced the pNP UGT activity (182 and 162% of the control, respectively). Combination of MC with DEX resulted in additive effect. Cl treatment did not affect pNP conjugation either alone or in combination with MC. Western blot analysis revealed that only the amount of UGT1A1 was elevated by Cl and DEX. In contrast, concentration of UGT1A6 was increased by MC. Previous studies demonstrated that UGT1A1 inducers like phenobarbital have no effect on T4 conjugation (). Our results suggest that Cl, a known inducer of UGT1A1, enhances the activity of other enzyme(s) involved in T4 glucuronidation as well. It is well documented that DEX potentiates the inductory effect of polycyclic aromatic hydrocarbon on UGT1A6 (). In our study, MC increased the rate of T4 glucuronidation, and DEX had no additional effect on this reaction, suggesting that UGT1A6 is not the only enzyme inducible by MC that can catalyze T4 conjugation. PMID:10611137

  1. Determination of dexamethasone in urine by gas chromatography with negative chemical ionization mass spectrometry.

    PubMed

    Huetos Hidalgo, Olga; Jiménez López, Manuel; Ajenjo Carazo, Elisa; San Andrés Larrea, Manuel; Reuvers, Thea B A

    2003-05-01

    Dexamethasone, as some other synthetic corticosteroids, is licensed for therapy in veterinary practice, but its misuse as a growth promotor, often in combination with beta-agonists, is forbidden. In this report an analytical method is described for the detection and confirmation of very low concentrations of dexamethasone in urine. The influence of enzymatic hydrolysis time of samples with glucuronidase was studied. The proposed method consisted of the enzymatic hydrolysis of urine samples, which were then extracted and concentrated using solid-phase cartridges with mixed reversed-phase materials (OASIS). No further clean-up step was found to be necessary. Eluates were derivatized following a previously described method [Analyst 119 (1994) 2557]. Detection, identification and quantification of residues of this compound was carried out by gas chromatography with mass spectrometry in the negative chemical ionization mode. The proposed procedure permits the determination of dexamethasone in urine at levels as low as 0.2 ng ml(-1)

  2. Effects of Celox and TraumaDEX on hemorrhage control in a porcine model.

    PubMed

    Gegel, Brian T; Burgert, James M; Lockhart, Cheryl; Austin, Robert; Davila, Alejandro; Deeds, Jacob; Hodges, Lonnie; Hover, Andrew; Roy, John; Simpson, Glenn; Weaver, Stephen; Wolfe, William; Johnson, Don

    2010-04-01

    The purpose of this study was to compare the effectiveness of 2 hemostatic agents, chitosan-based Celox and the biopolymeric, microporous particles TraumaDEX, with a control group in a porcine model of hemorrhage. The animals were randomly assigned to 1 of 3 groups: Celox (n = 5), TraumaDEX (n = 5), or a standard pressure dressing alone (n = 5). To simulate a battlefield injury, the investigators generated a compound groin injury with transection of the femoral artery and vein in 15 pigs. After 1 minute of uncontrolled hemorrhage, Celox or TraumaDEX was poured into the wound, followed by standard wound packing. The control group underwent the same procedures with the exception of the hemostatic agents. In all groups, 5 minutes of direct manual pressure was applied to the wound, followed by a standard pressure dressing (3M Coban). After 30 minutes, dressings were removed, and the amount of bleeding was measured. There were statistically significant differences in bleeding between Celox and control (P = .01) and between TraumaDEX and control (P = .038), but no statistically significant difference in bleeding between Celox and TraumaDEX (P = .478). Celox and TraumaDEX may be effective hemostatic agents for use in civilian and military trauma.

  3. Dexamethasone-induced muscular atrophy is mediated by functional expression of connexin-based hemichannels.

    PubMed

    Cea, Luis A; Balboa, Elisa; Puebla, Carlos; Vargas, Aníbal A; Cisterna, Bruno A; Escamilla, Rosalba; Regueira, Tomás; Sáez, Juan C

    2016-10-01

    Long-term treatment with high glucocorticoid doses induces skeletal muscle atrophy. However, the molecular mechanism of such atrophy remains unclear. We evaluated the possible involvement of connexin-based hemichannels (Cx HCs) in muscle atrophy induced by dexamethasone (DEX), a synthetic glucocorticoid, on control (Cx43(fl/fl)Cx45(fl/fl)) and Cx43/Cx45 expression-deficient (Cx43(fl/fl)Cx45(fl/fl):Myo-Cre) skeletal myofibers. Myofibers of Cx43(fl/fl)Cx45(fl/fl) mice treated with DEX (5h) expressed several proteins that form non-selective membrane channels (Cx39, Cx43, Cx45, Panx1, P2X7 receptor and TRPV2). After 5h DEX treatment in vivo, myofibers of Cx43(fl/fl)Cx45(fl/fl) mice showed Evans blue uptake, which was absent in myofibers of Cx43(fl/fl)Cx45(fl/fl):Myo-Cre mice. Similar results were obtained in vitro using ethidium as an HC permeability probe, and DEX-induced dye uptake in control myofibers was blocked by P2X7 receptor inhibitors. DEX also induced a significant increase in basal intracellular Ca(2+) signal and a reduction in resting membrane potential in Cx43(fl/fl)Cx45(fl/fl) myofibers, changes that were not elicited by myofibers deficient in Cx43/Cx45 expression. Moreover, treatment with DEX induced NFκB activation and increased mRNA levels of TNF-α in control but not in Cx43/Cx45 expression-deficient myofibers. Finally, a prolonged DEX treatment (7days) increased atrogin-1 and Murf-1 and reduced the cross sectional area of Cx43(fl/fl)Cx45(fl/fl) myofibers, but these parameters remained unaffected in Cx43(fl/fl)Cx45(fl/fl):Myo-Cre myofibers. Therefore, DEX-induced expression of Cx43 and Cx45 plays a critical role in early sarcolemma changes that lead to atrophy. Consequently, this side effect of chronic glucocorticoid treatment might be avoided by co-administration with a Cx HC blocker.

  4. Impedance Changes and Fibrous Tissue Growth after Cochlear Implantation Are Correlated and Can Be Reduced Using a Dexamethasone Eluting Electrode

    PubMed Central

    Mugridge, Kenneth; Jolly, Claude; Fehr, Michael; Lenarz, Thomas; Scheper, Verena

    2016-01-01

    Background The efficiency of cochlear implants (CIs) is affected by postoperative connective tissue growth around the electrode array. This tissue formation is thought to be the cause behind post-operative increases in impedance. Dexamethasone (DEX) eluting CIs may reduce fibrous tissue growth around the electrode array subsequently moderating elevations in impedance of the electrode contacts. Methods For this study, DEX was incorporated into the silicone of the CI electrode arrays at 1% and 10% (w/w) concentration. Electrodes prepared by the same process but without dexamethasone served as controls. All electrodes were implanted into guinea pig cochleae though the round window membrane approach. Potential additive or synergistic effects of electrical stimulation (60 minutes) were investigated by measuring impedances before and after stimulation (days 0, 7, 28, 56 and 91). Acoustically evoked auditory brainstem responses were recorded before and after CI insertion as well as on experimental days 7, 28, 56, and 91. Additionally, histology performed on epoxy embedded samples enabled measurement of the area of scala tympani occupied with fibrous tissue. Results In all experimental groups, the highest levels of fibrous tissue were detected in the basal region of the cochlea in vicinity to the round window niche. Both DEX concentrations, 10% and 1% (w/w), significantly reduced fibrosis around the electrode array of the CI. Following 3 months of implantation impedance levels in both DEX-eluting groups were significantly lower compared to the control group, the 10% group producing a greater effect. The same effects were observed before and after electrical stimulation. Conclusion To our knowledge, this is the first study to demonstrate a correlation between the extent of new tissue growth around the electrode and impedance changes after cochlear implantation. We conclude that DEX-eluting CIs are a means to reduce this tissue reaction and improve the functional benefits of

  5. Effects of Dexamethasone on Satellite Cells and Tissue Engineered Skeletal Muscle Units.

    PubMed

    Syverud, Brian C; VanDusen, Keith W; Larkin, Lisa M

    2016-03-01

    Tissue engineered skeletal muscle has potential for application as a graft source for repairing soft tissue injuries, a model for testing pharmaceuticals, and a biomechanical actuator system for soft robots. However, engineered muscle to date has not produced forces comparable to native muscle, limiting its potential for repair and for use as an in vitro model for pharmaceutical testing. In this study, we examined the trophic effects of dexamethasone (DEX), a glucocorticoid that stimulates myoblast differentiation and fusion into myotubes, on our tissue engineered three-dimensional skeletal muscle units (SMUs). Using our established SMU fabrication protocol, muscle isolates were cultured with three experimental DEX concentrations (5, 10, and 25 nM) and compared to untreated controls. Following seeding onto a laminin-coated Sylgard substrate, the administration of DEX was initiated on day 0 or day 6 in growth medium or on day 9 after the switch to differentiation medium and was sustained until the completion of SMU fabrication. During this process, total cell proliferation was measured with a BrdU assay, and myogenesis and structural advancement of muscle cells were observed through immunostaining for MyoD, myogenin, desmin, and α-actinin. After SMU formation, isometric tetanic force production was measured to quantify function. The histological and functional assessment of the SMU showed that the administration of 10 nM DEX beginning on either day 0 or day 6 yielded optimal SMUs. These optimized SMUs exhibited formation of advanced sarcomeric structure and significant increases in myotube diameter and myotube fusion index, compared with untreated controls. Additionally, the optimized SMUs matured functionally, as indicated by a fivefold rise in force production. In conclusion, we have demonstrated that the addition of DEX to our process of engineering skeletal muscle tissue improves myogenesis, advances muscle structure, and increases force production in the

  6. Dexamethasone induces different morphological changes in the dorsal and ventral hippocampus of rats.

    PubMed

    Silva-Gómez, Adriana Berenice; Aguilar-Salgado, Yuritze; Reyes-Hernández, Diego Octavio; Flores, Gonzalo

    2013-01-01

    Dexamethasone (DEX), a synthetic glucocorticoid widely used in neurological illnesses because of its antiinflammatory properties, has many serious side effects, including severe psychiatric symptoms such as psychoses. The hippocampus is divided in the dorsal hippocampus (DH) and ventral hippocampus (VH) with each region having a subfield of CA1 and CA3 pyramidal layers. Great interest has recently emerged showing that the DH and VH are functionally different. In our work we determined whether, and what, changes occurred, after five days of DEX (0.2mg/kg) treatment, on the dendritic morphology of the CA1 and CA3 pyramidal neurons of the DH and VH of adult Sprague-Dawley rats. The dendritic morphology and characteristics were measured by using the Golgi-Cox procedure followed by a Sholl analysis. DEX decreased the number of dendritic spines of both apical and basolateral dendrites. Interestingly, this decrease was more pronounced in the VH. Only the VH neurons were affected by DEX with a decrease in their total dendritic length (TDL). An interesting point is that the VH neurons are longer that the DH neurons among the groups injected with saline only as the control. The length per branch order was only altered in the apical dendritic tree of the CA1 neurons. These data taken together show that the VH is more susceptible to DEX and its neurons are larger than the DH neurons. These results support previous observations related to differences between the DH and VH and suggest differences in the expression of the glucocorticoid receptors in connectivity and the space to elongate their dendritic arbor.

  7. The synergistic effect of nano-hydroxyapatite and dexamethasone in the fibrous delivery system of gelatin and poly(l-lactide) on the osteogenesis of mesenchymal stem cells.

    PubMed

    Amjadian, Sara; Seyedjafari, Ehsan; Zeynali, Bahman; Shabani, Iman

    2016-06-30

    Recently, electrospun nanofibrous scaffolds are vastly taken into consideration in the bone tissue engineering due to mimicking the natural structure of native tissue. In our study, surface features of nanofibers were modified through simultaneous electrospining of the synthetic and natural polymers using poly l-lactide (PLLA) and gelatin to fabricate the hybrid scaffold (PLLA/gelatin). Then, hydroxyapatite nanoparticles (nHA) were loaded in electrospun PLLA nanofibers (PLLA,nHA/gelatin) and also dexamethasone (DEX) was incorporated in these fibers (PLLA,nHA,DEX/gelatin) in the second experiment. Fabricated nanofibrous composite scaffolds were characterized via SEM, FTIR spectroscopy, contact angle, tensile strength measurements, DEX release profile and MTT assay. After seeding adipose derived mesenchymal stem cells, osteoinductivity and osteoconductivity of fabricated scaffolds were analyzed using common osteogenic markers such as alkaline phosphatase activity, calcium depositions and gene expression. These results confirmed that all properties of nanofibers were improved by modifications. Moreover, osteogenic differentiation of stem cells increased in PLLA,nHA/gelatin group in comparison with PLLA/gelatin. The sustained release of DEX was obtained from PLLA,nHA,DEX/gelatin which subsequently led to more osteogenic differentiation. Taken together, PLLA,nHA,DEX/gelatin showed significant potential to support the stem cell proliferation and ostogenic differentiation, and can be a good candidates for tissue engineering and regenerative medicine applications.

  8. The synergistic effect of nano-hydroxyapatite and dexamethasone in the fibrous delivery system of gelatin and poly(l-lactide) on the osteogenesis of mesenchymal stem cells.

    PubMed

    Amjadian, Sara; Seyedjafari, Ehsan; Zeynali, Bahman; Shabani, Iman

    2016-06-30

    Recently, electrospun nanofibrous scaffolds are vastly taken into consideration in the bone tissue engineering due to mimicking the natural structure of native tissue. In our study, surface features of nanofibers were modified through simultaneous electrospining of the synthetic and natural polymers using poly l-lactide (PLLA) and gelatin to fabricate the hybrid scaffold (PLLA/gelatin). Then, hydroxyapatite nanoparticles (nHA) were loaded in electrospun PLLA nanofibers (PLLA,nHA/gelatin) and also dexamethasone (DEX) was incorporated in these fibers (PLLA,nHA,DEX/gelatin) in the second experiment. Fabricated nanofibrous composite scaffolds were characterized via SEM, FTIR spectroscopy, contact angle, tensile strength measurements, DEX release profile and MTT assay. After seeding adipose derived mesenchymal stem cells, osteoinductivity and osteoconductivity of fabricated scaffolds were analyzed using common osteogenic markers such as alkaline phosphatase activity, calcium depositions and gene expression. These results confirmed that all properties of nanofibers were improved by modifications. Moreover, osteogenic differentiation of stem cells increased in PLLA,nHA/gelatin group in comparison with PLLA/gelatin. The sustained release of DEX was obtained from PLLA,nHA,DEX/gelatin which subsequently led to more osteogenic differentiation. Taken together, PLLA,nHA,DEX/gelatin showed significant potential to support the stem cell proliferation and ostogenic differentiation, and can be a good candidates for tissue engineering and regenerative medicine applications. PMID:27107902

  9. Localized delivery of dexamethasone-21-phosphate via microdialysis implants in rat induces M(GC) macrophage polarization and alters CCL2 concentrations.

    PubMed

    Keeler, Geoffrey D; Durdik, Jeannine M; Stenken, Julie A

    2015-01-01

    Microdialysis sampling probes were implanted into the subcutaneous space on the dorsal side of male Sprague Dawley rats to locally deliver dexamethasone-21-phosphate (Dex) with the aim of altering in vivo macrophage polarization. Macrophage polarization is of significant interest in the field of biomaterials since wound-healing macrophages are a possible means to extend implant life as well as improve tissue remodeling to an implant. Quantitative analysis of CCL2 in collected dialysates, gene expression and immunohistochemistry performed on the tissue surrounding the microdialysis implant were used to evaluate if Dex polarized macrophages. Dex infusion down-regulated IL-6 and CCL2 gene expression and decreased CCL2 concentrations in dialysates collected at the implant site. Dex appeared to have no significant effect on the gene regulation of CD163, a commonly used M2c macrophage surface marker; Arg2; and iNOS2. However, Dex infusion was effective at increasing the number of CD163(+) cells surrounding the implanted microdialysis probe. This work demonstrates the use of microdialysis sampling to deliver agents such as Dex to alter macrophage polarization in vivo while allowing the ability to collect cytokines in the surrounding microenvironment.

  10. A placebo-controlled study of sertraline’s effect on cortisol response to the dexamethasone/corticotropin-releasing hormone test in healthy adults

    PubMed Central

    Tyrka, Audrey R.; Lee, Janet K.; Tracy, Aaron P.; Wilkinson, Charles W.; Price, Lawrence H.

    2015-01-01

    Rationale The dexamethasone/corticotropin-releasing hormone (Dex/CRH) test is a neuroendocrine probe involving serial blood sampling of cortisol during a standardized pharmacological challenge without inducing psychological distress in humans. Some past studies in depressed patients have shown a “normalization” or decrease in cortisol response to the Dex/CRH test following successful treatment with an antidepressant. Studies in nondepressed healthy adult samples have also shown aberrant cortisol reactivity to be associated with depression risk factors. These findings prompted research into the use of the Dex/CRH test as a tool for developing antidepressant drugs. Objectives In this study, the Dex/CRH test was evaluated with regard to its potential utility for drug development in nonclinical samples. Methods The Dex/CRH test was administered before and after 6 weeks of blinded treatment with either sertraline 100 mg/day or matching placebo in 22 healthy adults (13 women, nine men). Results Cortisol response to the Dex/CRH test increased following treatment with standard doses of sertraline, compared to placebo, after controlling for age and sex. Conclusions The observed pattern of change contrasts with results from published studies in depressed patients and with our initial hypothesis. PMID:21617914

  11. Cortisol suppression and hearing thresholds in tinnitus after low-dose dexamethasone challenge

    PubMed Central

    2012-01-01

    Background Tinnitus is a frequent, debilitating hearing disorder associated with severe emotional and psychological suffering. Although a link between stress and tinnitus has been widely recognized, the empirical evidence is scant. Our aims were to test for dysregulation of the stress-related hypothalamus-pituitary adrenal (HPA) axis in tinnitus and to examine ear sensitivity variations with cortisol manipulation. Methods Twenty-one tinnitus participants and 21 controls comparable in age, education, and overall health status but without tinnitus underwent basal cortisol assessments on three non-consecutive days and took 0.5 mg of dexamethasone (DEX) at 23:00 on the first day. Cortisol levels were measured hourly the next morning. Detection and discomfort hearing thresholds were measured before and after dexamethasone suppression test. Results Both groups displayed similar basal cortisol levels, but tinnitus participants showed stronger and longer-lasting cortisol suppression after DEX administration. Suppression was unrelated to hearing loss. Discomfort threshold was lower after cortisol suppression in tinnitus ears. Conclusions Our findings suggest heightened glucocorticoid sensitivity in tinnitus in terms of an abnormally strong glucocorticoid receptor (GR)-mediated HPA-axis feedback (despite a normal mineralocorticoid receptor (MR)-mediated tone) and lower tolerance for sound loudness with suppressed cortisol levels. Long-term stress exposure and its deleterious effects therefore constitute an important predisposing factor for, or a significant pathological consequence of, this debilitating hearing disorder. PMID:22449242

  12. Cromoglycate and nedocromil enhanced the reactive oxygen species-dependent suppressions with, but not without, dexamethasone in ischaemic and histamine paw oedema of mice

    PubMed Central

    Oyanagui, Y.

    1997-01-01

    Anti-inflammatory actions of two anti-allergic drugs, alone or with dexamethasone (Dex) were examined in two models, because inflammation is claimed to be important for allergic events, especially for asthma. Cromoglycate and nedocromil were tested in ischaemic- and histamineinduced paw oedema models of mice. These antiallergic drugs (1–100 mg/kg, i.p.) failed to suppress these oedemata, but enhanced the suppressions by a low dose of dexamethasone (0.1 mg/kg, s.c.) at 3–8 h after Dex injection. The mode of effects by anti-allergic drugs resembled that of a natural antioxidant (α-tocopherol, β-carotene etc.), and was different from that of an immunosuppressant like FK506. The enhancing potencies of the two anti-allergic drugs were similar at 6 h after Dex in both oedemata, and were diminished by superoxide dismutase (SOD) or catalase (i.p.). Cycloheximide completely abolished suppressions. Nedocromil, but not cromoglycate, inhibits inflammatory events. Therefore, there are common unknown actions by which the two anti-allergics enhance suppression by Dex. A possible mechanism of this action was supposed to enhance the superoxide and/or hydrogen peroxide-dependent glucocorticoid receptor (GR) signalling in the target cells. PMID:18472872

  13. Combinatorial release of dexamethasone and amiodarone from a nano-structured parylene-C film to reduce perioperative inflammation and atrial fibrillation

    NASA Astrophysics Data System (ADS)

    Robinson, Erik; Kaushal, Sunjay; Alaboson, Justice; Sharma, Sudhish; Belagodu, Amogh; Watkins, Claire; Walker, Brandon; Webster, Gregory; McCarthy, Patrick; Ho, Dean

    2016-02-01

    Suppressing perioperative inflammation and post-operative atrial fibrillation requires effective drug delivery platforms (DDP). Localized anti-inflammatory and anti-arrhythmic agent release may be more effective than intravenous treatment to improve patient outcomes. This study utilized a dexamethasone (DEX) and amiodarone (AMIO)-loaded Parylene-C (PPX) nano-structured film to inhibit inflammation and atrial fibrillation. The PPX film was tested in an established pericardial adhesion rabbit model. Following sternotomy, the anterior pericardium was resected and the epicardium was abraded. Rabbits were randomly assigned to five treatment groups: control, oxidized PPX (PPX-Oxd), PPX-Oxd infused with DEX (PPX-Oxd[DEX]), native PPX (PPX), and PPX infused with DEX and AMIO (PPX[AMIO, DEX]). 4 weeks post-sternotomy, pericardial adhesions were evaluated for gross adhesions using a 4-point grading system and histological evaluation for epicardial neotissue fibrosis (NTF). Atrial fibrillation duration and time per induction were measured. The PPX[AMIO, DEX] group had a significant reduction in mean adhesion score compared with the control group (control 2.75 +/- 0.42 vs. PPX[AMIO, DEX] 0.25 +/- 0.42, P < 0.001). The PPX[AMIO, DEX] group was similar to native PPX (PPX 0.38 +/- 0.48 vs. PPX[AMIO, DEX] 0.25 +/- 0.42, P&z.dbd;NS). PPX-Oxd group adhesions were indistinguishable from controls (PPX-Oxd 2.83 +/- 0.41 vs. control 2.75 +/- 0.42, P&z.dbd;NS). NTF was reduced in the PPX[AMIO, DEX] group (0.80 +/- 0.10 mm) compared to control (1.78 +/- 0.13 mm, P < 0.001). Total duration of atrial fibrillation was decreased in rabbits with PPX[AMIO, DEX] films compared to control (9.5 +/- 6.8 s vs. 187.6 +/- 174.7 s, p = 0.003). Time of atrial fibrillation per successful induction decreased among PPX[AMIO, DEX] films compared to control (2.8 +/- 1.2 s vs. 103.2 +/- 178 s, p = 0.004). DEX/AMIO-loaded PPX films are associated with reduced perioperative inflammation and a diminished atrial

  14. Dexamethasone downregulates the expression of parathyroid hormone-related protein (PTHrP) in mesenchymal stem cells.

    PubMed

    Ahlström, Mikael; Pekkinen, Minna; Lamberg-Allardt, Christel

    2009-02-01

    Parathyroid hormone-related protein (PTHrP) has been shown to have anabolic effects in women with postmenopausal osteoporosis. PTHrP promotes the recruitment of osteogenic cells and prevents apoptotic death of osteoblasts and osteocytes. The receptor responsible for the effects of PTHrP is the common PTH/PTHrP receptor (PTH1R). Glucocorticoids (GC) are commonly used as drugs to treat inflammatory diseases. Long-term GC treatments are often associated with bone loss which can lead to GC-induced osteoporosis. The aim of this work was to study the effects of the glucocorticoid dexamethasone (Dex) on the expression of PTHrP and PTH1R in adult human mesenchymal stem cells, the progenitor cells of osteoblasts. Adult human mesenchymal stem cells (hMSC) were cultured and differentiated by standard methods. The expression of PTHrP and PTH1R mRNA was assayed by real-time qPCR. The PTHrP release into the culture media was measured by an immunoradiometric assay. Treatment with Dex (10 nM) resulted in an 80% drop in the PTHrP release within 6 h. A 24 h Dex treatment also reduced the expression of PTHrP mRNA by up to 90%. The expression of PTH1R receptor mRNA was simultaneously increased up to 20-fold by 10 nM Dex. The effects of Dex on PTHrP and PTH1R were dose-dependent and experiments with the GC-receptor antagonist mifepristone showed an involvement of GC-receptors in these effects. In addition to the Dex-induced effects on PTHrP and PTH1R, Dex also increased mineralization and the expression of the osteoblast markers Runx2 and alkaline phosphatase. In our studies, we show that dexamethasone decreases the expression of PTHrP and increases the expression of the PTH1R receptor. This could have an impact on PTHrP-mediated anabolic actions on bone and could also affect the responsiveness of circulating PTH. The results indicate that glucocorticoids affect the signalling pathway of PTHrP by regulating both PTHrP and PTH1R expression and these mechanisms could be involved in

  15. Dexamethasone rapidly inhibits glucose uptake via non-genomic mechanisms in contracting myotubes.

    PubMed

    Gong, Hong; Liu, Lei; Ni, Chen-Xu; Zhang, Yi; Su, Wen-Jun; Lian, Yong-Jie; Peng, Wei; Zhang, Jun-Ping; Jiang, Chun-Lei

    2016-08-01

    Glucocorticoids (GCs) are a class of steroid hormones that regulate multiple aspects of glucose homeostasis. In skeletal muscle, it is well established that prolonged GC excess inhibits glucose uptake and utilization through glucocorticoid receptor (GR)-mediated transcriptional changes. However, it remains obscure that whether the rapid non-genomic effects of GC on glucose uptake are involved in acute exercise stress. Therefore, we used electric pulse stimulation (EPS)-evoked contracting myotubes to determine whether the non-genomic actions of GC were involved and its underlying mechanism(s). Pretreatment with dexamethasone (Dex, 10 μM) significantly prevented contraction-stimulated glucose uptake and glucose transporter 4 (Glut4) translocation within 20 min in C2C12 myotubes. Neither GC nuclear receptor antagonist (RU486) nor protein synthesis inhibitor (cycloheximide, Chx) affected the rapid inhibition effects of Dex. AMPK and CaMKII-dependent signaling pathways were associated with the non-genomic effects of Dex. These results provide evidence that GC rapidly suppresses glucose uptake in contracting myotubes via GR-independent non-genomic mechanisms. AMPK and CaMKII-mediated Glut4 translocation may play a critical role in GC-induced rapid inhibition of glucose uptake. PMID:27246478

  16. Tolerability of the Dexamethasone-Corticotropin Releasing Hormone Test in Major Depressive Disorder

    PubMed Central

    Dunlop, Boadie W.; Betancourt, Yara; Binder, Elisabeth B.; Heim, Christine; Holsboer, Florian; Ising, Marcus; McKenzie, Melissa; Mletzko, Tanja; Pfister, Hildegard; Nemeroff, Charles B.; Craighead, W. Edward; Mayberg, Helen S.

    2010-01-01

    Background The dexamethasone-corticotropin releasing hormone (Dex-CRH) test may differentially predict which depressed patients will respond to antidepressant medication. However, a comprehensive analysis of the safety of this test in psychiatric patients has not been previously been performed. Methods We conducted a pooled analysis of depressed patients in four clinical studies. Observed and subjectively reported side effects in 454 patients were collected for 90 minutes following CRH administration. Pre-test electrocardiograms were available in 250 patients to assess cardiac safety. Descriptive statistics were performed to evaluate these safety data. Results Eight-six (18.9%) of all subjects experienced no side effects from the procedure. The mean number of side effects per subject was 1.4 ± 1.0. The most frequent adverse events were: flushing (n=216, 47.6%), feeling of warmth (144, 31.7%), hyperpnea/tachypnea (108, 23.8%), palpitations (37, 8.1%), and tachycardia (28, 6.2%). Side effects were consistently mild and brief in duration. There were no serious adverse events. Conclusion The Dex-CRH test produces a mild, predictable side-effect profile, characterized by flushing, feelings of warmth, hyperpnea/tachypnea, palpitations, and tachycardia. These results provide reassurance that the Dex-CRH test is well tolerated in psychiatric patients. PMID:20488460

  17. Involvement of proton-sensing receptor TDAG8 in the anti-inflammatory actions of dexamethasone in peritoneal macrophages

    SciTech Connect

    He, Xiao-dong; Tobo, Masayuki; Mogi, Chihiro; Nakakura, Takashi; Komachi, Mayumi; Murata, Naoya; Takano, Mutsumi; Tomura, Hideaki; Sato, Koichi; Okajima, Fumikazu

    2011-12-02

    Highlights: Black-Right-Pointing-Pointer Glucocorticoid (GC) induced the expression of proton-sensing TDAG8 in macrophages. Black-Right-Pointing-Pointer GC enhanced acidic pH-induced cAMP accumulation and inhibition of TNF-{alpha} production. Black-Right-Pointing-Pointer The enhancement of the GC-induced actions was lost by TDAG8 deficiency. Black-Right-Pointing-Pointer GC-induced anti-inflammatory actions are partly mediated by TDAG8 expression. -- Abstract: Dexamethasone (DEX), a potent glucocorticoid, increased the expression of T-cell death associated gene 8 (TDAG8), a proton-sensing G protein-coupled receptor, which is associated with the enhancement of acidic pH-induced cAMP accumulation, in peritoneal macrophages. We explored the role of increased TDAG8 expression in the anti-inflammatory actions of DEX. The treatment of macrophages with either DEX or acidic pH induced the cell death of macrophages; however, the cell death was not affected by TDAG8 deficiency. While DEX inhibited lipopolysaccharide-induced production of tumor necrosis factor-{alpha}, an inflammatory cytokine, which was independent of TDAG8, at neutral pH, the glucocorticoid enhanced the acidic pH-induced inhibition of tumor necrosis factor-{alpha} production in a manner dependent on TDAG8. In conclusion, the DEX-induced increase in TDAG8 expression is in part involved in the glucocorticoid-induced anti-inflammatory actions through the inhibition of inflammatory cytokine production under the acidic pH environment. On the other hand, the role of TDAG8 in the DEX-induced cell death is questionable.

  18. Dexamethasone in the treatment of hypernatraemic dehydration.

    PubMed

    Haque, K N

    1981-03-01

    Ninety infants with severe hypernatraemic dehydration (plasma sodium greater than 150 mmol/l) were studied. Most had had a convulsion before admission. They were allocated to two treatment groups. Both groups received intravenous plasma followed by slow intravenous rehydration and correction of acidosis. In addition, one group received intramuscular phenobarbitone, the other group received dexamethasone 0.3 mg by intramuscular injection every 6 hours for 48 hours. Fewer infants receiving dexamethasone had convulsions during treatment (18% compared with 52%), and fewer (18%) of them died than in the group who did not receive dexamethasone (40%). Dexamethasone may have a role in the management of hypernatraemic dehydration in infants.

  19. Successful treatment of POEMS syndrome with bortezomib and dexamethasone, combined with radiotherapy, and followed by autologous stem cell transplantation.

    PubMed

    Ishii, Yoshimi; Yamazaki, Etsuko; Ishiyama, Yasufumi; Yamamoto, Eri; Hattori, Yukako; Hagihara, Maki; Tomita, Naoto; Ishigatsubo, Yoshiaki

    2013-12-01

    POEMS syndrome is a monoclonal plasma cell disorder characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes. High-dose therapy (HDT) and autologous stem cell transplantation (ASCT) are an effective therapy, but optimal treatment options are still under debate. Bortezomib is an important agent for the treatment of patients with multiple myeloma and has recently been reported as efficacious in the treatment of patients with POEMS syndrome. We present a case of POEMS syndrome in a 33-year-old woman, who was successfully treated with BorDex (bortezomib and dexamethasone) combined with radiotherapy, and followed by ASCT. She was diagnosed with POEMS syndrome with a localized plasmacytoma of bone 5 months after her initial symptoms of heart failure. Her Eastern Cooperative Oncology Group (ECOG) performance status was 4. She was first administered BorDex therapy, which was subsequently combined with radiotherapy. Her general condition including heart failure dramatically improved after four cycles of BorDex therapy and radiation, resulting in partial response. After chemoradiotherapy, HDT and ASCT were performed. After treatment, she was able to walk unassisted and her plasma endothelial growth factor (VEGF) level decreased. She did not experience neurotoxicity induced by bortezomib. Bortezomib was well tolerated and we suggest that BorDex therapy followed by HDT and ASCT may be an effective therapy for POEMS syndrome. PMID:24166587

  20. Successful treatment of POEMS syndrome with bortezomib and dexamethasone, combined with radiotherapy, and followed by autologous stem cell transplantation.

    PubMed

    Ishii, Yoshimi; Yamazaki, Etsuko; Ishiyama, Yasufumi; Yamamoto, Eri; Hattori, Yukako; Hagihara, Maki; Tomita, Naoto; Ishigatsubo, Yoshiaki

    2013-12-01

    POEMS syndrome is a monoclonal plasma cell disorder characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes. High-dose therapy (HDT) and autologous stem cell transplantation (ASCT) are an effective therapy, but optimal treatment options are still under debate. Bortezomib is an important agent for the treatment of patients with multiple myeloma and has recently been reported as efficacious in the treatment of patients with POEMS syndrome. We present a case of POEMS syndrome in a 33-year-old woman, who was successfully treated with BorDex (bortezomib and dexamethasone) combined with radiotherapy, and followed by ASCT. She was diagnosed with POEMS syndrome with a localized plasmacytoma of bone 5 months after her initial symptoms of heart failure. Her Eastern Cooperative Oncology Group (ECOG) performance status was 4. She was first administered BorDex therapy, which was subsequently combined with radiotherapy. Her general condition including heart failure dramatically improved after four cycles of BorDex therapy and radiation, resulting in partial response. After chemoradiotherapy, HDT and ASCT were performed. After treatment, she was able to walk unassisted and her plasma endothelial growth factor (VEGF) level decreased. She did not experience neurotoxicity induced by bortezomib. Bortezomib was well tolerated and we suggest that BorDex therapy followed by HDT and ASCT may be an effective therapy for POEMS syndrome.

  1. Efficacy and Safety of a Dexamethasone Implant in Patients with Diabetic Macular Edema at Tertiary Centers in Korea

    PubMed Central

    Moon, Byung Gil; Lee, Joo Yong; Song, Ji Hun; Park, Young-Hoon; Kim, Hyun Woong; Ji, Yong-Sok; Chang, Woohyok; Lee, Joo Eun; Oh, Jaeryung; Chung, Inyoung

    2016-01-01

    Purpose. To evaluate the real-world efficacy and safety of the dexamethasone implant (DEX implant) in patients with diabetic macular edema (DME). Methods. Retrospective, multicenter, and noncomparative study of DME patients who were treated with at least one DEX implant. A total of 186 eyes from 165 patients were included. Best-corrected visual acuity (BCVA), central retinal thickness (CRT), complications, and number of retreatments were collected. Data at baseline and monthly for 6 months were analyzed. Results. The average baseline BCVA and CRT were 0.60 LogMAR and 491.6 μm, respectively. The mean BCVA improved until 3 months and then decreased up to 6 months of follow-up (0.53, 0.49, and 0.55 LogMAR at 1, 3, and 6 months; p = 0.001, <0.001, and 0.044, resp.). The change of mean CRT was similar to BCVA (345.0, 357.7, and 412.5 μm at 1, 3, and 6 months, p < 0.001, <0.001, and <0.001, resp.). 91 eyes (48.9%) received additional treatment with anti-VEGF or DEX implant. The average treatment-free interval was 4.4 months. In group analyses, the DEX implant was more effective in pseudophakic eyes, DME with subretinal fluid (SRF), or diffuse type. Conclusions. Intravitreal dexamethasone implants are an effective treatment for patients with DME, most notably in pseudophakic eyes, DME with SRF, or diffuse type. A half of these patients require additional treatment within 6 months. PMID:27293879

  2. Efficacy and Safety of a Dexamethasone Implant in Patients with Diabetic Macular Edema at Tertiary Centers in Korea.

    PubMed

    Moon, Byung Gil; Lee, Joo Yong; Yu, Hyeong Gon; Song, Ji Hun; Park, Young-Hoon; Kim, Hyun Woong; Ji, Yong-Sok; Chang, Woohyok; Lee, Joo Eun; Oh, Jaeryung; Chung, Inyoung

    2016-01-01

    Purpose. To evaluate the real-world efficacy and safety of the dexamethasone implant (DEX implant) in patients with diabetic macular edema (DME). Methods. Retrospective, multicenter, and noncomparative study of DME patients who were treated with at least one DEX implant. A total of 186 eyes from 165 patients were included. Best-corrected visual acuity (BCVA), central retinal thickness (CRT), complications, and number of retreatments were collected. Data at baseline and monthly for 6 months were analyzed. Results. The average baseline BCVA and CRT were 0.60 LogMAR and 491.6 μm, respectively. The mean BCVA improved until 3 months and then decreased up to 6 months of follow-up (0.53, 0.49, and 0.55 LogMAR at 1, 3, and 6 months; p = 0.001, <0.001, and 0.044, resp.). The change of mean CRT was similar to BCVA (345.0, 357.7, and 412.5 μm at 1, 3, and 6 months, p < 0.001, <0.001, and <0.001, resp.). 91 eyes (48.9%) received additional treatment with anti-VEGF or DEX implant. The average treatment-free interval was 4.4 months. In group analyses, the DEX implant was more effective in pseudophakic eyes, DME with subretinal fluid (SRF), or diffuse type. Conclusions. Intravitreal dexamethasone implants are an effective treatment for patients with DME, most notably in pseudophakic eyes, DME with SRF, or diffuse type. A half of these patients require additional treatment within 6 months. PMID:27293879

  3. DEAD/DExH-Box RNA Helicases in Selected Human Parasites.

    PubMed

    Marchat, Laurence A; Arzola-Rodríguez, Silvia I; Hernandez-de la Cruz, Olga; Lopez-Rosas, Itzel; Lopez-Camarillo, Cesar

    2015-10-01

    DEAD/DExH-box RNA helicases catalyze the folding and remodeling of RNA molecules in prokaryotic and eukaryotic cells, as well as in many viruses. They are characterized by the presence of the helicase domain with conserved motifs that are essential for ATP binding and hydrolysis, RNA interaction, and unwinding activities. Large families of DEAD/DExH-box proteins have been described in different organisms, and their role in all molecular processes involving RNA, from transcriptional regulation to mRNA decay, have been described. This review aims to summarize the current knowledge about DEAD/DExH-box proteins in selected protozoan and nematode parasites of medical importance worldwide, such as Plasmodium falciparum, Leishmania spp., Trypanosoma spp., Giardia lamblia, Entamoeba histolytica, and Brugia malayi. We discuss the functional characterization of several proteins in an attempt to understand better the molecular mechanisms involving RNA in these pathogens. The current data also highlight that DEAD/DExH-box RNA helicases might represent feasible drug targets due to their vital role in parasite growth and development.

  4. DEAD/DExH-Box RNA Helicases in Selected Human Parasites

    PubMed Central

    Marchat, Laurence A.; Arzola-Rodríguez, Silvia I.; Hernandez-de la Cruz, Olga; Lopez-Rosas, Itzel; Lopez-Camarillo, Cesar

    2015-01-01

    DEAD/DExH-box RNA helicases catalyze the folding and remodeling of RNA molecules in prokaryotic and eukaryotic cells, as well as in many viruses. They are characterized by the presence of the helicase domain with conserved motifs that are essential for ATP binding and hydrolysis, RNA interaction, and unwinding activities. Large families of DEAD/DExH-box proteins have been described in different organisms, and their role in all molecular processes involving RNA, from transcriptional regulation to mRNA decay, have been described. This review aims to summarize the current knowledge about DEAD/DExH-box proteins in selected protozoan and nematode parasites of medical importance worldwide, such as Plasmodium falciparum, Leishmania spp., Trypanosoma spp., Giardia lamblia, Entamoeba histolytica, and Brugia malayi. We discuss the functional characterization of several proteins in an attempt to understand better the molecular mechanisms involving RNA in these pathogens. The current data also highlight that DEAD/DExH-box RNA helicases might represent feasible drug targets due to their vital role in parasite growth and development. PMID:26537038

  5. DEX1, a Novel Plant Protein, Is Required for Exine Pattern Formation during Pollen Development in Arabidopsis1

    PubMed Central

    Paxson-Sowders, Dawn M.; Dodrill, Craig H.; Owen, Heather A.; Makaroff, Christopher A.

    2001-01-01

    To identify factors that are required for proper pollen wall formation, we have characterized the T-DNA-tagged, dex1 mutation of Arabidopsis, which results in defective pollen wall pattern formation. This study reports the isolation and molecular characterization of DEX1 and morphological and ultrastructural analyses of dex1 plants. DEX1 encodes a novel plant protein that is predicted to be membrane associated and contains several potential calcium-binding domains. Pollen wall development in dex1 plants parallels that of wild-type plants until the early tetrad stage. In dex1 plants, primexine deposition is delayed and significantly reduced. The normal rippling of the plasma membrane and production of spacers observed in wild-type plants is also absent in the mutant. Sporopollenin is produced and randomly deposited on the plasma membrane in dex1 plants. However, it does not appear to be anchored to the microspore and forms large aggregates on the developing microspore and the locule walls. Based on the structure of DEX1 and the phenotype of dex1 plants, several potential roles for the protein are proposed. PMID:11743117

  6. Dexamethasone and Azathioprine Promote Cytoskeletal Changes and Affect Mesenchymal Stem Cell Migratory Behavior

    PubMed Central

    Schneider, Natália; Gonçalves, Fabiany da Costa; Pinto, Fernanda Otesbelgue; Lopez, Patrícia Luciana da Costa; Araújo, Anelise Bergmann; Pfaffenseller, Bianca; Passos, Eduardo Pandolfi; Cirne-Lima, Elizabeth Obino; Meurer, Luíse; Lamers, Marcelo Lazzaron; Paz, Ana Helena

    2015-01-01

    Glucocorticoids and immunosuppressive drugs are commonly used to treat inflammatory disorders, such as inflammatory bowel disease (IBD), and despite a few improvements, the remission of IBD is still difficult to maintain. Due to their immunomodulatory properties, mesenchymal stem cells (MSCs) have emerged as regulators of the immune response, and their viability and activation of their migratory properties are essential for successful cell therapy. However, little is known about the effects of immunosuppressant drugs used in IBD treatment on MSC behavior. The aim of this study was to evaluate MSC viability, nuclear morphometry, cell polarity, F-actin and focal adhesion kinase (FAK) distribution, and cell migratory properties in the presence of the immunosuppressive drugs azathioprine (AZA) and dexamethasone (DEX). After an initial characterization, MSCs were treated with DEX (10 μM) or AZA (1 μM) for 24 hrs or 7 days. Neither drug had an effect on cell viability or nuclear morphometry. However, AZA treatment induced a more elongated cell shape, while DEX was associated with a more rounded cell shape (P < 0.05) with a higher presence of ventral actin stress fibers (P < 0.05) and a decrease in protrusion stability. After 7 days of treatment, AZA improved the cell spatial trajectory (ST) and increased the migration speed (24.35%, P < 0.05, n = 4), while DEX impaired ST and migration speed after 24 hrs and 7 days of treatment (-28.69% and -25.37%, respectively; P < 0.05, n = 4). In conclusion, our data suggest that these immunosuppressive drugs each affect MSC morphology and migratory capacity differently, possibly impacting the success of cell therapy. PMID:25756665

  7. Low-intensity resistance training attenuates dexamethasone-induced atrophy in the flexor hallucis longus muscle.

    PubMed

    Macedo, Anderson G; Krug, André L O; Herrera, Naiara A; Zago, Anderson S; Rush, James W E; Amaral, Sandra L

    2014-09-01

    This study investigated the potential protective effect of low-intensity resistance training (RT) against dexamethasone (DEX) treatment induced muscle atrophy. Rats underwent either an 8 week period of ladder climbing RT or remained sedentary. During the last 10 days of the exercise protocol, animals were submitted to a DEX treatment or a control saline injection. Muscle weights were assessed and levels of AKT, mTOR, FOXO3a, Atrogin-1 and MuRF-1 proteins were analyzed in flexor hallucis longus (FHL), tibialis anterior (TA), and soleus muscles. DEX induced blood glucose increase (+46%), body weight reduction (-19%) and atrophy in FHL (-28%) and TA (-21%) muscles, which was associated with a decrease in AKT and an increase in MuRF-1 proteins levels. Low-intensity RT prevented the blood glucose increase, attenuated the FHL atrophy effects of DEX, and was associated with increased mTOR and reductions in Atrogin-1 and MuRF-1 in FHL. In contrast, TA muscle atrophy and signaling proteins were not affected by RT. These are the first data to demonstrate that low-intensity ladder-climbing RT specifically mitigates the FHL atrophy, which is the main muscle recruited during the training activity, while not preventing atrophy in other limb muscle not as heavily recruited. The recruitment-dependent prevention of atrophy by low intensity RT likely occurs by a combination of attenuated muscle protein degradation signals and enhanced muscle protein synthesis signals including mTOR, Atrogin-1 and MuRF-1.

  8. ICAM-1 Targeted Nanogels Loaded with Dexamethasone Alleviate Pulmonary Inflammation

    PubMed Central

    Coll Ferrer, M. Carme; Shuvaev, Vladimir V.; Zern, Blaine J.; Composto, Russell J.; Muzykantov, Vladimir R.; Eckmann, David M.

    2014-01-01

    Lysozyme dextran nanogels (NG) have great potential in vitro as a drug delivery platform, combining simple chemistry with rapid uptake and cargo release in target cells with “stealth” properties and low toxicity. In this work, we study for the first time the potential of targeted NG as a drug delivery platform in vivo to alleviate acute pulmonary inflammation in animal model of LPS-induced lung injury. NG are targeted to the endothelium via conjugation with an antibody (Ab) directed to Intercellular Adhesion Molecule-1(ICAM-NG), whereas IgG conjugated NG (IgG-NG) are used for control formulations. The amount of Ab conjugated to the NG and distribution in the body after intravenous (IV) injection have been quantitatively analyzed using a tracer isotope-labeled [125I]IgG. As a proof of concept, Ab-NG are loaded with dexamethasone, an anti-inflammatory therapeutic, and the drug uptake and release kinetics are measured by HPLC. In vivo studies in mice showed that: i) ICAM-NG accumulates in mouse lungs (∼120% ID/g vs ∼15% ID/g of IgG-NG); and, ii) DEX encapsulated in ICAM-NG, but not in IgG-NG practically blocks LPS-induced overexpression of pro-inflammatory cell adhesion molecules including ICAM-1 in the pulmonary inflammation. PMID:25019304

  9. Salvianolic acid B stimulates osteogenesis in dexamethasone-treated zebrafish larvae

    PubMed Central

    Luo, Shi-ying; Chen, Jing-feng; Zhong, Zhi-guo; Lv, Xiao-hua; Yang, Ya-jun; Zhang, Jing-jing; Cui, Liao

    2016-01-01

    Aim: Our previous studies show that salvianolic acid B (Sal B) promotes osteoblast differentiation and matrix mineralization. In this study, we evaluated the protective effects of Sal B on the osteogenesis in dexamethasone (Dex)-treated larval zebrafish, and elucidated the underlying mechanisms. Methods: At 3 d post fertilization, wild-type AB zebrafish larvae or bone transgenic tg (sp7:egfp) zebrafish larvae were exposed to Sal B, Dex, or a mixture of Dex+Sal B for 6 d. Bone mineralization in AB strain larval zebrafish was assessed with alizarin red staining, and osteoblast differentiation in tg (sp7:egfp) larval zebrafish was examined with fluorescence scanning. The expression of osteoblast-specific genes in the larvae was detected using qRT-PCR assay. The levels of oxidative stress markers (ROS and MDA) in the larvae were also measured. Results: Exposure to Dex (5–20 μmol/L) dose-dependently decreased the bone mineralization area and integral optical density (IOD) in wild-type AB zebrafish larvae and the osteoblast fluorescence area and IOD in tg (sp7:egfp) zebrafish larvae. Exposure to Dex (10 μmol/L) significantly reduced the expression of osteoblast-specific genes, including runx2a, osteocalcin (OC), alkaline phosphatase (ALP) and osterix (sp7), and increased the accumulation of ROS and MDA in the larvae. Co-exposure to Sal B (0.2–2 μmol/L) dose-dependently increased the bone mineralization area and IOD in AB zebafish larvae and osteoblast fluorescence in tg (sp7:egfp) zebrafish larvae. Co-exposure to Sal B (2 μmol/L) significantly attenuated deleterious alterations in bony tissue and oxidative stress in both Dex-treated AB zebafish larvae and tg (sp7:egfp) zebrafish larvae. Conclusion: Sal B stimulates bone formation and rescues GC-caused inhibition on osteogenesis in larval zebrafish by counteracting oxidative stress and increasing the expression of osteoblast-specific genes. Thus, Sal B may have protective effects on bone loss trigged by GC. PMID

  10. Dexamethasone-Mediated Activation of Fibronectin Matrix Assembly Reduces Dispersal of Primary Human Glioblastoma Cells

    PubMed Central

    Shannon, Stephen; Vaca, Connan; Jia, Dongxuan; Entersz, Ildiko; Schaer, Andrew; Carcione, Jonathan; Weaver, Michael; Avidar, Yoav; Pettit, Ryan; Nair, Mohan; Khan, Atif; Foty, Ramsey A.

    2015-01-01

    Despite resection and adjuvant therapy, the 5-year survival for patients with Glioblastoma multiforme (GBM) is less than 10%. This poor outcome is largely attributed to rapid tumor growth and early dispersal of cells, factors that contribute to a high recurrence rate and poor prognosis. An understanding of the cellular and molecular machinery that drive growth and dispersal is essential if we are to impact long-term survival. Our previous studies utilizing a series of immortalized GBM cell lines established a functional causation between activation of fibronectin matrix assembly (FNMA), increased tumor cohesion, and decreased dispersal. Activation of FNMA was accomplished by treatment with Dexamethasone (Dex), a drug routinely used to treat brain tumor related edema. Here, we utilize a broad range of qualitative and quantitative assays and the use of a human GBM tissue microarray and freshly-isolated primary human GBM cells grown both as conventional 2D cultures and as 3D spheroids to explore the role of Dex and FNMA in modulating various parameters that can significantly influence tumor cell dispersal. We show that the expression and processing of fibronectin in a human GBM tissue-microarray is variable, with 90% of tumors displaying some abnormality or lack in capacity to secrete fibronectin or assemble it into a matrix. We also show that low-passage primary GBM cells vary in their capacity for FNMA and that Dex treatment reactivates this process. Activation of FNMA effectively “glues” cells together and prevents cells from detaching from the primary mass. Dex treatment also significantly increases the strength of cell-ECM adhesion and decreases motility. The combination of increased cohesion and decreased motility discourages in vitro and ex vivo dispersal. By increasing cell-cell cohesion, Dex also decreases growth rate of 3D spheroids. These effects could all be reversed by an inhibitor of FNMA and by the glucocorticoid receptor antagonist, RU-486. Our

  11. The effect of hydroalcoholic extract from the leaves of Moringa peregrina (Forssk.) Fiori. on blood pressure and oxidative status in dexamethasone-induced hypertensive rats

    PubMed Central

    Safaeian, Leila; Asghari, Gholamreza; Javanmard, Shaghayegh Haghjoo; Heidarinejad, Arman

    2015-01-01

    Background: Moringa peregrina (Forssk.) Fiori. is a tropical tree growing in southeast of Iran. All parts of this plant have nutritional uses and pharmacological activities. The present study was designed to evaluate the effect of hydroalcoholic extract from the leaves of M. peregrina in dexamethasone (Dex)-induced hypertension in rats. Materials and Methods: Male Wistar rats received Dex (30 μg/kg, subcutaneously; s.c.) or saline (as vehicle, 1 ml/kg, s.c.) for 14 days. In a prevention study, the rats received M. peregrina extract (100, 200 and 400 mg/kg, orally) for 4 days, followed by Dex for 14 days. In a reversal study, the animals received M. peregrina extract orally from day 8 to 14. The systolic blood pressure (SBP) was measured using tail-cuff method. The hydrogen peroxide (H2O2) concentration and ferric reducing antioxidant power (FRAP) were assessed in plasma samples. Results: Dex significantly increased the SBP and the plasma H2O2 and decreased the plasma FRAP value (P < 0.001). M. peregrina extract at a dose of 400 mg/kg prevented (P < 0.01) but did not reverse Dex-induced hypertension in rats. It also dose-dependently reduced the plasma H2O2 concentration and improved the FRAP value upon Dex administration. Conclusions: The findings of the present study indicated the antioxidant and partially antihypertensive effects of the hydroalcoholic extract from the leaves of M. peregrina in Dex-induced hypertension. Further experiments on other fractions of the leaves and also other parts of this plant are suggested for better evaluation of its antihypertensive effect and finding its mechanisms of action. PMID:26015927

  12. Dexamethasone protection from TNF-alpha-induced cell death in MCF-7 cells requires NF-kappaB and is independent from AKT

    PubMed Central

    Machuca, Catalina; Mendoza-Milla, Criselda; Córdova, Emilio; Mejía, Salvador; Covarrubias, Luis; Ventura, José; Zentella, Alejandro

    2006-01-01

    Background The biochemical bases for hormone dependence in breast cancer have been recognized as an important element in tumor resistance, proliferation and metastasis. On this respect, dexamethasone (Dex) dependent protection against TNF-alpha-mediated cell death in the MCF-7 cell line has been demonstrated to be a useful model for the study of this type of cancer. Recently, cytoplasmic signaling induced by steroid receptors has been described, such as the activation of the PI3K/Akt and NF-kappaB pathways. We evaluated their possible participation in the Dex-dependent protection against TNF-alpha-mediated cell death. Results Cellular cultures of the MCF-7 cell line were exposed to either, TNF-alpha or TNF-alpha and Dex, and cell viability was evaluated. Next, negative dominants of PI3K and IkappaB-alpha, designed to block the PI3K/Akt and NF-kappaB pathways, respectively, were transfected and selection and evaluation of several clones overexpressing the mutants were examined. Also, correlation with inhibitor of apoptosis proteins (IAPs) expression was examined. Independent inhibition of these two pathways allowed us to test their participation in Dex-dependent protection against TNF-alpha-cytotoxicity in MCF-7 cells. Expression of the PI3K dominant negative mutant did not alter the protection conferred by Dex against TNF-alpha mediated cell death. Contrariwise, clones expressing the IkappaB-alpha dominant negative mutant lost the Dex-conferred protection against TNF-alpha. In these clones degradation of c-IAP was accelerated, while that of XIAP was remained unaffected. Conclusion NF-kappaB, but not PI3K/Akt activation, is required for the Dex protective effect against TNF-alpha-mediated cell death, and correlates with lack of degradation of the anti-apoptotic protein c-IAP1. PMID:16504042

  13. Dexamethasone and BCAA Failed to Modulate Muscle Mass and mTOR Signaling in GH-Deficient Rats

    PubMed Central

    Nishida, Hikaru; Ikegami, Ayaka; Kaneko, Chiaki; Kakuma, Hitomi; Nishi, Hisano; Tanaka, Noriko; Aoyama, Michiko; Usami, Makoto; Okimura, Yasuhiko

    2015-01-01

    Branched-chain amino acids (BCAAs) and IGF-I, the secretion of which is stimulated by growth hormone (GH), prevent muscle atrophy. mTOR plays a pivotal role in the protective actions of BCAA and IGF-1. The pathway by which BCAA activates mTOR is different from that of IGF-1, which suggests that BCAA and GH work independently. We tried to examine whether BCAA exerts a protective effect against dexamethasone (Dex)-induced muscle atrophy independently of GH using GH-deficient spontaneous dwarf rats (SDRs). Unexpectedly, Dex did not induce muscle atrophy assessed by the measurement of cross-sectional area (CSA) of the muscle fibers and did not increase atrogin-1, MuRF1 and REDD1 expressions, which are activated during protein degradation. Glucocorticoid (GR) mRNA levels were higher in SDRs compared to GH-treated SDRs, indicating that the low expression of GR is not the reason of the defect of Dex’s action in SDRs. BCAA did not stimulate the phosphorylation of p70S6K or 4E-BP1, which stimulate protein synthesis. BCAA did not decrease the mRNA level of atrogin-1 or MuRF1. These findings suggested that Dex failed to modulate muscle mass and that BCAA was unable to activate mTOR in SDRs because these phosphorylations of p70S6K and 4E-BP1 and the reductions of these mRNAs are regulated by mTOR. In contrast, after GH supplementation, these responses to Dex were normalized and muscle fiber CSA was decreased by Dex. BCAA prevented the Dex-induced decrease in CSA. BCAA increased the phosphorylation of p70S6K and decreased the Dex-induced elevations of atrogin-1 and Bnip3 mRNAs. However, the amount of mTORC1 components including mTOR was not decreased in the SDRs compared to the normal rats. These findings suggest that GH increases mTORC1 activity but not its content to recover the action of BCAA in SDRs and that GH is required for actions of Dex and BCAA in muscles. PMID:26086773

  14. Effect of early handling of turkey poults on later responses to a dexamethasone-Escherichia coli challenge. 1. Production values and physiological response.

    PubMed

    Huff, G R; Huff, W E; Balog, J M; Rath, N C

    2001-09-01

    The stress responses of mice and rats has been shown to be permanently altered by brief, gentle handling during the first 10 d of life, resulting in increased BW and resistance to stress-induced immunosuppression. The purpose of this study was to determine whether early handling of turkey poults could permanently affect production values and physiology of adult turkeys. Turkey poults were handled 0, 1 (1x), or 2 (2x) times daily for the first 10 d after hatch. Handling consisted of gently catching each poult and holding it for 10 s. On Day 11 after hatch, half of the birds from each handling treatment were treated with three injections of 2 mg dexamethasone (DEX)/kg BW on alternating days. On the day of the third DEX injection, duplicate pens of birds were also inoculated in the airsac with 0 or 50 cfu of Escherichia coli. The same birds were treated with a second series of DEX injections at 5 wk of age. Two weeks later, all birds were weighed, and 3 wk later four birds per pen were bled and 10 birds per pen were necropsied; relative organ weights were then determined. Surviving birds were treated with a third series of DEX injections at 10 wk of age; 2 wk later, all surviving turkeys were bled, weighed, and necropsied. Feed consumption was determined weekly. There were no differences due to handling treatment on the body weights or on the relative organ weights of birds that died after the first DEX treatment. Birds treated with a second DEX injection at 5 wk of age and handled 1x daily had decreased BW. Those handled 1x or 2x daily had higher feed conversion ratios. Surviving birds that were given a third DEX treatment had higher BW and no difference in feed conversion when handled 1x or 2x daily. Relative liver, heart, and spleen weights were affected by handling of DEX-E. coli-treated birds, as were serum chemistry values for calcium, iron, glucose, total protein, blood urea nitogen, uric acid, aspartate aminotransferase, alanine aminotransferase, lactate

  15. Remote-controlled eradication of astrogliosis in spinal cord injury via electromagnetically-induced dexamethasone release from "smart" nanowires.

    PubMed

    Gao, Wen; Borgens, Richard Ben

    2015-08-10

    We describe a system to deliver drugs to selected tissues continuously, if required, for weeks. Drugs can be released remotely inside the small animals using pre-implanted, novel vertically aligned electromagnetically-sensitive polypyrrole nanowires (PpyNWs). Approximately 1-2mm(2) dexamethasone (DEX) doped PpyNWs was lifted on a single drop of sterile water by surface tension, and deposited onto a spinal cord lesion in glial fibrillary acidic protein-luc transgenic mice (GFAP-luc mice). Overexpression of GFAP is an indicator of astrogliosis/neuroinflammation in CNS injury. The corticosteroid DEX, a powerful ameliorator of inflammation, was released from the polymer by external application of an electromagnetic field for 2h/day for a week. The GFAP signal, revealed by bioluminescent imaging in the living animal, was significantly reduced in treated animals. At 1week, GFAP was at the edge of detection, and in some experimental animals, completely eradicated. We conclude that the administration of drugs can be controlled locally and non-invasively, opening the door to many other known therapies, such as the cases that dexamethasone cannot be safely applied systemically in large concentrations. PMID:25979326

  16. Melatonin ameliorates dexamethasone-induced inhibitory effects on the proliferation of cultured progenitor cells obtained from adult rat hippocampus.

    PubMed

    Ekthuwapranee, Kasima; Sotthibundhu, Areechun; Tocharus, Chainarong; Govitrapong, Piyarat

    2015-01-01

    Glucocorticoids, hormones that are released in response to stress, induce neuronal cell damage. The hippocampus is a primary target of glucocorticoids in the brain, the effects of which include the suppression of cell proliferation and diminished neurogenesis in the dentate gyrus. Our previous study found that melatonin, synthesized primarily in the pineal, pretreatment prevented the negative effects of dexamethasone, the glucocorticoid receptor agonist, on behavior and neurogenesis in rat hippocampus. In the present study, we attempted to investigate the interrelationship between melatonin and dexamethasone on the underlying mechanism of neural stem cell proliferation. Addition of dexamethasone to hippocampal progenitor cells from eight-week old rats resulted in a decrease in the number of neurospheres; pretreatment with melatonin precluded these effects. The immunocytochemical analyses indicated a reduction of Ki67 and nestin-positive cells in the dexamethasone-treated group, which was minimized by melatonin pretreatment. A reduction of the extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation and G1-S phase cell cycle regulators cyclin E and CDK2 in dexamethasone-treated progenitor cells were prevented by pretreatment of melatonin. Moreover, luzindole, a melatonin receptor antagonist blocked the positive effect of melatonin whereas RU48, the glucocorticoid receptor antagonist blocked the negative effect of dexamethasone on the number of neurospheres. Moreover, we also found that dexamethasone increased the glucocorticoid receptor protein but decreased the level of MT1 melatonin receptor, whereas melatonin increased the level of MT1 melatonin receptor but decreased the glucocorticoid receptor protein. These suggest the crosstalk and cross regulation between the melatonin receptor and the glucocorticoid receptor on hippocampal progenitor cell proliferation.

  17. The Impact of Prenatal Exposure to Dexamethasone on Gastrointestinal Function in Rats

    PubMed Central

    Ramalhosa, Fátima; Soares-Cunha, Carina; Seixal, Rui Miguel; Sousa, Nuno; Carvalho, Ana Franky

    2016-01-01

    Antenatal treatment with synthetic glucocorticoids is commonly used in pregnant women at risk of preterm delivery to accelerate tissue maturation. Exposure to glucocorticoids during development has been hypothesized to underlie different functional gastrointestinal (GI) and motility disorders. Herein, we investigated the impact of in utero exposure to synthetic glucocorticoids (iuGC) on GI function of adult rats. Wistar male rats, born from pregnant dams treated with dexamethasone (DEX), were studied at different ages. Length, histologic analysis, proliferation and apoptosis assays, GI transit, permeability and serotonin (5-HT) content of GI tract were measured. iuGC treatment decreased small intestine size and decreased gut transit. However, iuGC had no impact on intestinal permeability. iuGC differentially impacts the structure and function of the GI tract, which leads to long-lasting alterations in the small intestine that may predispose subjects prone to disorders of the GI tract. PMID:27584049

  18. The Impact of Prenatal Exposure to Dexamethasone on Gastrointestinal Function in Rats.

    PubMed

    Ramalhosa, Fátima; Soares-Cunha, Carina; Seixal, Rui Miguel; Sousa, Nuno; Carvalho, Ana Franky

    2016-01-01

    Antenatal treatment with synthetic glucocorticoids is commonly used in pregnant women at risk of preterm delivery to accelerate tissue maturation. Exposure to glucocorticoids during development has been hypothesized to underlie different functional gastrointestinal (GI) and motility disorders. Herein, we investigated the impact of in utero exposure to synthetic glucocorticoids (iuGC) on GI function of adult rats. Wistar male rats, born from pregnant dams treated with dexamethasone (DEX), were studied at different ages. Length, histologic analysis, proliferation and apoptosis assays, GI transit, permeability and serotonin (5-HT) content of GI tract were measured. iuGC treatment decreased small intestine size and decreased gut transit. However, iuGC had no impact on intestinal permeability. iuGC differentially impacts the structure and function of the GI tract, which leads to long-lasting alterations in the small intestine that may predispose subjects prone to disorders of the GI tract. PMID:27584049

  19. Early dexamethasone relieves trigeminal neuropathic pain.

    PubMed

    Han, S R; Yeo, S P; Lee, M K; Bae, Y C; Ahn, D K

    2010-09-01

    The analgesic effects of dexamethasone on neuropathic pain have been controversial. The present study investigated the effects of dexamethasone on mechanical allodynia in rats with mal-positioned dental implants. Under anesthesia, the left mandibular second molar was extracted and replaced by a miniature dental implant to injure the inferior alveolar nerve. Nociceptive behavior was examined on each designated day after surgery. Mal-positioned dental implants significantly decreased air-puff thresholds both ipsilateral and contralateral to the injury site. Distinct mechanical hyperalgesia and cold and thermal hypersensitivity were also observed bilaterally. Daily administration of dexamethasone produced prolonged anti-allodynic effects (25 or 50 mg/kg, i.p.), but failed to reduce mechanical allodynia when it had already been established. Therefore, our findings provide that early treatment with dexamethasone is important in the treatment of nociceptive behavior suggestive of trigeminal neuropathic pain. PMID:20581355

  20. Effect of dexamethasone on babesiasis in hamsters.

    PubMed

    Eckblad, W P; Stiller, D; Woodard, L F; Kuttler, K L

    1984-09-01

    Three subcutaneous injections of 0.20 mg of dexamethasone/kg of body weight caused a substantial increase in Babesia microti-parasitized RBC of hamsters, indicating that this was a useful method for revealing the presence of latent infections. A relative neutrophilia, lymphocytopenia, and eosinopenia were also seen in the long-term B microti-infected carrier hamsters after 0.20 mg or 0.02 mg of dexamethasone/kg. Noninfected hamsters treated with dexamethasone had a neutrophilic leukocytosis and a transient lymphocytopenia. Spleen to body weight ratios of noninfected hamsters decreased significantly (P less than 0.02) after 4 injections with either dosage level. These ratios did not significantly (P greater than 0.05) decrease in dexamethasone-treated infected hamsters.

  1. Dexamethasone suppresses gonadotropin-releasing hormone (GnRH) secretion and has direct pituitary effects in male rats: differential regulation of GnRH receptor and gonadotropin responses to GnRH.

    PubMed

    Rosen, H; Jameel, M L; Barkan, A L

    1988-06-01

    Endogenous or exogenous glucocorticoid excess leads to the development of hypogonadotropic hypogonadism, but the site(s) and mechanisms of glucocorticoid action are uncertain. We studied the effects of various doses of dexamethasone (Dex) on the hypothalamic-pituitary-gonadal axis in intact and castrate testosterone-replaced (cast + T) male rats and attempted to determine possible sites of Dex effects. A dose-dependent suppression of basal gonadotropin secretion was induced by 5 days of Dex treatment (20, 100, 500, or 2,500 micrograms/kg.day), and the highest dose completely abolished the postcastration rise in pituitary GnRH receptor number (GnRH-R) and serum gonadotropin levels. Administration of exogenous GnRH (0.02-200 micrograms/day over 2 days) resulted in a dose-dependent induction in GnRH-R in both intact and cast + T rats, but the effect was significantly (P less than 0.01) augmented in Dex-treated animals. In contrast, acute LH and FSH responses to GnRH (10, 25, 50, 100, or 250 ng, iv) were significantly blunted in Dex-treated rats. The data suggest that 1) Dex suppresses hypothalamic GnRH secretion, thereby preventing the postcastration rises in GnRH-R and gonadotropins; 2) at the pituitary level, Dex dissociates GnRH-R and gonadotropin responses to GnRH, augmenting GnRH-R induction by GnRH and suppressing gonadotropin responses to GnRH at a postreceptor site; and 3) the model of Dex-treated rats may be useful to study differential GnRH regulation of GnRH-R and gonadotropin secretion.

  2. Intra-Erythrocyte Infusion of Dexamethasone Reduces Neurological Symptoms in Ataxia Teleangiectasia Patients: Results of a Phase 2 Trial

    PubMed Central

    2014-01-01

    Background Ataxia Teleangiectasia [AT] is a rare neurodegenerative disease characterized by early onset ataxia, oculocutaneous teleangiectasias, immunodeficiency, recurrent infections, radiosensitivity and proneness to cancer. No therapies are available for this devastating disease. Recent observational studies in few patients showed beneficial effects of short term treatment with betamethasone. To avoid the characteristic side effects of long-term administration of steroids we developed a method for encapsulation of dexamethasone sodium phosphate (DSP) into autologous erythrocytes (EryDex) allowing slow release of dexamethasone for up to one month after dosing. Aims of the study were: the assessment of the effect of EryDex in improving neurological symptoms and adaptive behaviour of AT patients; the safety and tolerability of the therapy. Methods Twenty two patients (F:M = 1; mean age 11.2 ± 3.5) with a confirmed diagnosis of AT and a preserved or partially supported gait were enrolled for the study. The subjects underwent for six months a monthly infusion of EryDex. Ataxia was assessed by the International Cooperative Ataxia Rating Scale (ICARS) and the adaptive behavior by Vineland Adaptive Behavior Scales (VABS). Clinical evaluations were performed at baseline and 1, 3, and 6 months. Results An improvement in ICARS (reduction of the score) was detected in the intention-to-treat (ITT) population (n = 22; p = 0.02) as well as in patients completing the study (per protocol PP) (n = 18; p = 0.01), with a mean reduction of 4 points (ITT) or 5.2 points (PP). When compared to baseline, a significant improvement were also found in VABS (increase of the score) (p < 0.0001, ITT, RMANOVA), with statistically significant increases at 3 and 6 months (p < 0.0001). A large inter-patient variability in the incorporation of DSP into erythrocytes was observed, with an evident positive effect of higher infusion dose on ICARS score decline

  3. The effects of BMP6 overexpression on adipose stem cell chondrogenesis: Interactions with dexamethasone and exogenous growth factors.

    PubMed

    Diekman, Brian O; Estes, Bradley T; Guilak, Farshid

    2010-06-01

    Adipose-derived stem cells (ASCs) are multipotent progenitors that can be chondrogenically induced by growth factors such as bone morphogenetic protein 6 (BMP-6). We hypothesized that nonviral transfection of a BMP-6 construct (pcDNA3-BMP6) would induce chondrogenic differentiation of ASCs encapsulated in alginate beads and that differentiation would be enhanced by the presence of the synthetic glucocorticoid dexamethasone (DEX) or the combination of epidermal growth factor (EGF), fibroblast growth factor-2 (FGF-2), and transforming growth factor beta-1 (TGF-beta1), collectively termed expansion factors (EFs). Chondrogenesis was assessed using quantitative real-time polymerase chain reaction for types I, II, and X collagen, aggrecan, and BMP6. Immunohistochemistry was performed with antibodies for types I, II, and X collagen and chondroitin-4-sulfate. BMP6 overexpression alone induced a moderate chondrogenic response. The inclusion of EFs promoted robust type II collagen expression but also increased type I and X collagen deposition, consistent with a hypertrophic chondrocyte phenotype. Early gene expression data indicated that DEX was synergistic with BMP-6 for chondrogenesis, but immunohistochemistry at 28 days showed that DEX reduced glycosaminoglycan accumulation. These results suggest that chondrogenic differentiation of ASCs depends on complex interactions among various growth factors and media supplements, as well as the concentration and duration of growth factor exposure. PMID:19722282

  4. Upregulation of nucleoside triphosphate diphosphohydrolase-1 and ecto-5'-nucleotidase in rat hippocampus after repeated low-dose dexamethasone administration.

    PubMed

    Drakulić, Dunja; Stanojlović, Miloš; Nedeljković, Nadežda; Grković, Ivana; Veličković, Nataša; Guševac, Ivana; Mitrović, Nataša; Buzadžić, Ivana; Horvat, Anica

    2015-04-01

    Although dexamethasone (DEX), a synthetic glucocorticoid receptor (GR) analog with profound effects on energy metabolism, immune system, and hypothalamic-pituitary-adrenal axis, is widely used therapeutically, its impact on the brain is poorly understood. The aim of the present study was to explore the effect of repeated low-dose DEX administration on the activity and expression of the ectonucleotidase enzymes which hydrolyze and therefore control extracellular ATP and adenosine concentrations in the synaptic cleft. Ectonucleotidases tested were ectonucleoside triphosphate diphosphohydrolase 1-3 (NTPDase1-3) and ecto-5'-nucleotidase (eN), whereas the effects were evaluated in two brain areas that show different sensitivity to glucocorticoid action, hippocampus, and cerebral cortex. In the hippocampus, but not in cerebral cortex, modest level of neurodegenerative changes as well as increase in ATP, ADP, and AMP hydrolysis and upregulation of NTPDase1 and eN mRNA expression ensued under the influence of DEX. The observed pattern of ectonucleotidase activation, which creates tissue volume with enhanced capacity for adenosine formation, is the hallmark of the response after different insults to the brain.

  5. The effects of sympathectomy and dexamethasone in rats ingesting sucrose

    PubMed Central

    Franco-Colín, Margarita; Villanueva, Iván; Piñón, Manuel; Racotta, Radu

    2006-01-01

    Both high-sucrose diet and dexamethasone (D) treatment increase plasma insulin and glucose levels and induce insulin resistance. We showed in a previous work (Franco-Colin, et al. Metabolism 2000; 49:1289-1294) that combining both protocols for 7 weeks induced less body weight gain in treated rats without affecting mean daily food intake. Since such an effect may be explained by an increase in caloric expenditure, possibly due to activation of the sympathetic nervous system by sucrose ingestion, in this work, and using 10% sucrose in the drinking water, male Wistar rats were divided into 4 groups. Two groups were sympathectomized using guanethidine (Gu) treatment for 3 weeks. One of these groups of rats received D in the drinking water. Of the 2 groups not receiving Gu, one was the control (C) and the other received D. After 8 weeks a glucose tolerance test was done. The rats were sacrificed and liver triglyceride (TG), perifemoral muscle lipid, and norepinephrine (NE) levels in the liver spleen, pancreas, and heart were determined. Gu-treated rats (Gu and Gu+D groups) showed less than 10% NE concentration compared to C and D rats, less daily caloric intake and body-weight gain, more sucrose intake, and better glucose tolerance. The area under the curve after glucose administration correlated significantly with the mean body weight gain of the rats, except for D group. Groups D (D and Gu+D) also showed less caloric intake and body-weight gain but higher liver weight and TG concentration and lower peripheral muscle mass. The combination of Gu+D treatments showed some peculiar results: negative body weight gain, a fatty liver, and low muscle mass. Though the glucose tolerance test had the worst results for the D group, it showed the best results in the Gu+D group. There were significant interactions for Guan X Dex by two-way ANOVA test for the area under the curve in the glucose tolerance test, muscle mass, and muscle lipids. The results suggest that dexamethasone

  6. Hydroxyapatite/polylactide biphasic combination scaffold loaded with dexamethasone for bone regeneration.

    PubMed

    Son, Jun-Sik; Kim, Su-Gwan; Oh, Ji-Su; Appleford, Mark; Oh, Sunho; Ong, Joo L; Lee, Kyu-Bok

    2011-12-15

    This study presents a novel design of a ceramic/polymer biphasic combination scaffold that mimics natural bone structures and is used as a bone graft substitute. To mimic the natural bone structures, the outside cortical-like shells were composed of porous hydroxyapatite (HA) with a hollow interior using a polymeric template-coating technique; the inner trabecular-like core consisted of porous poly(D,L-lactic acid) (PLA) that was loaded with dexamethasone (DEX) and was directly produced using a particle leaching/gas forming technique to create the inner diameter of the HA scaffold. It was observed that the HA and PLA parts of the fabricated HA/PLA biphasic scaffold contained open and interconnected pore structures, and the boundary between both parts was tightly connected without any gaps. It was found that the structure of the combination scaffold was analogous to that of natural bone based on micro-computed tomography analysis. Additionally, the dense, uniform apatite layer was formed on the surface of the HA/PLA biphasic scaffold through a biomimetic process, and DEX was successfully released from the PLA of the biphasic scaffold over a 1-month period. This release caused human embryonic palatal mesenchyme cells to proliferate, differentiate, produce ECM, and form tissue in vitro. Therefore, it was concluded that this functionally graded scaffold is similar to natural bone and represents a potential bone-substitute material.

  7. Antihypertensive and antioxidant effects of hydroalcoholic extract from the aerial parts of Kelussia odoratissima Mozaff. in dexamethasone-induced hypertensive rats

    PubMed Central

    Safaeian, Leila; Sajjadi, Seyed Ebrahim; Javanmard, Shaghayegh Haghjoo; Gholamzadeh, Hadi

    2016-01-01

    Background: Kelussia odoratissima Mozaff. is a monotypic endemic plant of Apiaceae growing wild in Iran. The aerial parts of this plant are used for treatment of hypertension, ulcer, and inflammatory conditions in folk medicine. In this study, the effects of hydroalcoholic extract of the aerial parts of K. odoratissima were evaluated in dexamethasone (Dex)-induced hypertension in male Wistar rats. Materials and Methods: For induction of hypertension, Dex (30 μg/kg/day) was administered subcutaneously for 14 days. In a prevention study, rats received oral K. odoratissima extract (100, 200, and 400 mg/kg) from 4 days before Dex administration and during the test period (days 1–18). In a reversal study, K. odoratissima extract was administered orally from day 8 to 14. Systolic blood pressure (SBP) was evaluated using tail-cuff method. The hydrogen peroxide (H2O2) concentration and ferric-reducing antioxidant power (FRAP) were measured in plasma samples. Results: Administrations of Dex significantly induced an increase in SBP and in plasma H2O2 and a decrease in body and thymus weights, and in FRAP value (P < 0.001). K. odoratissima extract dose-dependently prevented and reversed hypertension (P < 0.001). It also prevented and reduced the plasma H2O2 concentration and prevented the body weight loss upon Dex administration at all doses (100–400 mg/kg, P < 0.001) but failed to improve FRAP value. Conclusions: These results suggest antihypertensive and antioxidant effects of K. odoratissima extract in Dex-induced hypertension. Further studies are needed to elucidate the exact mechanism of the antihypertensive effect of this herbal medicine. PMID:27014652

  8. Age-related changes in thirst, salt appetite, and arterial blood pressure in response to aldosterone-dexamethasone combination in rats

    PubMed Central

    Xue, Baojian; Beltz, Terry G.; Johnson, Alan Kim

    2015-01-01

    This work examined the effects of age on daily water and sodium ingestion and cardiovascular responses to chronic administration of the mineralocorticoid, aldosterone (ALDO) either alone or together with the glucocorticoid, dexamethasone (DEX). Young (4 mo), adult (12 mo), and aged (30 mo) male Brown Norway rats were prepared for continuous telemetry recording of blood pressure (BP) and heart rate (HR). Baseline water and sodium (i.e., 0.3 M NaCl) intake, BP, and HR were established for 10 days. Then ALDO (60 μg/day sc) was infused alone, or together with DEX (2.5 or 20 μg/day sc), for another 10 days. Compared with baseline levels, ALDO stimulated comparable increases in daily saline intake at all ages. ALDO together with the higher dose of DEX (i.e., ALDO/DEX20) increased daily saline intake more than did ALDO, but less so in aged rats. Infusion of ALDO/DEX20 increased mean arterial pressure (MAP), and decreased HR, more than did infusion of ALDO. The changes in MAP in response to both treatments depended on age. For all ages, MAP and saline intake increased simultaneously during ALDO, while MAP always increased before saline intake did during ALDO/DEX20. Contrary to our predictions, MAP did not increase more in old rats in response to either treatment. We speculate that age-related declines in cardiovascular responses to glucocorticoids contributed to the attenuated increases in sodium intake in response to glucocorticoids that were observed in older animals. PMID:25833938

  9. Electrophoretic Deposition of Dexamethasone-Loaded Mesoporous Silica Nanoparticles onto Poly(L-Lactic Acid)/Poly(ε-Caprolactone) Composite Scaffold for Bone Tissue Engineering.

    PubMed

    Qiu, Kexin; Chen, Bo; Nie, Wei; Zhou, Xiaojun; Feng, Wei; Wang, Weizhong; Chen, Liang; Mo, Xiumei; Wei, Youzhen; He, Chuanglong

    2016-02-17

    The incorporation of microcarriers as drug delivery vehicles into polymeric scaffold for bone regeneration has aroused increasing interest. In this study, the aminated mesoporous silica nanoparticles (MSNs-NH2) were prepared and used as microcarriers for dexamethasone (DEX) loading. Poly(l-lactic acid)/poly(ε-caprolactone) (PLLA/PCL) nanofibrous scaffold was fabricated via thermally induced phase separation (TIPS) and served as template, onto which the drug-loaded MSNs-NH2 nanoparticles were deposited by electrophoretic deposition (EPD). The physicochemical and release properties of the prepared scaffolds (DEX@MSNs-NH2/PLLA/PCL) were examined, and their osteogenic activities were also evaluated through in vitro and in vivo studies. The release of DEX from the scaffolds revealed an initial rapid release followed by a slower and sustained one. The in vitro results indicated that the DEX@MSNs-NH2/PLLA/PCL scaffold exhibited good biocompatibility to rat bone marrow-derived mesenchymal stem cells (BMSCs). Also, BMSCs cultured on the DEX@MSNs-NH2/PLLA/PCL scaffold exhibited a higher degree of osteogenic differentiation than those cultured on PLLA/PCL and MSNs-NH2/PLLA/PCL scaffolds, in terms of alkaline phosphatase (ALP) activity, mineralized matrix formation, and osteocalcin (OCN) expression. Furthermore, the in vivo results in a calvarial defect model of Sprague-Dawley (SD) rats demonstrated that the DEX@MSNs-NH2/PLLA/PCL scaffold could significantly promote calvarial defect healing compared with the PLLA/PCL scaffold. Thus, the EPD technique provides a convenient way to incorporate osteogenic agents-containing microcarriers to polymer scaffold, and thus, prepared composite scaffold could be a potential candidate for bone tissue engineering application due to its capacity for delivery of osteogenic agents.

  10. Comparison of In Vivo Gene Expression Profiling of RPE/Choroid following Intravitreal Injection of Dexamethasone and Triamcinolone Acetonide.

    PubMed

    Smit-McBride, Zeljka; Moisseiev, Elad; Modjtahedi, Sara P; Telander, David G; Hjelmeland, Leonard M; Morse, Lawrence S

    2016-01-01

    Purpose. To identify retinal pigment epithelium (RPE)/choroid genes and their relevant expression pathways affected by intravitreal injections of dexamethasone and triamcinolone acetonide in mice at clinically relevant time points for patient care. Methods. Differential gene expression of over 34,000 well-characterized mouse genes in the RPE/choroid of 6-week-old C57BL/6J mice was analyzed after intravitreal steroid injections at 1 week and 1 month postinjection, using Affymetrix Mouse Genome 430 2.0 microarrays. The data were analyzed using GeneSpring GX 12.5 and Ingenuity Pathway Analysis (IPA) microarray analysis software for biologically relevant changes. Results. Both triamcinolone and dexamethasone caused differential activation of genes involved in "Circadian Rhythm Signaling" pathway at both time points tested. Triamcinolone (TAA) uniquely induced significant changes in gene expression in "Calcium Signaling" (1 week) and "Glutamate Receptor Signaling" pathways (1 month). In contrast, dexamethasone (Dex) affected the "GABA Receptor Signaling" (1 week) and "Serotonin Receptor Signaling" (1 month) pathways. Understanding how intraocular steroids affect the gene expression of RPE/choroid is clinically relevant. Conclusions. This in vivo study has elucidated several genes and pathways that are potentially altering the circadian rhythms and several other neurotransmitter pathways in RPE/choroid during intravitreal steroid injections, which likely has consequences in the dysregulation of RPE function and neurodegeneration of the retina. PMID:27429799

  11. Comparison of In Vivo Gene Expression Profiling of RPE/Choroid following Intravitreal Injection of Dexamethasone and Triamcinolone Acetonide

    PubMed Central

    Smit-McBride, Zeljka; Moisseiev, Elad; Modjtahedi, Sara P.; Telander, David G.; Hjelmeland, Leonard M.; Morse, Lawrence S.

    2016-01-01

    Purpose. To identify retinal pigment epithelium (RPE)/choroid genes and their relevant expression pathways affected by intravitreal injections of dexamethasone and triamcinolone acetonide in mice at clinically relevant time points for patient care. Methods. Differential gene expression of over 34,000 well-characterized mouse genes in the RPE/choroid of 6-week-old C57BL/6J mice was analyzed after intravitreal steroid injections at 1 week and 1 month postinjection, using Affymetrix Mouse Genome 430 2.0 microarrays. The data were analyzed using GeneSpring GX 12.5 and Ingenuity Pathway Analysis (IPA) microarray analysis software for biologically relevant changes. Results. Both triamcinolone and dexamethasone caused differential activation of genes involved in “Circadian Rhythm Signaling” pathway at both time points tested. Triamcinolone (TAA) uniquely induced significant changes in gene expression in “Calcium Signaling” (1 week) and “Glutamate Receptor Signaling” pathways (1 month). In contrast, dexamethasone (Dex) affected the “GABA Receptor Signaling” (1 week) and “Serotonin Receptor Signaling” (1 month) pathways. Understanding how intraocular steroids affect the gene expression of RPE/choroid is clinically relevant. Conclusions. This in vivo study has elucidated several genes and pathways that are potentially altering the circadian rhythms and several other neurotransmitter pathways in RPE/choroid during intravitreal steroid injections, which likely has consequences in the dysregulation of RPE function and neurodegeneration of the retina. PMID:27429799

  12. Contralateral eye-to-eye comparison of intravitreal ranibizumab and a sustained-release dexamethasone intravitreal implant in recalcitrant diabetic macular edema

    PubMed Central

    Thomas, Benjamin J; Yonekawa, Yoshihiro; Wolfe, Jeremy D; Hassan, Tarek S

    2016-01-01

    Objective To compare the effects of intravitreal ranibizumab (RZB) or dexamethasone (DEX) intravitreal implant in cases of recalcitrant diabetic macular edema (DME). Methods Retrospective, interventional study examining patients with symmetric bilateral, center-involved DME recalcitrant to treatment with RZB, who received DEX in one eye while the contralateral eye continued to receive RZB every 4–5 weeks for a study period of 3 months. Results Eleven patients (22 eyes) were included: mean logarithm of the minimal angle of resolution (logMAR) visual acuity (VA) for the DEX arm improved from 0.415 (standard deviation [SD] ±0.16) to 0.261 (SD ±0.18) at final evaluation, and mean central macular thickness (CMT) improved from 461 µm (SD ±156) to 356 µm (SD ±110; net decrease: 105 µm, P=0.01). Mean logMAR VA for the RZB arm improved from 0.394 (SD ±0.31) to 0.269 (SD ±0.19) at final evaluation. Mean CMT improved from 421 µm (SD ±147) to 373 µm (SD ±129; net decrease: 48 µm, P=0.26). Conclusion A subset of recalcitrant DME patients demonstrated significant CMT reduction and VA improvement after a single DEX injection. PMID:27621587

  13. Insights from the predicted interactions of plant derived compounds to the gluco-corticoid receptor as an alternative to dexa-methasone

    PubMed Central

    Sarmah, Rajeev

    2012-01-01

    Dexamethasone (DEX) an anti-inflamatory 9-fluoro-glucocorticoid, activates the cytosolic glucocorticoid receptor (GR) binding to its Ligand Binding Domain (LBD). The GR-ligand complex then translocates to the nucleus and binds to the Glucocorticoid Response Element (GRE) resulting up-regulation of target gene expression of anti-inflamatory proteins. DEX is one of the most effective ligand for GR activation but comply to side effects. Therefore, alternative for DEX – plant metabolites of Calotropis sp and Swertia chirata were screened using docking appraoch. These plants compounds were selected because; parts of these plants are widely used againsts inflamation, allergy, asthma etc. Three metabolites of Swertia chirata namely Gentianine (GENT), Xanthone (XANT) and Swerchirin (SWER) are found to be occupying the same binding pocket in the LBD of the GR (PDB ID 1M2Z). The binding affinity as reflected by binding energies of GENT-1M2Z, XANT-1M2Z and SWER-1M2Z are -5.6, -6.7 and -6.7, and all the output parameter of the respective compounds positively correlates with that of DEX-1M2Z with r = 0.9, 0.6 and 0.6 respectively indicating similar GR activation function. Visualization analysis of the models clearly indicates that GENT and SWER may be GR activators. Rest of the compounds mostly docked onto the surface of the receptor molecule. PMID:23275688

  14. Dexamethasone potentiates in vitro blood-brain barrier recovery after primary blast injury by glucocorticoid receptor-mediated upregulation of ZO-1 tight junction protein.

    PubMed

    Hue, Christopher D; Cho, Frances S; Cao, Siqi; Dale Bass, Cameron R; Meaney, David F; Morrison, Barclay

    2015-07-01

    Owing to the frequent incidence of blast-induced traumatic brain injury (bTBI) in recent military conflicts, there is an urgent need to develop effective therapies for bTBI-related pathologies. Blood-brain barrier (BBB) breakdown has been reported to occur after primary blast exposure, making restoration of BBB function and integrity a promising therapeutic target. We tested the hypothesis that treatment with dexamethasone (DEX) after primary blast injury potentiates recovery of an in vitro BBB model consisting of mouse brain endothelial cells (bEnd.3). DEX treatment resulted in complete recovery of transendothelial electrical resistance and hydraulic conductivity 1 day after injury, compared with 3 days for vehicle-treated injured cultures. Administration of RU486 (mifepristone) inhibited effects of DEX, confirming that barrier restoration was mediated by glucocorticoid receptor signaling. Potentiated recovery with DEX treatment was accompanied by stronger zonula occludens (ZO)-1 tight junction immunostaining and expression, suggesting that increased ZO-1 expression was a structural correlate to BBB recovery after blast. Interestingly, augmented ZO-1 protein expression was associated with specific upregulation of the α(+) isoform but not the α(-) isoform. This is the first study to provide a mechanistic basis for potentiated functional recovery of an in vitro BBB model because of glucocorticoid treatment after primary blast injury.

  15. Insights from the predicted interactions of plant derived compounds to the gluco-corticoid receptor as an alternative to dexa-methasone.

    PubMed

    Sarmah, Rajeev

    2012-01-01

    Dexamethasone (DEX) an anti-inflamatory 9-fluoro-glucocorticoid, activates the cytosolic glucocorticoid receptor (GR) binding to its Ligand Binding Domain (LBD). The GR-ligand complex then translocates to the nucleus and binds to the Glucocorticoid Response Element (GRE) resulting up-regulation of target gene expression of anti-inflamatory proteins. DEX is one of the most effective ligand for GR activation but comply to side effects. Therefore, alternative for DEX - plant metabolites of Calotropis sp and Swertia chirata were screened using docking appraoch. These plants compounds were selected because; parts of these plants are widely used againsts inflamation, allergy, asthma etc. Three metabolites of Swertia chirata namely Gentianine (GENT), Xanthone (XANT) and Swerchirin (SWER) are found to be occupying the same binding pocket in the LBD of the GR (PDB ID 1M2Z). The binding affinity as reflected by binding energies of GENT-1M2Z, XANT-1M2Z and SWER-1M2Z are -5.6, -6.7 and -6.7, and all the output parameter of the respective compounds positively correlates with that of DEX-1M2Z with r = 0.9, 0.6 and 0.6 respectively indicating similar GR activation function. Visualization analysis of the models clearly indicates that GENT and SWER may be GR activators. Rest of the compounds mostly docked onto the surface of the receptor molecule.

  16. Risk-adapted autologous stem cell transplantation with adjuvant dexamethasone +/- thalidomide for systemic light-chain amyloidosis: results of a phase II trial.

    PubMed

    Cohen, Adam D; Zhou, Ping; Chou, Joanne; Teruya-Feldstein, Julie; Reich, Lilian; Hassoun, Hani; Levine, Beth; Filippa, Daniel A; Riedel, Elyn; Kewalramani, Tarun; Stubblefield, Michael D; Fleisher, Martin; Nimer, Stephen; Comenzo, Raymond L

    2007-10-01

    High-dose melphalan (MEL) with autologous stem cell transplant (SCT) is an effective therapy for systemic AL amyloidosis (AL), but treatment-related mortality (TRM) has historically been high. We performed a phase II trial of risk-adapted SCT followed by adjuvant dexamethasone (dex) and thalidomide (thal) in an attempt to reduce TRM and improve response rates. Patients (n = 45) with newly diagnosed AL involving < or =2 organ systems were assigned to MEL 100, 140, or 200 mg/m(2) with SCT, based on age, renal function and cardiac involvement. Patients with persistent clonal plasma cell disease 3 months post-SCT received 9 months of adjuvant thal/dex (or dex if there was a history of deep vein thrombosis or neuropathy). Organ involvement was kidney (67%), heart (24%), liver/GI (22%) and peripheral nervous system (18%), with 31% having two organs involved. TRM was 4.4%. Thirty-one patients began adjuvant therapy, with 16 (52%) completing 9 months of treatment and 13 (42%) achieving an improvement in haematological response. By intention-to-treat, overall haematological response rate was 71% (36% complete response), with 44% having organ responses. With a median follow-up of 31 months, 2-year survival was 84% (95% confidence interval: 73%, 94%). Risk-adapted SCT with adjuvant thal/dex is feasible and results in low TRM and high haematological and organ response rates in AL patients. PMID:17897298

  17. Exon ligation is proofread by the DExD/H-box ATPase Prp22p.

    PubMed

    Mayas, Rabiah M; Maita, Hiroshi; Staley, Jonathan P

    2006-06-01

    To produce messenger RNA, the spliceosome excises introns from precursor (pre)-mRNA and splices the flanking exons. To establish fidelity, the spliceosome discriminates against aberrant introns, but current understanding of such fidelity mechanisms is limited. Here we show that an ATP-dependent activity represses formation of mRNA from aberrant intermediates having mutations in any of the intronic consensus sequences. This proofreading activity is disabled by mutations that impair the ATPase or RNA unwindase activity of Prp22p, a conserved spliceosomal DExD/H-box ATPase. Further, cold-sensitive prp22 mutants permit aberrant mRNA formation from a mutated 3' splice-site intermediate in vivo. We conclude that Prp22p generally represses splicing of aberrant intermediates, in addition to its known ATP-dependent role in promoting release of genuine mRNA. This dual function for Prp22p validates a general model in which fidelity can be enhanced by a DExD/H-box ATPase.

  18. Lactoferrin inhibits dexamethasone-induced chondrocyte impairment from osteoarthritic cartilage through up-regulation of extracellular signal-regulated kinase 1/2 and suppression of FASL, FAS, and Caspase 3

    SciTech Connect

    Tu, Yihui; Xue, Huaming; Francis, Wendy; Davies, Andrew P.; Pallister, Ian; Kanamarlapudi, Venkateswarlu; Xia, Zhidao

    2013-11-08

    Highlights: •Dex exerts dose-dependant inhibition of HACs viability and induction of apoptosis. •Dex-induced impairment of chondrocytes was attenuated by rhLF. •ERK and FASL/FAS signaling are involved in the effects of rhLF. •OA patients with glucocorticoid-induced cartilage damage may benefit from treatment with rhLF. -- Abstract: Dexamethasone (Dex) is commonly used for osteoarthritis (OA) with excellent anti-inflammatory and analgesic effect. However, Dex also has many side effects following repeated use over prolonged periods mainly through increasing apoptosis and inhibiting proliferation. Lactoferrin (LF) exerts significantly anabolic effect on many cells and little is known about its effect on OA chondrocytes. Therefore, the aim of this study is to investigate whether LF can inhibit Dex-induced OA chondrocytes apoptosis and explore its possible molecular mechanism involved in. MTT assay was used to determine the optimal concentration of Dex and recombinant human LF (rhLF) on chondrocytes at different time and dose points. Chondrocytes were then stimulated with Dex in the absence or presence of optimal concentration of rhLF. Cell proliferation and viability were evaluated using MTT and LIVE/DEAD assay, respectively. Cell apoptosis was evaluated by multi-parameter apoptosis assay kit using both confocal microscopy and flow cytometry, respectively. The expression of extracellular signal-regulated kinase (ERK), FAS, FASL, and Caspase-3 (CASP3) at the mRNA and protein levels were examined by real-time polymerase chain reaction (PCR) and immunocytochemistry, respectively. The optimal concentration of Dex (25 μg/ml) and rhLF (200 μg/ml) were chosen for the following experiments. rhLF significantly reversed the detrimental effect of Dex on chondrocytes proliferation, viability, and apoptosis. In addition, rhLF significantly prevented Dex-induced down-regulation of ERK and up-regulation of FAS, FASL, and CASP3. These findings demonstrated that rhLF acts as

  19. PhoDEx ' a mission to explore the interiors of Phobos and Deimos

    NASA Astrophysics Data System (ADS)

    Oberst, Jürgen; Wickhusen, Kai; Willner, Konrad

    2015-04-01

    PhoDEx (Phobos and Deimos Explorer) shall be launched on a Soyuz Fregat in 2024 or 2026, to explore the origin and evolution of Phobos and Deimos, as well as their interactions with the environments. The mission will shed light on the formation of the Martian satellites and thus on evolution processes of the solar system. Do they represent captured asteroids, or did they form from Martian ejecta? What are the interactions of Phobos/Deimos with Mars today? PhoDEx will use a variety of complementary techniques to study interior structures, chemical and mineralogical compositions of the two Martian companions as well as their environmental interactions. When arriving in the Martian system the spacecraft will first rendezvous with Deimos before proceeding to Phobos. At the two satellites comprehensive mapping and characterization for morphology, gravity field, and studies of their spectral and thermal soil characteristics will be carried out on a global scale. Crater statistics will be used to determine the ages of surface geological units and time scales of processes. A powerful short-wave radar will explore the global regolith structure. Sensors will monitor the solar wind interaction with the surfaces to help understand the evolution of regolith and space weathering. Using impact detectors, we wish to identify sources and sinks of the micrometeoroid population and address the question of Phobos/Deimos dust rings. The spacecraft will then deploy an experiment platform in the polar areas of Phobos for an operation through the summer season of more than 3 months. The package is equipped with a powerful LIBS/Raman sensor to obtain precise data on the chemistry and mineralogy of Phobos soils at the landing site. A seismometer will capture seismic signals from impacts and thermal quakes. A radio science experiment will provide accurate measurements of Phobos orbital motion and rotational librations to determine the time scales of Phobos' orbital decay. PhoDEx, benefitting

  20. Proliferation, differentiation and gene expression of osteoblasts in boron-containing associated with dexamethasone deliver from mesoporous bioactive glass scaffolds.

    PubMed

    Wu, Chengtie; Miron, Richard; Sculean, Anton; Kaskel, Stefan; Doert, Thomas; Schulze, Renate; Zhang, Yufeng

    2011-10-01

    Boron is one of the trace elements in the human body which plays an important role in bone growth. Porous mesopore bioactive glass (MBG) scaffolds are proposed as potential bone regeneration materials due to their excellent bioactivity and drug-delivery ability. The aims of the present study were to develop boron-containing MBG (B-MBG) scaffolds by sol-gel method and to evaluate the effect of boron on the physiochemistry of B-MBG scaffolds and the response of osteoblasts to these scaffolds. Furthermore, the effect of dexamethasone (DEX) delivery in B-MBG scaffold system was investigated on the proliferation, differentiation and bone-related gene expression of osteoblasts. The composition, microstructure and mesopore properties (specific surface area, nano-pore volume and nano-pore distribution) of B-MBG scaffolds have been characterized. The effect of boron contents and large-pore porosity on the loading and release of DEX in B-MBG scaffolds were also investigated. The results have shown that the incorporation of boron into MBG scaffolds slightly decreases the specific surface area and pore volume, but maintains well-ordered mesopore structure and high surface area and nano-pore volume compared to non-mesopore bioactive glass. Boron contents in MBG scaffolds did not influence the nano-pore size distribution or the loading and release of DEX. B-MBG scaffolds have the ability to maintain a sustained release of DEX in a long-term span. Incorporating boron into MBG glass scaffolds led to a controllable release of boron ions and significantly improved the proliferation and bone-related gene expression (Col I and Runx2) of osteoblasts. Furthermore, the sustained release of DEX from B-MBG scaffolds significantly enhanced alkaline phosphatase (ALP) activity and gene expressions (Col I, Runx2, ALP and BSP) of osteoblasts. These results suggest that boron plays an important role in enhancing osteoblast proliferation in B-MBG scaffold system and DEX-loaded B-MBG scaffolds

  1. Cross-Comparison of Leaching Strains Isolated from Two Different Regions: Chambishi and Dexing Copper Mines

    PubMed Central

    Ngom, Baba; Liang, Yili; Liu, Xueduan

    2014-01-01

    A cross-comparison of six strains isolated from two different regions, Chambishi copper mine (Zambia, Africa) and Dexing copper mine (China, Asia), was conducted to study the leaching efficiency of low grade copper ores. The strains belong to the three major species often encountered in bioleaching of copper sulfide ores under mesophilic conditions: Acidithiobacillus ferrooxidans, Acidithiobacillus thiooxidans, and Leptospirillum ferriphilum. Prior to their study in bioleaching, the different strains were characterized and compared at physiological level. The results revealed that, except for copper tolerance, strains within species presented almost similar physiological traits with slight advantages of Chambishi strains. However, in terms of leaching efficiency, native strains always achieved higher cell density and greater iron and copper extraction rates than the foreign microorganisms. In addition, microbial community analysis revealed that the different mixed cultures shared almost the same profile, and At. ferrooxidans strains always outcompeted the other strains. PMID:25478575

  2. Cross-comparison of leaching strains isolated from two different regions: Chambishi and Dexing copper mines.

    PubMed

    Ngom, Baba; Liang, Yili; Liu, Xueduan

    2014-01-01

    A cross-comparison of six strains isolated from two different regions, Chambishi copper mine (Zambia, Africa) and Dexing copper mine (China, Asia), was conducted to study the leaching efficiency of low grade copper ores. The strains belong to the three major species often encountered in bioleaching of copper sulfide ores under mesophilic conditions: Acidithiobacillus ferrooxidans, Acidithiobacillus thiooxidans, and Leptospirillum ferriphilum. Prior to their study in bioleaching, the different strains were characterized and compared at physiological level. The results revealed that, except for copper tolerance, strains within species presented almost similar physiological traits with slight advantages of Chambishi strains. However, in terms of leaching efficiency, native strains always achieved higher cell density and greater iron and copper extraction rates than the foreign microorganisms. In addition, microbial community analysis revealed that the different mixed cultures shared almost the same profile, and At. ferrooxidans strains always outcompeted the other strains.

  3. A Novel Technique for Performing Space Based Radiation Dosimetry Using DNA: Results from GRaDEx-I and the Design of GRaDEx-II

    NASA Technical Reports Server (NTRS)

    Ritter, Joe; Branly, R.; Theodorakis, C.; Bickham, J.; Swartz, C.; Friedfeld, R.; Ackerman, E.; Carruthers, C.; DiGirolamo, A.; Faranda, J.; Howard, E.; Bruno, C.

    1999-01-01

    systems (e.g. astronauts and greenhouses) in space. The payload was flown in a 2.5 cubic foot Get Away Special (GAS) container through NASA's GAS program. It was subjected to the environment of the space shuttle cargo bay for the duration of the STS-91 mission (9 days). Results of the genotoxicology and radiation dosimetry experiment (GRaDEx-I) as well as the design of an improved follow on payload are presented.

  4. A Novel Technique for Performing Space Based Radiation Dosimetry Using DNA-Results from GRaDEx-I and the Design of GRaDEx-II

    NASA Technical Reports Server (NTRS)

    Ritter, Joe; Branly, R.; Theodorakis, C.; Bickham, J.; Swartz, C.; Friedfeld, R.; Ackerman, E.; Carruthers, C.; DiGirolamo, A.; Faranda, J.

    1999-01-01

    systems (e.g. astronauts and greenhouses) in space. The payload was flown in a 2.5 cubic foot Get Away Special (GAS) container through NASA's GAS program. It was subjected to the environment of the space shuttle cargo bay for the duration of the STS-91 mission (9 days). Results of the genotoxicology and radiation dosimetry experiment (GRaDEx-1) as well as the design of an improved follow on payload are presented.

  5. Antidepressants attenuate the dexamethasone-induced decrease in viability and proliferation of human neuroblastoma SH-SY5Y cells: a involvement of extracellular regulated kinase (ERK1/2).

    PubMed

    Leskiewicz, M; Jantas, D; Regulska, M; Kaczanowska, J; Basta-Kaim, A; Budziszewska, B; Kubera, M; Lason, W

    2013-11-01

    Excessive glucocorticoid levels in depressed patients have been associated with atrophic changes in some brain regions, but only few studies suggest that some antidepressants can interfere with deleterious effect of glucocorticoids on neuronal cells. The aim of the present study was to examine the effect of dexamethasone (DEX), a synthetic glucocorticoid and some antidepressants from different chemical groups (imipramine, desipramine, amitriptyline, citalopram, fluoxetine, reboxetine and tianeptine) on SH-SY5Y cells cultured in the medium containing steroid-free serum. DEX in concentrations from 1 to 100 μM did not change LDH release but exposure to 10 μM and 100 μM DEX for 24, 48 and 72 h caused a significant reduction in cell viability and proliferation as confirmed by MTT reduction and BrdU ELISA assays, respectively. Twenty four-hour incubation of cells with antidepressants (0.05-10 μM) and DEX (10 μM) showed that imipramine, amitriptyline, desipramine, citalopram and fluoxetine at concentrations from 0.1 up to 1 μM, reboxetine (0.1 μM) and tianeptine (0.05 μM) prevented the DEX-induced decreases in cell viability and proliferation rate. The protective effects of antidepressants were ameliorated by inhibitors of MAPK/ERK1/2, but not PI3-K/Akt pathway as shown for imipramine, fluoxetine and reboxetine. Moreover, Western blot analysis showed the decrease in the activated form of ERK1/2 (p-ERK) after DEX treatment and this effect was inhibited by imipramine. Thus, the reduction in SH-SY5Y cell viability caused by DEX appears to be related to its antiproliferative activity and some antidepressant drugs in low concentrations attenuate this effect by mechanism which involves the activation of MAPK/ERK1/2 pathway. PMID:23906970

  6. The Toxicokinetic Profile of Dex40-GTMAC3—a Novel Polysaccharide Candidate for Reversal of Unfractionated Heparin

    PubMed Central

    Sokolowska, Emilia; Kalaska, Bartlomiej; Kaminski, Kamil; Lewandowska, Alicja; Blazejczyk, Agnieszka; Wietrzyk, Joanna; Kasacka, Irena; Szczubialka, Krzysztof; Pawlak, Dariusz; Nowakowska, Maria; Mogielnicki, Andrzej

    2016-01-01

    Though protamine sulfate is the only approved antidote of unfractionated heparin (UFH), yet may produce life threatening side effects such as systemic hypotension, catastrophic pulmonary vasoconstriction or allergic reactions. We have described 40 kDa dextrans (Dex40) substituted with glycidyltrimethylammonium chloride (GTMAC) as effective, immunogenically and hemodynamically neutral inhibitors of UFH. The aim of the present study was to evaluate in mice and rats toxicokinetic profile of the most promising polymer—Dex40-GTMAC3. Polymer was rapidly eliminated with a half-time of 12.5 ± 3.0 min in Wistar rats, and was mainly distributed to the kidneys and liver in mice. The safety studies included the measurement of blood count and blood biochemistry, erythrocyte osmotic fragility and the evaluation of the histological alterations in kidneys, liver and lungs of mice and rats in acute and chronic experiments. We found that Dex40-GTMAC3 is not only effective but also very well tolerated. Additionally, we found that protamine may cause overt hemolysis with appearance of permanent changes in the liver and kidneys. In summary, fast renal clearance behavior and generally low tissue accumulation of Dex40-GTMAC3 is likely to contribute to its superior to protamine biocompatibility. Intravenous administration of therapeutic doses to living animals does not result in the immunogenic, hemodynamic, blood, and organ toxicity. Dex40-GTMAC3 seems to be a promising effective and safe candidate for further clinical development as new UFH reversal agent. PMID:27014072

  7. Effect of maternal/fetal vitamin A deficiency on fetal rat lung surfactant protein expression and the response to prenatal dexamethasone.

    PubMed

    Zachman, R D; Grummer, M A

    1998-02-01

    The purpose of this work was to determine whether maternal/fetal vitamin A deficiency in vivo had an effect on fetal lung surfactant protein expression and its response to antenatal maternal dexamethasone (DEX). Weanling female rats at 21 d (30-35 g) were fed control (C) (4 mg of vitamin A/kg of diet) or a vitamin A-deficient (D) (0.06 of mg vitamin A/kg) diet. These females were mated, and at selected pregnancy dates fetal and maternal tissues were obtained. Control mothers had liver retinyl palmitate (RP) concentrations of 246 +/- 32 nmol/g of wet weight; those in the D group had 6.1 +/- 2.9 nmol/g of wet weight. Control fetal liver RP was 12-fold higher and control fetal lung RP was 3-fold higher than in the D group (liver: 18.5 +/- 0.4 nmol/g versus 1.5 +/- 0.25 nmol/g; lung: 1.8 +/- 0.98 nmol/g versus 0.6 +/- 0.2 nmol/g). Neither fetal lung surfactant protein (SP)-C mRNA nor SP-A mRNA was affected by vitamin A deficiency. In a second experiment, pregnant rats from both C and D groups were injected with either DEX (1 mg/kg) or an equal volume of saline on d 15-17, and killed on d 18. DEX increased fetal lung SP-C mRNA 2-fold over the level found in the saline-injected group (saline, 1.0 +/- 0.2 versus DEX, 2.1 +/- 0.2, p < 0.02). This increase in SP-C mRNA also occurred in fetal lungs from the D group (saline, 1.8 +/- 0.4 versus DEX 3.7 +/- 0.2, p < 0.01). Retinoic acid receptor-beta mRNA, which responds to vitamin A levels and DEX in many systems, was lower in fetal lungs of the D group that had been treated with DEX. We conclude that fetal rat lung development, as measured by SP-C mRNA and SP-A mRNA, and the SP-C mRNA response to DEX, was not affected by vitamin A deficiency. PMID:9475281

  8. Therapeutic effect of dexamethasone implant in retinal vein occlusions resistant to anti-VEGF therapy

    PubMed Central

    Wallsh, Josh; Sharareh, Behnam; Gallemore, Ron

    2016-01-01

    Purpose To test the efficacy of the intravitreal dexamethasone (DEX) implant in patients with retinal vein occlusions (RVOs) who have failed multiple anti-vascular endothelial growth factor (anti-VEGF) treatments. Methods A randomized exploratory study of ten patients with branch RVO or central RVO who received at least two previous anti-VEGF treatments and had persistent or unresponsive cystoid macular edema. Treatment with the DEX implant was either every 4 months or pro re nata (PRN) depending on their group assignment for 1 year. Multifocal electroretinography and microperimetry were the primary end points, with high-resolution optical coherence tomography and best-corrected visual acuity as the secondary end points. Results All patients in both the every 4 month and PRN cohorts who completed the study received the three maximal injections of DEX; therefore, the data from both cohorts were combined and reported as a case series. On average, the multifocal electroretinography amplitude increased significantly from 5.11±0.66 to 24.19±5.30 nV/deg2 at 12 months (P<0.005), mean macular sensitivity increased from 7.67±2.10 to 8.01±1.98 dB at 4 months (P=0.32), best-corrected visual acuity increased significantly from 51.0±5.1 to 55.4±5.1 early treatment of diabetic retinopathy study letters at 2 months (P<0.05), and central retinal thickness decreased from 427.6±39.5 to 367.1±37.8 μm at 4 months (P<0.05). Intraocular pressure increased significantly in one patient, with that patient requiring an additional glaucoma medication for management. Additionally, cataract progression increased significantly (P<0.05) in this patient population and partially limited analysis of other end points. Conclusion DEX should be considered as a treatment option in patients with RVOs who have failed anti-VEGF therapy, as the results of this study demonstrated an improvement in retinal morphology and macular function. Cataract progression did occur following multiple consecutive

  9. 21 CFR 522.540 - Dexamethasone solution.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... Note: For Federal Register citations affecting § 522.540, see the List of CFR Sections Affected, which...) dexamethasone. (2) Sponsors. See sponsors in § 510.600(c) of this chapter: (i) Nos. 000061, 000859, and 061623 for use as in paragraph (a)(3) of this section. (ii) Sponsors. See Nos. 054925 and 058005 for use...

  10. Human keratinocyte caspase-14 expression is altered in human epidermal 3D models by dexamethasone and by natural products used in cosmetics.

    PubMed

    Kataoka, Saori; Hattori, Kenji; Date, Akira; Tamura, Hiroomi

    2013-10-01

    Caspase-14 is a cysteinyl-aspartate-specific proteinase that is specifically expressed in epidermal keratinocytes. Dysregulation of caspase-14 expression is implicated in impaired skin barrier formation. To elucidate the regulation of caspase-14 in differentiated keratinocytes, we characterized the expression of caspase-14 in normal human epidermal keratinocytes (NHEKs) and two types of three-dimensional (3D) human epidermis culture models, EPI-200 and EPI-201, via RT-PCR and immunoblot analyses. Caspase-14 expression was absent in subconfluent NHEKs, but was present in confluent NHEKs as well as those induced to differentiate by calcium. Caspase-14 expression levels in the 3D epidermis models were almost equal to that in the Ca(2+)-treated differentiated NHEKs. Despite the presence of caspase-14 expression in these models, caspase-14 activity was found only in the mature 3D skin model, EPI-200. This was confirmed by detection of a 17 kDa cleaved fragment of caspase-14 present only in the EPI-200 model. Since glucocorticoid (GC) receptor is required for skin barrier competence, we investigated whether the GC dexamethasone (Dex) and various natural components of common skin moisturizers affect caspase-14 expression in keratinocytes. Dex decreased caspase-14 expression in undifferentiated, but not differentiated, NHEKs. Conversely, Dex increased caspase-14 expression in both 3D skin models, although it did not alter caspase protease activity. Similar to treatment with Dex, treatment of the premature 3D skin mode, EPI-201 with a Galactomyces ferment filtrate markedly increased expression of caspase-14. Further, these results suggest that the effect of Dex, or lack thereof, on caspase-14 expression is dependent on the stage of keratinocyte differentiation.

  11. New plant growth-modifying properties of the Agrobacterium T-6b oncogene revealed by the use of a dexamethasone-inducible promoter.

    PubMed

    Grémillon, Louis; Helfer, Anne; Clément, Bernadette; Otten, Léon

    2004-01-01

    Agrobacterium 6b oncogenes induce tumours on Nicotiana glauca and enations and associated modifications in transgenic N. tabacum plants. 2x35S-AB-6b tobacco rootstocks produced a graft-transmissible factor that induced enations in wild-type scions; the nature of this enation factor remains to be identified. Here, we report on the properties of tobacco plants carrying a dexamethasone-inducible T-6b gene (dex-T-6b). Induction with dex led to complex growth modifications, many of which have not been reported previously. Modifications were only found in growing tissues; mature tissues remained unaffected. Growth could be either stimulated or inhibited. Dex induction of young plants led to morphogenetic gradients that included enations, tubular leaves and fragmented leaf primordia. Root elongation was increased or slowed down, while radial root growth was strongly enhanced. Additional cell divisions were found in the root pericycle and vasculature. Enation factor import from mature tissues did not have the same effects on growing tissues as local T-6b synthesis: normal scions grafted on induced dex-T-6b rootstocks formed enations, whereas local dex-T-6b induction at the shoot apex led to numerous dark-green spots on the abaxial side of the leaves. In leaf patch assays, the 23-kDa T-6b protein was found to move through leaves and to enter the vascular system. This and the fact that rootstocks of spontaneous tobacco enation mutants did not modify wild-type scions contrary to 6b plants indicate that the 6b protein might be the enation factor. PMID:14690506

  12. In vitro modulation of macrophage phenotype and inhibition of polymer degradation by dexamethasone in a human macrophage/Fe/stress system.

    PubMed

    Casas, J; Zhao, Q; Donovan, M; Schroeder, P; Stokes, K; Untereker, D

    1999-09-15

    A new in vitro accelerated biological model, the macrophage-FeCl2-stress system was used for the evaluation of dexamethasone (DEX)-polymer formulations. This model combines the effects of cells (macrophages), transition metal ions (Fe2+), and polymer stress to promote material biodegradation. The cell and material effects of DEX, either in solution or incorporated into a polyetherurethane matrix (DEX/PEU), were monitored. Cell morphology and hydroperoxide formation in the polymer during cell culturing were characterized. After a subsequent treatment with FeCl2 the development of environmental stress cracking in the polymer was evaluated. We attempted to duplicate the biodegradation of PEU in terms of environmental stress cracking (ESC). Our results support the direct involvement of macrophages in polyetherurethane oxidation, probably by inducing hydroperoxide formation in the polymer structure. Under the influence of stress or strain, polymers with sufficient hydroperoxides degrade in the presence of Fe2+ metal ions in a manner that closely resembles the stress cracking that is observed in vivo. By contrast, polymers treated with either agents that inhibit cell activation and/or the oxidative burst, or with cells with no oxidative burst did not show signs of the biodegradative process. We demonstrated a reduction in hydroperoxide formation and no later ESC development in macrophage-cultured PEU in the presence of DEX in solution or in DEX-loaded PEU. We believe the prevention of initial polymer oxidation by reducing the cell's potential to produce oxidative stress at the tissue-biomaterial interface can directly inhibit the ESC degradation of chronically implanted polymers. The in vitro macrophage-Fe-stress system is a valuable tool for reliable assessment and cost-effective evaluation of biomaterials. PMID:10398008

  13. The effect of hydroalcoholic extract of Ferula foetida stems on blood pressure and oxidative stress in dexamethasone-induced hypertensive rats

    PubMed Central

    Safaeian, Leila; Ghannadi, Alireza; Javanmard, Shaghayegh Haghjoo; Vahidian, Mohammad Hadi

    2015-01-01

    Ferula foetida (Bunge) Regel. is one of the most widespread and important Ferula species with nutritional and medicinal applications. Some phytochemicals with helpful cardiovascular effects have been isolated from Ferula species. The present study was designed to evaluate the effects of hydroalcoholic extract of the stems of F. foetida in dexamethasone (Dex)-induced hypertension in rats. Hypertension was induced by subcutaneous injection of Dex (30 µg/kg) for 14 days. In a prevention study, rats received oral F. foetida extract (200, 400 and 800 mg/kg) for 4 days prior to Dex administration and during the test period (Days 1-18). In a treatment study, F. foetida extract was administered from day 8 to 14. Systolic blood pressure (SBP) was evaluated using tail-cuff method. The thymus weight was measured as an indicator of glucocorticoid activity. The hydrogen peroxide (H2O2) concentration and ferric reducing antioxidant power (FRAP) were measured in plasma samples. Dex-induced hypertensive rats showed significant increases in SBP and in plasma H2O2 and decreases in the body and thymus weights and in FRAP value (P<0.001). Administration of F. foetida extract significantly prevented and reversed hypertension at all doses. It also increased plasma FRAP value (P<0.001) but failed to decrease plasma H2O2 concentration. These results suggest antihypertensive and antioxidant effects of F. foetida stem extract in Dex-induced hypertension. More investigations are needed to elucidate the exact mechanism of antihypertensive effect of this traditional phytomedicine. PMID:26600859

  14. The inhibitory effect of dexamethasone on platelet-derived growth factor-induced vascular smooth muscle cell migration through up-regulating PGC-1{alpha} expression

    SciTech Connect

    Xu, Wei; Guo, Ting; Zhang, Yan; Jiang, Xiaohong; Zhang, Yongxian; Zen, Ke; Yu, Bo; Zhang, Chen-Yu

    2011-05-01

    Dexamethasone has been shown to inhibit vascular smooth muscle cell (VSMC) migration, which is required for preventing restenosis. However, the mechanism underlying effect of dexamethasone remains unknown. We have previously demonstrated that peroxisome proliferator-activated receptor gamma (PPAR{gamma}) coactivator-1 alpha (PGC-1{alpha}) can inhibit VSMC migration and proliferation. Here, we investigated the role of PGC-1{alpha} in dexamethasone-reduced VSMC migration and explored the possible mechanism. We first examined PGC-1{alpha} expression in cultured rat aortic VSMCs. The results revealed that incubation of VSMCs with dexamethasone could significantly elevate PGC-1{alpha} mRNA expression. In contrast, platelet-derived growth factor (PDGF) decreased PGC-1{alpha} expression while stimulating VSMC migration. Mechanistic study showed that suppression of PGC-1{alpha} by small interfering RNA strongly abrogated the inhibitory effect of dexamethasone on VSMC migration, whereas overexpression of PGC-1{alpha} had the opposite effect. Furthermore, an analysis of MAPK signal pathways showed that dexamethasone inhibited ERK and p38 MAPK phosphorylation in VSMCs. Overexpression of PGC-1{alpha} decreased both basal and PDGF-induced p38 MAPK phosphorylation, but it had no effect on ERK phosphorylation. Finally, inhibition of PPAR{gamma} activation by a PPAR{gamma} antagonist GW9662 abolished the suppressive effects of PGC-1{alpha} on p38 MAPK phosphorylation and VSMC migration. These effects of PGC-1{alpha} were enhanced by a PPAR{gamma} agonist troglitazone. Collectively, our data indicated for the first time that one of the anti-migrated mechanisms of dexamethasone is due to the induction of PGC-1{alpha} expression. PGC-1{alpha} suppresses PDGF-induced VSMC migration through PPAR{gamma} coactivation and, consequently, p38 MAPK inhibition.

  15. Ranking of Business Process Simulation Software Tools with DEX/QQ Hierarchical Decision Model.

    PubMed

    Damij, Nadja; Boškoski, Pavle; Bohanec, Marko; Mileva Boshkoska, Biljana

    2016-01-01

    The omnipresent need for optimisation requires constant improvements of companies' business processes (BPs). Minimising the risk of inappropriate BP being implemented is usually performed by simulating the newly developed BP under various initial conditions and "what-if" scenarios. An effectual business process simulations software (BPSS) is a prerequisite for accurate analysis of an BP. Characterisation of an BPSS tool is a challenging task due to the complex selection criteria that includes quality of visual aspects, simulation capabilities, statistical facilities, quality reporting etc. Under such circumstances, making an optimal decision is challenging. Therefore, various decision support models are employed aiding the BPSS tool selection. The currently established decision support models are either proprietary or comprise only a limited subset of criteria, which affects their accuracy. Addressing this issue, this paper proposes a new hierarchical decision support model for ranking of BPSS based on their technical characteristics by employing DEX and qualitative to quantitative (QQ) methodology. Consequently, the decision expert feeds the required information in a systematic and user friendly manner. There are three significant contributions of the proposed approach. Firstly, the proposed hierarchical model is easily extendible for adding new criteria in the hierarchical structure. Secondly, a fully operational decision support system (DSS) tool that implements the proposed hierarchical model is presented. Finally, the effectiveness of the proposed hierarchical model is assessed by comparing the resulting rankings of BPSS with respect to currently available results. PMID:26871694

  16. Ranking of Business Process Simulation Software Tools with DEX/QQ Hierarchical Decision Model

    PubMed Central

    2016-01-01

    The omnipresent need for optimisation requires constant improvements of companies’ business processes (BPs). Minimising the risk of inappropriate BP being implemented is usually performed by simulating the newly developed BP under various initial conditions and “what-if” scenarios. An effectual business process simulations software (BPSS) is a prerequisite for accurate analysis of an BP. Characterisation of an BPSS tool is a challenging task due to the complex selection criteria that includes quality of visual aspects, simulation capabilities, statistical facilities, quality reporting etc. Under such circumstances, making an optimal decision is challenging. Therefore, various decision support models are employed aiding the BPSS tool selection. The currently established decision support models are either proprietary or comprise only a limited subset of criteria, which affects their accuracy. Addressing this issue, this paper proposes a new hierarchical decision support model for ranking of BPSS based on their technical characteristics by employing DEX and qualitative to quantitative (QQ) methodology. Consequently, the decision expert feeds the required information in a systematic and user friendly manner. There are three significant contributions of the proposed approach. Firstly, the proposed hierarchical model is easily extendible for adding new criteria in the hierarchical structure. Secondly, a fully operational decision support system (DSS) tool that implements the proposed hierarchical model is presented. Finally, the effectiveness of the proposed hierarchical model is assessed by comparing the resulting rankings of BPSS with respect to currently available results. PMID:26871694

  17. Ranking of Business Process Simulation Software Tools with DEX/QQ Hierarchical Decision Model.

    PubMed

    Damij, Nadja; Boškoski, Pavle; Bohanec, Marko; Mileva Boshkoska, Biljana

    2016-01-01

    The omnipresent need for optimisation requires constant improvements of companies' business processes (BPs). Minimising the risk of inappropriate BP being implemented is usually performed by simulating the newly developed BP under various initial conditions and "what-if" scenarios. An effectual business process simulations software (BPSS) is a prerequisite for accurate analysis of an BP. Characterisation of an BPSS tool is a challenging task due to the complex selection criteria that includes quality of visual aspects, simulation capabilities, statistical facilities, quality reporting etc. Under such circumstances, making an optimal decision is challenging. Therefore, various decision support models are employed aiding the BPSS tool selection. The currently established decision support models are either proprietary or comprise only a limited subset of criteria, which affects their accuracy. Addressing this issue, this paper proposes a new hierarchical decision support model for ranking of BPSS based on their technical characteristics by employing DEX and qualitative to quantitative (QQ) methodology. Consequently, the decision expert feeds the required information in a systematic and user friendly manner. There are three significant contributions of the proposed approach. Firstly, the proposed hierarchical model is easily extendible for adding new criteria in the hierarchical structure. Secondly, a fully operational decision support system (DSS) tool that implements the proposed hierarchical model is presented. Finally, the effectiveness of the proposed hierarchical model is assessed by comparing the resulting rankings of BPSS with respect to currently available results.

  18. Knockout and functional analysis of two DExD/H-box family helicase genes in Sulfolobus islandicus REY15A.

    PubMed

    Song, Xueguo; Huang, Qihong; Ni, Jinfeng; Yu, Yang; Shen, Yulong

    2016-07-01

    DExD/H-box helicases represent the largest family of helicases. They belong to superfamily 2 helicases and participate in nucleotide metabolism, ribosome biogenesis, and nucleocytoplasmic transport. The biochemical properties and structures of some DExD/H-box helicases in the archaea have been documented, but many of them have not been characterized; and reports on in vivo functional analyses are limited. In this study, we attempted gene knockout of 8 putative DExD/H-box helicases in Sulfolobus islandicus REY15A and obtained two deletion mutants, SiRe_0681 and SiRe_1605. We determined that ΔSiRe_0681 grew faster than wild type cells in the presence of methyl methanesulfonate (MMS). Flow cytometry analysis showed that this strain had fewer G1/S phase cells than the wild type, and the genes coding for cell division proteins were up-regulated. The stain ΔSiRe_1605 was more sensitive to MMS than the wild type cell, and many nucleotide metabolism and DNA repair enzymes were found to be down-regulated. Intriguingly, deletion of either gene led to silencing simultaneously of over 80 genes located at a specific region. This study provides a novel insight into the in vivo functions of predicted DExD/H-box family helicases in the archaea. PMID:27290726

  19. Cyclodextrin-poloxamer aggregates as nanocarriers in eye drop formulations: dexamethasone and amphotericin B.

    PubMed

    Jansook, Phatsawee; Pichayakorn, Wiwat; Muankaew, Chutimon; Loftsson, Thorsteinn

    2016-09-01

    In this present study cyclodextrin (CD)-poloxamer aggregates were characterized and developed as ophthalmic drug carriers. The combined effect of γCD/2-hydroxypropyl-γCD (HPγCD) mixtures and poloxamer on solubilization and permeability of two model drugs, dexamethasone (Dex) and amphotericin B (AmB), was investigated. The CD-poloxamer interaction and complex aggregation were examined by (1)H nuclear magnetic resonance ((1)H-NMR), their solubilizing ability by high-performance liquid chromatography, and their particle size determined by dynamic light scattering and transmission electron microscopy. Formulations containing either 1.5% w/v Dex or 0.15% w/v AmB in eye drop suspensions containing various γCD/HPγCD ratios and poloxamer 407 (P407) were prepared. The solubility of the drugs, surface tension and hemolytic effect of the eye drops and drug permeation from selected formulations were determined. The (1)H-NMR study showed that P407 formed inclusion complex with CDs by inserting its poly(propylene oxide) segment into the CD cavity. P407 and γCD interacted with each other to form nanosized aggregates, and the observed concentration of dissolved γCD and P407 progressively decreased with increasing γCD and P407 concentrations. Including a high proportion of HPγCD improved the drug solubilization and reduced the hemolytic effect. The surface tension of the formulations decreased with increasing P407 concentration. Furthermore, increasing P407 content in the formulations enhanced formation of complex aggregates with consequent slower drug release. It was concluded that the drug/γCD/HPγCD complex was stabilized by P407 through formation of multi-component aggregates. Thus, CD-poloxamer aggregates are self-assembled nanocarriers from which drug delivery characteristics can be adjusted by changing the γCD/HPγCD/P407 ratios. PMID:26765786

  20. Mucoadhesive dexamethasone acetate-polymyxin B sulfate cationic ocular nanoemulsion--novel combinatorial formulation concept.

    PubMed

    Li, X; Müller, R H; Keck, C M; Bou-Chacra, N A

    2016-06-01

    Dexamethasone acetate (DEX) and polymyxin B sulfate (polymyxin B) were formulated as a cationic nanoemulsion for the treatment of ophthalmic infections. As novel concept, the positive charge to achieve mucoadhesion was not generated by toxicologically and regulatorily problematic cationic lipids or polymers, but by using a positively charged drug in combination with positively charged preservatives. The preservative also acts as co-surfactant to stabilize the emulsion. Nanoemulsions with the lipid phase Eutanol G-Lipoid S 100 (70%:30%) containing 0.05% (w/w) DEX were produced by high pressure homogenization, followed by dissolving the hydrophilic molecules in the water phase, e.g. polymyxin B (0.1%, w/w), cetylpyridinium chloride (0.01%, w/w) and glycerol (2.6%, w/w) to yield a combination product. The particles were below 200 nm with narrow size distribution. The osmolality (374 mOsm/kg), pH (5.31) and viscosity (2.45 mPa s at 37 degrees C) were compatible to the ocular administration. The zeta potential of the optimized formulation was shifted from approx. +9 mV to -11 mV after mucin incubation. The in vitro test revealed no potential cytotoxicity. The final products were stable after 180 days of storage at 4 degrees C and room temperature. The developed product is a viable alternative to the commercial ophthalmic suspensions. Moreover, this concept of generating the positive charge by cationic drug and/or preservative addition can be transferred to other ophthalmic products. PMID:27455551

  1. Mimicking corticosterone's daily rhythm with specific receptor agonists: effects on food, water, and sodium intake.

    PubMed

    Devenport, L; Stith, R

    1992-06-01

    The endogenous pattern of type I and II corticosteroid receptor stimulation was systematically assembled from specific agonists in order to detect any unique receptor interactions in the control of ingestive behavior. The type II agonists dexamethasone (0, 5, or 25 micrograms/kg) or RU28362 (0, 5, or 25 micrograms/kg) were injected daily in the final hour of the light phase of the illumination cycle of adrenalectomized rats. This was carried out in the presence or absence of continuous aldosterone (type I agonist) infusion. Additional comparisons were made with sham-operated groups and animals receiving type II agonists by continuous infusion. Type II agonists increased the intake of 2% saline and the proportion of food taken at night, but had negligible effects on total food intake. Type II agonists did not interact with the type I agonist. Type II effects were greatly potentiated by continuous infusion, though administered at the same doses as acute injection. When the effects of type II receptor stimulation emerged, they always consisted of an exacerbation of the adrenalectomy syndrome, not a return to normal quantities or patterns. In contrast, type I receptor stimulation restored both the quantities and unique day-night patterns of saline, water, and food intake to values matching intact animals. The findings suggest that the behavioral significance of corticosterone's nocturnal peak of type II stimulation is small, and that its most important function may lie in the metabolic processes it instigates during its steady rise in the light phase.

  2. Effect of dexamethasone and Nigella sativa on inducible nitric oxide synthase in the lungs of a murine model of allergic Asthma.

    PubMed

    Abdel-Aziz, Mohamed; Abass, Ayman; Zalata, Khaled; Abd Al-Galel, Tarek; Allam, Umamma; Karrouf, Gamal

    2014-10-01

    The aim of this study was to investigate the effects of Nigella sativa (NS) fixed oil in comparison to dexamethasone (Dex) on inducible nitric oxide synthase (iNOS), peripheral blood eosinophils (PBE), allergen specific serum IgG1 and interleukins and airway inflammation in a murine model of allergic asthma. Thirty-one mice were divided into four groups. Group I (n = 6) served as the control group. Group II (n = 10) mice were sensitized intraperitoneally and challenged intratracheally with cone albumin with no treatment. Group III(n = 6) mice were sensitized, challenged, and treated with Dex for 17 days starting at 24 hours after the first challenge. Group IV (n = 9) mice were sensitized, challenged, and treated with NS fixed oil for 17 days as well. For all groups, the following procedures were carried out: immunohistochemical study of iNOS in lung tissues, detection of PBE percentage, and histopathological examination of lung tissues for inflammatory cells. Lung tissue iNOS expression increased in sensitized, non-treated mice compared with controls, but this increase was not significant. NS fixed oil treatment significantly reduced PBE and lung inflammation but did not significantly reduce lung tissue iNOS expression compared with the control group. These effects were comparable to the effects of Dex. These results suggest that Nigella sativa exhibits immunomodulatory and anti-inflammatory effect which may be useful for treatment of allergic asthma. PMID:25150073

  3. MEK Inhibition Sensitizes Precursor B-Cell Acute Lymphoblastic Leukemia (B-ALL) Cells to Dexamethasone through Modulation of mTOR Activity and Stimulation of Autophagy

    PubMed Central

    Polak, Anna; Kiliszek, Przemysław; Sewastianik, Tomasz; Szydłowski, Maciej; Jabłońska, Ewa; Białopiotrowicz, Emilia; Górniak, Patryk; Markowicz, Sergiusz; Nowak, Eliza; Grygorowicz, Monika A.; Prochorec-Sobieszek, Monika; Nowis, Dominika; Gołąb, Jakub; Giebel, Sebastian; Lech-Marańda, Ewa; Warzocha, Krzysztof; Juszczyński, Przemysław

    2016-01-01

    Resistance to glucocorticosteroids (GCs) is a major adverse prognostic factor in B-ALL, but the molecular mechanisms leading to GC resistance are not completely understood. Herein, we sought to elucidate the molecular background of GC resistance in B-ALL and characterize the therapeutic potential of targeted intervention in these mechanisms. Using exploratory bioinformatic approaches, we found that resistant cells exhibited significantly higher expression of MEK/ERK (MAPK) pathway components. We found that GC-resistant ALL cell lines had markedly higher baseline activity of MEK and small-molecule MEK1/2 inhibitor selumetinib increased GCs-induced cell death. MEK inhibitor similarly increased in vitro dexamethasone activity in primary ALL blasts from 19 of 22 tested patients. To further confirm these observations, we overexpressed a constitutively active MEK mutant in GC-sensitive cells and found that forced MEK activity induced resistance to dexamethasone. Since recent studies highlight the role GC-induced autophagy upstream of apoptotic cell death, we assessed LC3 processing, MDC staining and GFP-LC3 relocalization in cells incubated with either DEX, SEL or combination of drugs. Unlike either drug alone, only their combination markedly increased these markers of autophagy. These changes were associated with decreased mTOR activity and blocked 4E-BP1 phosphorylation. In cells with silenced beclin-1 (BCN1), required for autophagosome formation, the synergy of DEX and SEL was markedly reduced. Taken together, we show that MEK inhibitor selumetinib enhances dexamethasone toxicity in GC-resistant B-ALL cells. The underlying mechanism of this interaction involves inhibition of mTOR signaling pathway and modulation of autophagy markers, likely reflecting induction of this process and required for cell death. Thus, our data demonstrate that modulation of MEK/ERK pathway is an attractive therapeutic strategy overcoming GC resistance in B-ALL patients. PMID:27196001

  4. Effects of vitamin D and yeast extract supplementation on turkey mortality and clostridial dermatitis incidence in a dexamethasone immunosuppression model.

    PubMed

    Huff, G R; Huff, W E; Ratha, N C

    2014-12-01

    Clostridial dermatitis (CD) is a production disease of commercial turkeys that is characterized by sudden mortality in market-aged male birds and by lesions that include fluid and air bubbles under the skin of the thigh, breast, and tail area. We have developed a model for CD using dexamethasone (Dex) injection that suggests this disease may be related to stressors during the last stages of turkey production. Male turkeys were provided with control feed and water or with feed supplemented with a commercial yeast extract (YE) product, water supplemented with vitamin D (VD), or the combination. At 6, 11, and 15 wk of age birds were treated with three intramuscular injections of Dex over a 5-day period. Both YE and VD, but not the combination, decreased early mortality. At week 7 mortality was increased by VD, and cellulitis lesions were seen in 7/8 mortalities. Mortality at week 12 was decreased by both YE and the combination of YE and VD, and cellulitis lesions were seen in 8/17 mortalities. There were no significant differences in mortality at week 16. Total mortality was 66 birds, and 23 of these had cellulitis lesions (38%). There were no YE-treated birds with CD lesions; however, 67% of VD-treated birds had CD lesions. This study suggests that feed supplementation with YE may improve the ability of turkeys to withstand the stressors during late production and provide protection against the development of CD; however, high levels of VD supplementation may be detrimental.

  5. Research Resource: The Dexamethasone Transcriptome in Hypothalamic Embryonic Neural Stem Cells.

    PubMed

    Frahm, Krystle A; Peffer, Melanie E; Zhang, Janie Y; Luthra, Soumya; Chakka, Anish B; Couger, Matthew B; Chandran, Uma R; Monaghan, A Paula; DeFranco, Donald B

    2016-01-01

    Exposure to excess glucocorticoids during fetal development has long-lasting physiological and behavioral consequences, although the mechanisms are poorly understood. The impact of prenatal glucocorticoids exposure on stress responses in juvenile and adult offspring implicates the developing hypothalamus as a target of adverse prenatal glucocorticoid action. Therefore, primary cultures of hypothalamic neural-progenitor/stem cells (NPSCs) derived from mouse embryos (embryonic day 14.5) were used to identify the glucocorticoid transcriptome in both males and females. NPSCs were treated with vehicle or the synthetic glucocorticoid dexamethasone (dex; 100nM) for 4 hours and total RNA analyzed using RNA-Sequencing. Bioinformatic analysis demonstrated that primary hypothalamic NPSC cultures expressed relatively high levels of a number of genes regulating stem cell proliferation and hypothalamic progenitor function. Interesting, although these cells express glucocorticoid receptors (GRs), only low levels of sex-steroid receptors are expressed, which suggested that sex-specific differentially regulated genes identified are mediated by genetic and not hormonal influences. We also identified known or novel GR-target coding and noncoding genes that are either regulated equivalently in male and female NPSCs or differential responsiveness in one sex. Using gene ontology analysis, the top functional network identified was cell proliferation and using bromodeoxyuridine (BrdU) incorporation observed a reduction in proliferation of hypothalamic NPSCs after dexamethasone treatment. Our studies provide the first characterization and description of glucocorticoid-regulated pathways in male and female embryonically derived hypothalamic NPSCs and identified GR-target genes during hypothalamic development. These findings may provide insight into potential mechanisms responsible for the long-term consequences of fetal glucocorticoid exposure in adulthood.

  6. Protection by dexamethasone of the functional desensitization to β2-adrenoceptor-mediated responses in human lung mast cells

    PubMed Central

    Chong, Lee K; Drury, Duncan E J; Dummer, Jack F; Ghahramani, Parviz; Schleimer, Robert P; Peachell, Peter T

    1997-01-01

    The β-adrenoceptor agonist, isoprenaline, inhibited the IgE-mediated release of histamine from human lung mast cells (HLMC) in a dose-dependent manner. Maximal inhibitory effects were obtained with 0.1 μM isoprenaline. However, the inhibition of histamine release from HLMC by isoprenaline (0.1 μM) was highly variable ranging from 33 to 97% inhibition (mean, 59±3%, n=27). Long-term (24 h) incubation of HLMC with isoprenaline led to a subsequent reduction in the ability of a second exposure of isoprenaline to inhibit IgE-mediated histamine release from HLMC. The impairment in the ability of isoprenaline (0.1 μM) to inhibit histamine release following desensitizing conditions (1 μM isoprenaline for 24 h) was highly variable amongst HLMC preparations ranging from essentially negligible levels of desensitization in some preparations to complete abrogation of the inhibitory response in others (mean, 65±6% desensitization, n=27). The ability of HLMC to recover from desensitization was investigated. Following desensitizing conditions (1 μM isoprenaline for 24 h), HLMC were washed and incubated for 24 h in buffer and the effectiveness of isoprenaline (0.1 μM) to inhibit IgE-mediated histamine release from HLMC was assessed. The extent of recovery was highly variable with some HLMC preparations failing to recover and others displaying a complete restoration of responsiveness to isoprenaline (mean, 40±6% recovery, n=23). The effects of the glucocorticoid, dexamethasone, were also investigated. Long-term (24–72 h) treatments with dexamethasone (0.1 μM) had no effect on IgE-mediated histamine release from HLMC. Additionally, long-term (24–72 h) treatments with dexamethasone (0.1 μM) had no effect on the effectiveness of isoprenaline to inhibit histamine release. However, long-term (24–72 h) treatments with dexamethasone (0.1 μM) protected against the functional desensitization induced by incubation (24 h) of HLMC with

  7. Inotropic response to endothelin-1, isoprenaline and calcium in cardiomyocytes isolated from endotoxin treated rats: effects of ethyl-isothiourea and dexamethasone.

    PubMed

    Spiers, J P; Kelso, E J; Allen, J D; Silke, B; McDermott, B J

    2000-07-01

    1. The contractile effects of endothelin-1, isoprenaline and extracellular calcium were assessed on ventricular cardiomyocytes isolated from lipopolysaccharide-treated rats. The involvement of nitric oxide was investigated using dexamethasone (in vivo) and ethyl isothiourea (in vitro). 2. Male Wistar rats (n=70) were injected with either saline (1 ml kg(-1)) or lipopolysaccharide (LPS; 5 mg kg(-1)) alone, or following pre-treatment with dexamethasone (DEX+LPS; 5 mg kg(-1)). Ventricular cell shortening was recorded using a video edge detection system, and concentration-response relationships were established for endothelin-1, isoprenaline and calcium, in the absence or presence of ethyl isothiourea (ETU; 10 microM). iNOS expression was assessed using reverse transcription-polymerase chain reaction. 3. iNOS mRNA expression was greater (P<0.001) in the LPS (iNOS/GAPDH ratio: 0.90+/-0.09) treated group compared to saline (iNOS/GAPDH ratio: 0.36+/-0.02). Baseline contractile amplitude was reduced (P<0.05) in the LPS (7.3+/-0.2 microm) and DEX+LPS groups (6.7+/-0.3 microm) compared to saline (8. 0+/-0.2 microm). 4. The concentration-dependent contractile response to endothelin-1 was attenuated (P<0.05) in the LPS group compared to saline (maximum change: 0.45+/-0.2 vs 1.8+/-0.2 microm). Neither ETU nor dexamethasone improved contractile function in the LPS-treated animals. 5. The concentration-dependent increase in the contractile response to isoprenaline was attenuated in the LPS-treated group compared to saline (P<0.05; maximum change: 1.7+/-0.4 vs 3.1+/-0.4 microm). This effect was reversed by ETU (maximum change: 3.7+/-0.6 microm). Pre-treatment with dexamethasone prevented a significant fall in contraction amplitude (maximum change: 2.4+/-0.4 microm). 6. The contractile response to calcium was reduced (P<0.05) in the LPS group compared to saline (maximum change: 8.7+/-0.6 vs 10.7+/-0.8 microm). Neither ETU nor dexamethasone restored contractile function in the LPS

  8. Spectrophotometric and chemometric methods for determination of imipenem, ciprofloxacin hydrochloride, dexamethasone sodium phosphate, paracetamol and cilastatin sodium in human urine

    NASA Astrophysics Data System (ADS)

    El-Kosasy, A. M.; Abdel-Aziz, Omar; Magdy, N.; El Zahar, N. M.

    2016-03-01

    New accurate, sensitive and selective spectrophotometric and chemometric methods were developed and subsequently validated for determination of Imipenem (IMP), ciprofloxacin hydrochloride (CIPRO), dexamethasone sodium phosphate (DEX), paracetamol (PAR) and cilastatin sodium (CIL) in human urine. These methods include a new derivative ratio method, namely extended derivative ratio (EDR), principal component regression (PCR) and partial least-squares (PLS) methods. A novel EDR method was developed for the determination of these drugs, where each component in the mixture was determined by using a mixture of the other four components as divisor. Peak amplitudes were recorded at 293.0 nm, 284.0 nm, 276.0 nm, 257.0 nm and 221.0 nm within linear concentration ranges 3.00-45.00, 1.00-15.00, 4.00-40.00, 1.50-25.00 and 4.00-50.00 μg mL- 1 for IMP, CIPRO, DEX, PAR and CIL, respectively. PCR and PLS-2 models were established for simultaneous determination of the studied drugs in the range of 3.00-15.00, 1.00-13.00, 4.00-12.00, 1.50-9.50, and 4.00-12.00 μg mL- 1 for IMP, CIPRO, DEX, PAR and CIL, respectively, by using eighteen mixtures as calibration set and seven mixtures as validation set. The suggested methods were validated according to the International Conference of Harmonization (ICH) guidelines and the results revealed that they were accurate, precise and reproducible. The obtained results were statistically compared with those of the published methods and there was no significant difference.

  9. Dexamethasone promotes hypertrophy of H9C2 cardiomyocytes through calcineurin B pathway, independent of NFAT activation.

    PubMed

    Sangeetha, K N; Lakshmi, B S; Niranjali Devaraj, S

    2016-01-01

    Metabolic syndrome-induced cardiac hypertrophy is a global concern leading to an increase in the morbidity and mortality of patients, with the signalling mechanism associated with them still unclear. The present study attempts to understand the metabolic syndrome-associated cardiac hypertrophy through an in vitro model using external stimuli well known for inducing metabolic disorders, i.e. dexamethasone (DEX), a synthetic glucocorticoid. DEX (0.1 and 1 μM) promoted cardiac hypertrophy in H9C2 cells at 4 days of treatment as evidenced through increased cell size and protein content. A significant induction in foetal gene reprogramming was observed, confirming the establishment of hypertrophy. Moreover, the hypertrophic response at 4 days was perceived to be physiological at 0.1 μM and pathological at 1 μM based on α-MHC and IGF1R expression, but complete inhibition in the PKB/AKT expression confirmed it to be pathological hypertrophy at both the concentrations (0.1 and 1 μM). The present study reports for the first time the mechanistic insights into DEX-mediated hypertrophy. It is hypothesized to be orchestrated through the activation of AT1R that is involved in the alteration of the cardiac isoform of SERCA2 expression perturbing the calcium homeostasis. This leads to the activation of calcineurin B, independent of NFAT involvement, which in coordination with ROS induces the activation of JNK of the MAPK signalling. PMID:26511233

  10. Fingerprinting two metal contaminants in streams with Cu isotopes near the Dexing Mine, China.

    PubMed

    Song, Shiming; Mathur, Ryan; Ruiz, Joaquin; Chen, Dandan; Allin, Nicholas; Guo, Kunyi; Kang, Wenkai

    2016-02-15

    Transition metal isotope signatures are becoming useful for fingerprinting sources in surface waters. This study explored the use of Cu isotope values to trace dissolved metal contaminants in stream water throughout a watershed affected by mining by-products of the Dexing Mine, the largest porphyry Cu operation in Asia. Cu isotope values of stream water were compared to potential mineral sources of Cu in the mining operation, and to proximity to the known Cu sources. The first mineral source, chalcopyrite, CuFeS2 has a 'tight' cluster of Cu isotope values (-0.15‰ to +1.65‰; +0.37 ± 0.6‰, 1σ, n=10), and the second mineral source, pyrite (FeS2), has a much larger range of Cu isotope values (-4‰ to +11.9‰; 2.7 ± 4.3‰, 1σ, n=16). Dissolved Cu isotope values of stream water indicated metal derived from either chalcopyrite or pyrite. Above known Cu mineralization, stream waters are approximately +1.5‰ greater than the average chalcopyrite and are interpreted as derived from weathering of chalcopyrite. In contrast, dissolved Cu isotope values in stream water emanating from tailings piles had Cu isotope values similar to or greater than pyrite (>+6‰, a common mineral in the tailings). These values are interpreted as sourced from the tailings, even in solutions that possess significantly lower concentrations of Cu (<0.05 ppm). Elevated Cu isotope values were also found in two soil and two tailings samples (δ(65)Cu ranging between +2 to +5‰). These data point to the mineral pyrite in tailings as the mineral source for the elevated Cu isotope values. Therefore, Cu isotope values of waters emanating from a clearly contaminated drainage possess different Cu isotope values, permitting the discrimination of Cu derived from chalcopyrite and pyrite in solution. Data demonstrate the utility of Cu isotopic values in waters, minerals, and soils to fingerprint metallic contamination for environmental problems.

  11. Age-related changes in the induction of tyrosine aminotransferase by dexamethasone: correlation with the low-affinity glucocorticoid binding sites.

    PubMed

    Chirino, R; Fernández, L; López-Guerra, A; Valerón, P F; Navarro, D; Díaz-Chico, J C; Díaz-Chico, B N

    1994-09-01

    Rat liver membranes contain Low-affinity glucocorticoid binding sites (LAGS), capable of binding with low affinity (Kd approximately 100 nM) endogenous glucocorticoids. Unlike the glucocorticoid receptor (GR), the LAGS level undergoes abrupt changes throughout life. The investigation of these changes may be useful in determining whether the LAGS are involved in the cellular response to glucocorticoids. For this purpose, we have studied glucocorticoid induction of tyrosine aminotransferase (TAT), and its relationship with the LAGS level in adrenalectomized and fasted rats of different ages. No significant differences in the GR level, or in its Kd and activation, were observed among rats of 1, 3, and 12 months of age. On the other hand, the LAGS level showed an important variation with age, from almost undetectable in 1-month-old rats, to a maximum value in 3-month-old rats. With respect to TAT activity, an increase with age in the threshold of response to dexamethasone (DEX) administration was observed. The smallest dose of DEX capable of provoking a significant TAT induction rose from 0.1 microgram/kg body wt. in 1-month-old rats to 10 micrograms/kg body wt. in 12-month-old rats. However, the smallest dose of DEX able to elicit the maximal response was 10 micrograms/kg body wt. in all the assayed ages. This dose provoked a 40% decrease in the GR level, but did not significantly modify the LAGS content. From these results, we conclude that there is an age-related change in the threshold of response to DEX that cannot be explained by the GR-glucocorticoid interaction. The possibility that the LAGS modulate the cell response to glucocorticoids arises from the coincidence of this change with that observed in the LAGS concentration throughout life.

  12. Association of glycerol to dexamethasone in treatment of stroke patients.

    PubMed

    Albizzati, M G; Candelise, L; Capitani, E; Colombo, A; Spinnler, H

    1979-08-01

    A prospective study of 93 acute stroke patients randomly selected by type of antiedema treatment given (hypertonic glicerol infusion plus dexamethasone versus dexamethasone alone) failed to elicit any statistically significant difference between the two treatments on survival rates and quality of survival 7 and 30 days after the stroke. PMID:495045

  13. 21 CFR 520.540 - Dexamethasone oral dosage forms.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Dexamethasone oral dosage forms. 520.540 Section... (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.540 Dexamethasone oral dosage forms....

  14. 21 CFR 520.540 - Dexamethasone oral dosage forms.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Dexamethasone oral dosage forms. 520.540 Section... (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.540 Dexamethasone oral dosage forms....

  15. 21 CFR 520.540 - Dexamethasone oral dosage forms.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Dexamethasone oral dosage forms. 520.540 Section... (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.540 Dexamethasone oral dosage forms....

  16. 21 CFR 520.540 - Dexamethasone oral dosage forms.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Dexamethasone oral dosage forms. 520.540 Section... (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.540 Dexamethasone oral dosage forms....

  17. 21 CFR 520.540 - Dexamethasone oral dosage forms.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Dexamethasone oral dosage forms. 520.540 Section... (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.540 Dexamethasone oral dosage forms....

  18. Mechanisms of corticosteroid action on lymphocyte subpopulations. III. Differential effects of dexamethasone administration on subpopulations of effector cells mediating cellular cytotoxicity in man

    PubMed Central

    Parrillo, J. E.; Fauci, A. S.

    1978-01-01

    The present study investigated the effect of dexamethasone (DEX) administration on different populations of mononuclear cells and neutrophils mediating antibody-dependent cellular cytotoxicity (ADCC) against different target cells. Mononuclear cells (lymphocytes and monocytes) and neutrophils were obtained from twenty-seven normal volunteers at 0, 4, 24 and 48 hr after oral administration of 21 mg of DEX. ADCC was determined utilizing the following targets: human red blood cells (HRBC), Chang liver cells (Ch) and human heart cells (HHC). The predominant mononuclear effector in HRBC killing was shown to be a monocyte and in Ch and HHC killing, a K cell. As previously shown, DEX produced a profound monocytopenia and lymphocytopenia at 4 hr with a return of lymphocyte counts to normal and monocyte counts to supra-normal at 24 hr. At the point of maximal monocytopenia, monocyte-mediated HRBC killing decreased from a geometric mean of 14 to 4 lytic units per 108 effector cells (P<0·05) and rebounded at 24 hr to a mean of 39 lytic units (P<0·02) with the rebound monocytosis. At the point of absolute lymphopenia (4 hr), there was a relative enrichment in the proportion of lymphocytes bearing an Fc receptor (K cells, P<0·01). Concomitant with this was an increase in ADCC against Ch and HHC from geometric means of 1121 to 7172 lytic units and 939 to 7354 lytic units (P<0·001) respectively. Thus, a major action of DEX administration on mononuclear ADCC was to differentially enrich or deplete different effector cells to and from the circulation, causing changes in cytotoxicity. Since the cytotoxicity paralleled the proportion of effector cells, the cells remaining in the circulation following DEX administration retained normal antibody-dependent cytotoxic capabilities. Neutrophil-mediated ADCC against HRBC significantly increased at 4 hr from a geometric mean of 3785 to 20142 lytic units (P<0·02) concomitant with the blood neutrophilia and remained elevated for 72 hr

  19. Effects of a Glucocorticoid Receptor Agonist, Dexamethasone, on Fathead Minnow Reproduction and Development

    EPA Science Inventory

    Few studies have examined the effects of synthetic glucocorticoids on the reproductive axis of fish, despite the fact that these chemicals are therapeutically prescribed anti-inflammatory agents that are abundantly produced and consumed. To generate data to assess potential risk ...

  20. Effects of a Glucocorticoid Receptor Agonist, Dexamethasone, on Fathead Minnow Reproduction, Growth, and Development.

    EPA Science Inventory

    Few studies have examined the effects of synthetic glucocorticoids on the reproductive axis of fish, despite the fact that these chemicals are therapeutically prescribed anti-inflammatory agents that are abundantly produced and consumed. To generate data to assess potential risk ...

  1. Comparison of Corticotropin-Releasing Factor, Dexamethasone and Temozolomide: Treatment Efficacy and Toxicity in U87 and C6 Intracranial Gliomas

    PubMed Central

    Moroz, Maxim A.; Huang, Ruimin; Kochetkov, Tatiana; Shi, Weiji; Thaler, Howard; de Stanchina, Elisa; Gamez, Idoia; Ryan, Robert P.; Blasberg, Ronald G.

    2011-01-01

    Treatment of cerebral tumors and peritumoral brain edema remains a clinical challenge and is associated with high morbidity and mortality. Dexamethasone (DEX) is an effective drug to treat brain edema, but is associated with well-described side effects. Corticorelin acetate (Xerecept) or human corticotrophin releasing factor (hCRF) is a comparatively new drug and was evaluated in two orthotopic glioma models (U87 and C6), by a direct comparison with dexamethasone and temozolomide. In vitro mono- and combination-treatments showed a variable response in 6 different glioma cell lines. In vivo studies showed a dose-dependent effect of hCRF (0.03 and 0.1 mg/kg/q12h) on survival of U87 intracranial xenograft-bearing animals [median survival: control 41 days (95% CI 25–61 d); “low-hCRF” 74.5 d (95% CI 41–88 d); “high-hCRF” >130 d (95% CI not reached)]. Dexamethasone treatment had no effect on survival, but significant toxicity was observed. A survival benefit was observed with TMZ and TMZ + hCRF - treated animals, but with significant TMZ toxicity. C6-bearing animals showed no survival benefit, but similar treatment toxicities. The difference in hCRF-treatment response between U87- and C6-intracranial gliomas can be explained by a difference in receptor expression. RT-PCR identified CRF2r mRNA in U87-xenografts; no CRF-receptors were identified in C6-xenografts. HCRF was more effective than either dexamethasone or temozolomide in the treatment of U87 xenografts, with long-term survivors and only mild toxicity. HCRF therapeutic efficacy appears to be dependent on tumor hCRF-receptor expression. These results support further clinical assessment hCRF therapeutic efficacy and levels of CRFr expression in different human gliomas. PMID:21385926

  2. Cytokine-Induced Loss of Glucocorticoid Function: Effect of Kinase Inhibitors, Long-Acting β2-Adrenoceptor Agonist and Glucocorticoid Receptor Ligands

    PubMed Central

    Rider, Christopher F.; Shah, Suharsh; Miller-Larsson, Anna; Giembycz, Mark A.; Newton, Robert

    2015-01-01

    Acting on the glucocorticoid receptor (NR3C1), glucocorticoids are widely used to treat inflammatory diseases. However, glucocorticoid resistance often leads to suboptimal asthma control. Since glucocorticoid-induced gene expression contributes to glucocorticoid activity, the aim of this study was to use a 2×glucocorticoid response element (GRE) reporter and glucocorticoid-induced gene expression to investigate approaches to combat cytokine-induced glucocorticoid resistance. Pre-treatment with tumor necrosis factor-α (TNF) or interleukin-1β inhibited dexamethasone-induced mRNA expression of the putative anti-inflammatory genes RGS2 and TSC22D3, or just TSC22D3, in primary human airway epithelial and smooth muscle cells, respectively. Dexamethasone-induced DUSP1 mRNA was unaffected. In human bronchial epithelial BEAS-2B cells, dexamethasone-induced TSC22D3 and CDKN1C expression (at 6 h) was reduced by TNF pre-treatment, whereas DUSP1 and RGS2 mRNAs were unaffected. TNF pre-treatment also reduced dexamethasone-dependent 2×GRE reporter activation. This was partially reversed by PS-1145 and c-jun N-terminal kinase (JNK) inhibitor VIII, inhibitors of IKK2 and JNK, respectively. However, neither inhibitor affected TNF-dependent loss of dexamethasone-induced CDKN1C or TSC22D3 mRNA. Similarly, inhibitors of the extracellular signal-regulated kinase, p38, phosphoinositide 3-kinase or protein kinase C pathways failed to attenuate TNF-dependent repression of the 2×GRE reporter. Fluticasone furoate, fluticasone propionate and budesonide were full agonists relative to dexamethasone, while GSK9027, RU24858, des-ciclesonide and GW870086X were partial agonists on the 2×GRE reporter. TNF reduced reporter activity in proportion with agonist efficacy. Full and partial agonists showed various degrees of agonism on RGS2 and TSC22D3 expression, but were equally effective at inducing CDKN1C and DUSP1, and did not affect the repression of CDKN1C or TSC22D3 expression by TNF. Finally

  3. Controlled transdermal iontophoresis for poly-pharmacotherapy: Simultaneous delivery of granisetron, metoclopramide and dexamethasone sodium phosphate in vitro and in vivo.

    PubMed

    Cázares-Delgadillo, Jennyfer; Ganem-Rondero, Adriana; Merino, Virginia; Kalia, Yogeshvar N

    2016-03-31

    Iontophoresis has been used to deliver small molecules, peptides and proteins into and across the skin. In principle, it provides a controlled, non-invasive method for poly-pharmacotherapy since it is possible to formulate and to deliver multiple therapeutic agents simultaneously from the anodal and cathodal compartments. The objective of this proof-of-principle study was to investigate the simultaneous anodal iontophoretic delivery of granisetron (GST) and metoclopramide (MCL) and cathodal iontophoresis of dexamethasone sodium phosphate (DEX-P). In addition to validating the hypothesis, these are medications that are routinely used in combination to treat chemotherapy-induced emesis. Two preliminary in vitro studies using porcine skin were performed: Study 1 - effect of formulation composition on anodal co-iontophoresis of GST and MCL and Study 2 - combined anodal iontophoresis of GST (10mM) and MCL (110 mM) and cathodal iontophoresis of DEX-P (40 mM). The results from Study 1 demonstrated the dependence of GST/MCL transport on the respective drug concentrations when co-iontophoresed at 0.3 mA·cm(-2). Although they possess similar physicochemical properties, MCL seemed to be a more efficient charge carrier (JMCL=0.0591∗CMCLvs JGST=0.0414∗CGST). In Study 2, MCL permeation was markedly superior to that of GST (2324.83 ± 307.85 and 209.83 ± 24.84 μg·cm(-2), respectively); this was consistent with the difference in their relative concentrations; DEX-P permeation was 336.94 ± 71.91 μg·cm(-2). The in vivo studies in Wistar rats (10mM GST, 110 mM MCL and 40 mM DEX-P (0.5 mA·cm(-2) for 5h with Ag/AgCl electrodes and salt bridges) demonstrated that significant drug levels were achieved rapidly for each drug. This was most noticeable for dexamethasone (DEX) where relatively constant plasma levels were obtained from the 1 to 5h time-points; DEX-P was not detected in the plasma since it was completely hydrolyzed to the active metabolite. The calculated input

  4. The effect of dexamethasone on some immunological parameters in cattle.

    PubMed

    Anderson, B H; Watson, D L; Colditz, I G

    1999-11-01

    Immunosuppression as a consequence of acute and chronic stress can increase the susceptibility of cattle to a range of infectious diseases. In order to develop a panel of immune function assays for investigating the effects of potential stressors on immune competence in cattle, the effect of treatment with short- and long-acting preparations of the synthetic glucocorticoid dexamethasone was examined. Short-acting dexamethasone (dexamethasone sodium phosphate 0.08 mg/kg) followed 37 h later by long-acting dexamethasone (dexamethasone-21 isonicotinate 0.25 mg/kg) was injected intramuscularly and blood was collected to assess immune functions at intervals over the subsequent 11 days from 6 treated and 6 control Hereford steers. Dexamethasone induced leukocytosis (neutrophilia, eosinopenia, lymphopenia, monocytosis), an increased neutrophil:lymphocyte ratio, an elevated percentage of CD4+ lymphocytes, a decreased total CD8+ lymphocyte count, decreased total and percentage WC1+ lymphocytes, an elevated percentage of IL-2 receptor alpha (IL-2Ralpha)+ lymphocytes, and an elevated percentage of B lymphocytes. In vitro chemotaxis of peripheral blood neutrophils to human C5a and ovine IL-8 was increased by dexamethasone treatment. Lymphocyte proliferation in the presence of phytohaemagglutinin, and serum concentrations of IgM, but not IgA or IgG1, were suppressed by dexamethasone treatment, whereas mitogen-induced production of interferon-gamma (IFN-gamma), neutrophil expression of CD18, neutrophil myeloperoxidase activity and natural killer (NK) cell activity were not influenced by dexamethasone treatment. The results indicate the potential for haematology and immune function assays to reflect elevated activity of the hypothalamic-pituitary-adrenocortical axis in cattle. Immunological parameters may thus provide a useful adjunct to cortisol and behavioural observations for assessing the impact of stress on the welfare of cattle.

  5. Transplantation of fetal liver tissue suspension into the spleens of adult syngenic rats: inducibility of cytochrome P450 dependent monooxygenase functions by beta-naphthoflavone, phenobarbital and dexamethasone.

    PubMed

    Lupp, A; Lau, K; Trautmann, A K; Krausse, T; Klinger, W

    1999-01-01

    In the present study the effects of beta-naphthoflavone (BNF), phenobarbital (PB) and dexamethasone (DEX) on cytochrome P450 (P450) dependent monooxygenase functions were investigated in intrasplenic liver cell explants in comparison to adult liver. Fetal liver tissue suspensions were transplanted into the spleens of 60-90 days old adult male syngenic Fisher 344 inbred rats. 2, 4 or 6 months after surgery, transplant recipients and age matched controls were orally treated with BNF (1x50 mg/kg body weight (b.wt.)), PB (1x50 mg/kg b.wt.), DEX (for 3 days 4 mg/kg b.wt. per day), or the respective solvents (dimethylsulfoxide or 0.9% NaCl). The animals were sacrificed 24 (BNF, DEX) or 48 (PB) hours after the last treatment. P450 mediated monooxygenase functions were measured in spleen and liver 9000 g supernatants by three model reactions for different P450 subtypes: ethoxyresorufin O-deethylation (EROD; 1A), ethoxycoumarin O-deethylation (ECOD; 1A, 2A, 2B), and ethylmorphine N-demethylation (END; 3A). Spleen weights were significantly higher in transplanted rats, compared to controls, at all three time points after surgery. Induction with PB or DEX, and in some cases also with BNF, lead to a significant increase in liver weights of transplant recipients and control rats independent of the time after transplantation. In contrast, there was no influence on spleen weights due to BNF or PB. At all time points after surgery, with DEX a marked decrease in body weights, weights of adrenal glands and of lymphatic organs like thymus glands and spleens was observed, with the weights of the transplant containing spleens being still higher in comparison to control organs. Spleens of control animals displayed nearly no P450 mediated monooxygenase functions neither without nor with induction. After transplantation, however, significant EROD and ECOD, but hardly any END activities were seen in the host organs at all three time points after surgery. In transplant containing spleens

  6. A natural history of "agonist".

    PubMed

    Russo, Ruth

    2002-01-01

    This paper constructs a brief history of the biochemical term agonist by exploring the multiple meanings of the root agôn in ancient Greek literature and describing how agonist first appeared in the scientific literature of the 20th century in the context of neurophysiologists' debates about the existence and properties of cellular receptors. While the narrow scientific definition of agonist may appear colorless and dead when compared with the web of allusions spun by the ancient Greek agôn, the scientific power and creativity of agonist actually resides precisely in its exact, restricted meaning for biomedical researchers.

  7. Cell-laden photocrosslinked GelMA-DexMA copolymer hydrogels with tunable mechanical properties for tissue engineering.

    PubMed

    Wang, Hang; Zhou, Lei; Liao, Jingwen; Tan, Ying; Ouyang, Kongyou; Ning, Chenyun; Ni, Guoxin; Tan, Guoxin

    2014-09-01

    To effectively repair or replace damaged tissues, it is necessary to design three dimensional (3D) extracellular matrix (ECM) mimicking scaffolds with tunable biomechanical properties close to the desired tissue application. In the present work, gelatin methacrylate (GelMA) and dextran glycidyl methacrylate (DexMA) with tunable mechanical and biological properties were utilized to prepared novel bicomponent polymeric hydrogels by cross-linking polymerization using photoinitiation. We controlled the degree of substitution (DS) of glycidyl methacrylate in DexMA so that they could obtain relevant mechanical properties. The results indicated that copolymer hydrogels demonstrated a lower swelling ratio and higher compressive modulus as compared to the GelMA. Moreover, all of the hydrogels exhibited a honeycomb-like architecture, the pore sizes decreased as DS increased, and NIH-3T3 fibroblasts encapsulated in these hydrogels all exhibited excellent viability. These characteristics suggest a class of photocrosslinkable, tunable mechanically copolymer hydrogels that may find potential application in tissue engineering and regenerative medicine applications.

  8. Dexamethasone mimicks the antimotion sickness effects of amphetamine and scopolamine

    NASA Astrophysics Data System (ADS)

    Kohl, Randall Lee

    Based on preliminary suggestions that individual differences in susceptibility to stressful motion might be related to physiological differences in responses of the hypothalamic-pituitary-adrenal axis, we tested the efficacy of dexamethasone and metyrapone in subjects exposed to cross-coupled accelerative semicircular canal stimulation on a rotating chair. Subjects given 0.5 mg of dexamethasone every 6 h for 48 h could endure 80% more stressful motion ( P = 0.03) in a within-subjects design study, whereas, no improvement followed treatment with 750 mg of metryapone every 4 h for 24 h. The efficacy of dexamethasone might be explained in terms of its neurochemical actions on several neurotransmitter systems which are also modulated by such classical antimotion sickness drugs as amphetamine and scopolamine. Because dexamethasone induces adaptive changes within the central nervous system it may prove superior to scopolamine and amphetamine which possess significant side effects, are short acting, and rapidly tolerated.

  9. Dexamethasone mimicks the antimotion sickness effects of amphetamine and scopolamine

    NASA Technical Reports Server (NTRS)

    Kohl, Randall Lee

    1986-01-01

    Based on preliminary suggestions that individual differences in susceptibility to stressful motion might be related to physiological differences in responses of the hypothalamic-pituitary-adrenal axis, the efficacy of dexamethasone and metyrapone is tested in subjects exposed to cross-coupled accelerative semicircular canal stimulation on a rotating chair. Subjects given 0.5 mg of dexamethasone every 6 h for 48 h could endure 80 percent more stressful motion (P = 0.03) in a within-subjects design study, whereas, no improvement followed treatment with 750 mg of metryapone every 4 h for 24 h. The efficacy of dexamethasone might be explained in terms of its neurochemical actions on several neurotransmitter systems which are also modulated by such classical antimotion sickness drugs as amphetamine and scopolamine. Because dexamethasone induces adaptive changes within the central nervous system it may prove superior to scopolamine and amphetamine which possess significant side effects, are short acting, and rapidly tolerated.

  10. [Comparative pharmacological effectiveness of dexamethasone esters in pigs (author's transl)].

    PubMed

    Mormède, P; Moré, J

    1980-01-01

    Leucocytosis with neutrophilia, lymphopenia and eosinopenia, and decreases in plasma endogenous glucocorticoid levels were used to study the pharmacological kinetics of dexamethasone in pigs. The return to baseline of endogenous plasma glucocorticoid levels was the most sensitive index of dexamethasone action. Intravenous administration of 38 microgram/kg of the soluble phosphate ester produced a maximal response. Higher dosages (76 and 152 microgram/kg) did not increase the intensity of the response, but did increase its duration, which was less than 24 hours. The same response was obtained when dexamethasone phosphate (75 microgram/kg) was given by the intramuscular route. Insoluble esters had a weaker but longer action which lasted for 28 hours with terethoxy-acetate, and approximatively 48 hours with acetate and isonicotinate, on the basis of the pituitary-adrenal axis inhibition. After intramuscular administration, dexamethasone esters induced a weak hyperglycemia but no changes in plasma sodium, chloride or calcium levels were observed.

  11. Therapeutic Potential of 5-HT2C Receptor Agonists for Addictive Disorders.

    PubMed

    Higgins, Guy A; Fletcher, Paul J

    2015-07-15

    The neurotransmitter 5-hydroxytryptamine (5-HT; serotonin) has long been associated with the control of a variety of motivated behaviors, including feeding. Much of the evidence linking 5-HT and feeding behavior was obtained from studies of the effects of the 5-HT releaser (dex)fenfluramine in laboratory animals and humans. Recently, the selective 5-HT2C receptor agonist lorcaserin received FDA approval for the treatment of obesity. This review examines evidence to support the use of selective 5-HT2C receptor agonists as treatments for conditions beyond obesity, including substance abuse (particularly nicotine, psychostimulant, and alcohol dependence), obsessive compulsive, and excessive gambling disorder. Following a brief survey of the early literature supporting a role for 5-HT in modulating food and drug reinforcement, we propose that intrinsic differences between SSRI and serotonin releasers may have underestimated the value of serotonin-based pharmacotherapeutics to treat clinical forms of addictive behavior beyond obesity. We then highlight the critical involvement of the 5-HT2C receptor in mediating the effect of (dex)fenfluramine on feeding and body weight gain and the evidence that 5-HT2C receptor agonists reduce measures of drug reward and impulsivity. A recent report of lorcaserin efficacy in a smoking cessation trial further strengthens the idea that 5-HT2C receptor agonists may have potential as a treatment for addiction. This review was prepared as a contribution to the proceedings of the 11th International Society for Serotonin Research Meeting held in Hermanus, South Africa, July 9-12, 2014.

  12. Effects of Valproic Acid and Dexamethasone Administration on Early Bio-Markers and Gene Expression Profile in Acute Kidney Ischemia-Reperfusion Injury in the Rat

    PubMed Central

    Speir, Ryan W.; Stallings, Jonathan D.; Andrews, Jared M.; Gelnett, Mary S.; Brand, Timothy C.; Salgar, Shashikumar K.

    2015-01-01

    Renal ischemia-reperfusion (IR) causes acute kidney injury (AKI) with high mortality and morbidity. The objective of this investigation was to ameliorate kidney IR injury and identify novel biomarkers for kidney injury and repair. Under general anesthesia, left renal ischemia was induced in Wister rats by occluding renal artery for 45 minutes, followed by reperfusion and right nephrectomy. Thirty minutes prior to ischemia, rats (n = 8/group) received Valproic Acid (150 mg/kg; VPA), Dexamethasone (3 mg/kg; Dex) or Vehicle (saline) intraperitoneally. Animals were sacrificed at 3, 24 or 120 h post-IR. Plasma creatinine (mg/dL) at 24 h was reduced (P<0.05) in VPA (2.7±1.8) and Dex (2.3±1.2) compared to Vehicle (3.8±0.5) group. At 3 h, urine albumin (mg/mL) was higher in Vehicle (1.47±0.10), VPA (0.84±0.62) and Dex (1.04±0.73) compared to naïve (uninjured/untreated control) (0.14±0.26) group. At 24 h post-IR urine lipocalin-2 (μg/mL) was higher (P<0.05) in VPA, Dex and Vehicle groups (9.61–11.36) compared to naïve group (0.67±0.29); also, kidney injury molecule-1 (KIM-1; ng/mL) was higher (P<0.05) in VPA, Dex and Vehicle groups (13.7–18.7) compared to naïve group (1.7±1.9). Histopathology demonstrated reduced (P<0.05) ischemic injury in the renal cortex in VPA (Grade 1.6±1.5) compared to Vehicle (Grade 2.9±1.1). Inflammatory cytokines IL1β and IL6 were downregulated and anti-apoptotic molecule BCL2 was upregulated in VPA group. Furthermore, kidney DNA microarray demonstrated reduced injury, stress, and apoptosis related gene expression in the VPA administered rats. VPA appears to ameliorate kidney IR injury via reduced inflammatory cytokine, apoptosis/stress related gene expression, and improved regeneration. KIM-1, lipocalin-2 and albumin appear to be promising early urine biomarkers for the diagnosis of AKI. PMID:25970334

  13. Neonatal Dexamethasone Treatment Leads to Alterations in Cell Signaling Cascades Controlling Hepatic and Cardiac Function in Adulthood

    PubMed Central

    Adigun, Abayomi A.; Wrench, Nicola; Seidler, Frederic J.; Slotkin, Theodore A.

    2009-01-01

    Increasing evidence indicates that early-life glucocorticoid exposure, either involving stress or the therapy of preterm labor, contributes to metabolic and cardiovascular disorders in adulthood. We investigated cellular mechanisms underlying these effects by administering dexamethasone (DEX) to neonatal rats on postnatal (PN) days 1–3 or 7–9, using doses spanning the threshold for somatic growth impairment: 0.05, 0.2 and 0.8 mg/kg. In adulthood, we assessed the effects on hepatic and cardiac cell function mediated through the adenylyl cyclase (AC) signaling cascade, which controls neuronal and hormonal inputs that regulate hepatic glucose metabolism and cardiac contractility. Treatment on PN1-3 produced heterologous sensitization of hepatic signaling, with upregulation of AC itself leading to parallel increases in the responses to β-adrenergic or glucagon receptor stimulation, or to activation of G-proteins by fluoride. The effects were seen at the lowest dose but increasing DEX past the point of somatic growth impairment led to loss of the effect in females. Nonmonotonic effects were also present in the heart, where males showed AC sensitization at the lowest dose, with decreasing effects as the dose was raised; females showed progressive deficits of cardiac AC activity. Shifting the exposure to PN7-9 still elicited AC sensitization but with a greater offsetting contribution at the higher doses. Our findings show that, in contrast to growth restriction, the glucocorticoids associated with stress or the therapy of preterm labor are more sensitive and more important contributors to the cellular abnormalities underlying subsequent metabolic and cardiovascular dysfunction. PMID:19853034

  14. The long-acting β2-adrenoceptor agonist, indacaterol, enhances glucocorticoid receptor-mediated transcription in human airway epithelial cells in a gene- and agonist-dependent manner

    PubMed Central

    Joshi, T; Johnson, M; Newton, R; Giembycz, M A

    2015-01-01

    Background and Purpose Inhaled glucocorticoid (ICS)/long-acting β2-adrenoceptor agonist (LABA) combination therapy is a recommended treatment option for patients with moderate/severe asthma in whom adequate control cannot be achieved by an ICS alone. Previously, we discovered that LABAs can augment dexamethasone-inducible gene expression and proposed that this effect may explain how these two drugs interact to deliver superior clinical benefit. Herein, we extended that observation by analysing, pharmacodynamically, the effect of the LABA, indacaterol, on glucocorticoid receptor (GR)-mediated gene transcription induced by seven ligands with intrinsic activity values that span the spectrum of full agonism to antagonism. Experimental Approach BEAS-2B human airway epithelial cells stably transfected with a 2× glucocorticoid response element luciferase reporter were used to model gene transcription together with an analysis of several glucocorticoid-inducible genes. Key Results Indacaterol augmented glucocorticoid-induced reporter activation in a manner that was positively related to the intrinsic activity of the GR agonist. This effect was demonstrated by an increase in response maxima without a change in GR agonist affinity or efficacy. Indacaterol also enhanced glucocorticoid-inducible gene expression. However, the magnitude of this effect was dependent on both the GR agonist and the gene of interest. Conclusions and Implications These data suggest that indacaterol activates a molecular rheostat, which increases the transcriptional competency of GR in an agonist- and gene-dependent manner without apparently changing the relationship between fractional GR occupancy and response. These findings provide a platform to rationally design ICS/LABA combination therapy that is based on the generation of agonist-dependent gene expression profiles in target and off-target tissues. PMID:25598440

  15. Preparation and characterization of cross-linked microspheres C(Dex-g-PSSS) and their drug-carrying and colon-specific drug delivery properties.

    PubMed

    Jianping, Zhang; Jianfeng, Guo; Yao, Zhang; Jiao, Yang

    2014-01-01

    The graft polymer Dex-g-PSSS was obtained through poly(sodium 4-styrene sulfonate) (PSSS) grafted on dextran(Dex) by using the cerium salt-hydroxyl group redox initiation system. The cross-linked microspheres C(Dex-g-PSSS) were synthesized by suspension polymerization with epichlorohydrin as the cross-linking agent. The chemical structure and physicochemical characteristics of C(Dex-g-PSSS) microspheres were represented by infrared spectroscopy (FTIR), optical microscope, and zeta potential analysis. The aim of the study is to constitute a colon-specific drug delivery system via molecular design, using C(Dex-g-PSSS) microspheres as the drug-carrying material and taking 5-fluorouracil (5-FU) as the model drug. The drug-carrying ability and mechanism of the cross-linked microspheres C(Dex-g-PSSS) for 5-FU were investigated. Finally, in vitro release tests for the drug-carrying microspheres were conducted. The experimental results show that in the medium with pH 2, the cross-linked microspheres C(Dex-g-PSSS) exhibit a strong adsorption ability for 5-FU because of strong electrostatic interactions and have an adsorption capacity of 154 ± 7.5 mg/g, displaying high drug-carrying efficiency. The in vitro release behavior of the drug-carrying microspheres is highly dependent on pH and dextranase. In the medium with pH 2, the drug-carrying microspheres do not release the drug and in the medium with pH 1, they release a little, whereas in the medium with pH 7.4, a sudden delivery phenomenon of the drug will occur, and in the presence of dextranase, a more sudden delivery phenomenon of the drug will occur, displaying an excellent colon-specific drug delivery behavior.

  16. Preparation and characterization of cross-linked microspheres C(Dex-g-PSSS) and their drug-carrying and colon-specific drug delivery properties.

    PubMed

    Jianping, Zhang; Jianfeng, Guo; Yao, Zhang; Jiao, Yang

    2014-01-01

    The graft polymer Dex-g-PSSS was obtained through poly(sodium 4-styrene sulfonate) (PSSS) grafted on dextran(Dex) by using the cerium salt-hydroxyl group redox initiation system. The cross-linked microspheres C(Dex-g-PSSS) were synthesized by suspension polymerization with epichlorohydrin as the cross-linking agent. The chemical structure and physicochemical characteristics of C(Dex-g-PSSS) microspheres were represented by infrared spectroscopy (FTIR), optical microscope, and zeta potential analysis. The aim of the study is to constitute a colon-specific drug delivery system via molecular design, using C(Dex-g-PSSS) microspheres as the drug-carrying material and taking 5-fluorouracil (5-FU) as the model drug. The drug-carrying ability and mechanism of the cross-linked microspheres C(Dex-g-PSSS) for 5-FU were investigated. Finally, in vitro release tests for the drug-carrying microspheres were conducted. The experimental results show that in the medium with pH 2, the cross-linked microspheres C(Dex-g-PSSS) exhibit a strong adsorption ability for 5-FU because of strong electrostatic interactions and have an adsorption capacity of 154 ± 7.5 mg/g, displaying high drug-carrying efficiency. The in vitro release behavior of the drug-carrying microspheres is highly dependent on pH and dextranase. In the medium with pH 2, the drug-carrying microspheres do not release the drug and in the medium with pH 1, they release a little, whereas in the medium with pH 7.4, a sudden delivery phenomenon of the drug will occur, and in the presence of dextranase, a more sudden delivery phenomenon of the drug will occur, displaying an excellent colon-specific drug delivery behavior. PMID:25162633

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

    SciTech Connect

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

    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.

  18. Early postnatal dexamethasone treatment and increased incidence of cerebral palsy

    PubMed Central

    Shinwell, E; Karplus, M; Reich, D; Weintraub, Z; Blazer, S; Bader, D; Yurman, S; Dolfin, T; Kogan, A; Dollberg, S; Arbel, E; Goldberg, M; Gur, I; Naor, N; Sirota, L; Mogilner, S; Zaritsky, A; Barak, M; Gottfried, E

    2000-01-01

    OBJECTIVE—To study the long term neurodevelopmental outcome of children who participated in a randomised, double blind, placebo controlled study of early postnatal dexamethasone treatment for prevention of chronic lung disease.
METHODS—The original study compared a three day course of dexamethasone (n = 132) with a saline placebo (n = 116) administered from before 12 hours of age in preterm infants, who were ventilated for respiratory distress syndrome and had received surfactant treatment. Dexamethasone treatment was associated with an increased incidence of hypertension, hyperglycaemia, and gastrointestinal haemorrhage and no reduction in either the incidence or severity of chronic lung disease or mortality. A total of 195 infants survived to discharge and five died later. Follow up data were obtained on 159 of 190 survivors at a mean (SD) age of 53 (18) months.
RESULTS—No differences were found between the groups in terms of perinatal or neonatal course, antenatal steroid administration, severity of initial disease, or major neonatal morbidity. Dexamethasone treated children had a significantly higher incidence of cerebral palsy than those receiving placebo (39/80 (49%) v 12/79 (15%) respectively; odds ratio (OR) 4.62, 95% confidence interval (95% CI) 2.38 to 8.98). The most common form of cerebral palsy was spastic diplegia (incidence 22/80 (28%) v 5/79 (6%) in dexamethasone and placebo treated infants respectively; OR 4.45, 95% CI 1.95to 10.15). Developmental delay was significantly more common in the dexamethasone treated group (44/80 (55%)) than in the placebo treated group (23/79 (29%); OR 2.87, 95% CI 1.53 to 5.38). Dexamethasone treated infants had more periventricular leucomalacia and less intraventricular haemorrhage in the neonatal period than those in the placebo group, although these differences were not statistically significant. Eleven children with cerebral palsy had normal ultrasound scans in the neonatal period; all 11 had received

  19. 3D-Epitope-Explorer (3DEX): localization of conformational epitopes within three-dimensional structures of proteins.

    PubMed

    Schreiber, Andreas; Humbert, Michael; Benz, Alexander; Dietrich, Ursula

    2005-07-15

    Neutralizing antibodies often recognize conformational, discontinuous epitopes. Linear peptides mimicking such conformational epitopes can be selected from phage display peptide libraries by screening with the respective antibodies. However, it is difficult to localize these "mimotopes" within the three-dimensional (3D) structures of the target proteins. Knowledge of conformational epitopes of neutralizing antibodies would help to design antigens able to elicit protective immune responses. Therefore, we provide here a software that allows to localize linear peptide sequences within 3D structures of proteins. The 3D-Epitope-Explorer (3DEX) software allows to map conformational epitopes in 3D protein structures based on an algorithm that takes into account the physicochemical neighborhood of C(alpha)- or C(beta)-atoms of individual amino acids. A given amino acid of a peptide sequence is localized within the protein and the software searches within predefined distances for the amino acids neighboring that amino acid in the peptide. Surface exposure of the amino acids can also be taken into consideration. The procedure is then repeated for the remaining amino acids of the peptide. The introduction of a joker function allows to map peptide mimotopes, which do not necessarily have 100% sequence homology to the protein. Using this software we were able to localize mimotopes selected from phage displayed peptide libraries with polyclonal antibodies from HIV-positive patient plasma within the 3D structure of gp120, the exterior glycoprotein of HIV-1. We also analyzed two recently published peptide sequences corresponding to known conformational epitopes to further confirm the integrity of 3DEX.

  20. Effects of dexamethasone on palate mesenchymal cell phospholipase activity

    SciTech Connect

    Bulleit, R.F.; Zimmerman, E.F.

    1984-09-15

    Corticosteroids will induce cleft palate in mice. One suggested mechanism for this effect is through inhibition of phospholipase activity. This hypothesis was tested by measuring the effects of dexamethasone, a synthetic corticosteroid, on phospholipase activity in cultures of palate mesenchymal cells. Palate mesenchymal cells were prelabeled with (3H)arachidonic acid. The cells were subsequently treated with various concentrations of dexamethasone. Concurrently, cultures of M-MSV-transformed 3T3 cells were prepared identically. After treatment, phospholipase activity was stimulated by the addition of serum or epidermal growth factor (EGF), and radioactivity released into the medium was taken as a measure of phospholipase activity. Dexamethasone (1 X 10(-5) or 1 X 10(-4) M) could inhibit serum-stimulated phospholipase activity in transformed 3T3 cells after 1 to 24 hr of treatment. However, no inhibition of activity was measured in palate mesenchymal cells following this period of treatment. Not until 120 hr of treatment with dexamethasone (1 X 10(-4) M) was any significant inhibition of serum-stimulated phospholipase activity observed in palate mesenchymal cells. When EGF was used to stimulate phospholipase activity, dexamethasone (1 X 10(-5) M) caused an increase in phospholipase activity in palate mesenchymal cells. These observations suggested that phospholipase in transformed 3T3 cells was sensitive to inhibition by dexamethasone. However, palate mesenchymal cell phospholipase is only minimally sensitive to dexamethasone, and in certain instances can be enhanced. These results cannot support the hypothesis that corticosteroids mediate their teratogenic effect via inhibition of phospholipase activity.

  1. Degradation of dexamethasone by acclimated strain of Pseudomonas Alcaligenes

    PubMed Central

    Zhu, Lili; Yang, Zhibang; Yang, Qian; Tu, Zeng; Ma, Lianju; Shi, Zhongquan; Li, Xiaoyu

    2015-01-01

    This study is to investigate the use of microbial remediation technology for degradation of dexamethasone in polluted water. A strain of Pseudomonas Alcaligenes with the ability of dexamethasone degradation was isolated from hospital polluted water. This strain was further acclimated into a bacterial strain that could highly degrade dexamethasone. Domesticated bacterial proteins were separated by osmotic shock method and were analyzed using SDS-PAGE. Enzyme activity of dexamethasone degradation was detected by high performance liquid chromatography. Protein bands with different molecular weight were found in all regions of the bacteria and a band with molecular weight of about 100 kDa was most obvious. In intracellular and periplasmic liquid, there was a band with molecular weight of about 41 kDa. Enzyme activity mainly existed in intracellular liquid. The 41 kDa protease was purified using ammonium sulfate precipitation, DEAE-52 ion exchange column and Sephadex G-100 column. Dexamethasone and dexamethasone sodium phosphate degrading rates of the purified enzyme were 36% and 95%, respectively. The 100 kDa protein had a 19% coverage rate to TonB receptor dependent protein, with 11 peptides matching. The 41 kDa protein had a 56% coverage rate to isovaleryl coenzyme A dehydrogenase, with 5 peptides matching. The 41 kDa protein had good degradation between the temperature of 25-40°C and PH value of 6.5-8.5. The enzyme kinetics equation was Ct = C0 e-0.1769t, in accordance with the first-order kinetic equation. This study laid the foundation for further preparation of bioremediation agents for clearance of dexamethasone pollution in water. PMID:26379892

  2. Degradation of dexamethasone by acclimated strain of Pseudomonas Alcaligenes.

    PubMed

    Zhu, Lili; Yang, Zhibang; Yang, Qian; Tu, Zeng; Ma, Lianju; Shi, Zhongquan; Li, Xiaoyu

    2015-01-01

    This study is to investigate the use of microbial remediation technology for degradation of dexamethasone in polluted water. A strain of Pseudomonas Alcaligenes with the ability of dexamethasone degradation was isolated from hospital polluted water. This strain was further acclimated into a bacterial strain that could highly degrade dexamethasone. Domesticated bacterial proteins were separated by osmotic shock method and were analyzed using SDS-PAGE. Enzyme activity of dexamethasone degradation was detected by high performance liquid chromatography. Protein bands with different molecular weight were found in all regions of the bacteria and a band with molecular weight of about 100 kDa was most obvious. In intracellular and periplasmic liquid, there was a band with molecular weight of about 41 kDa. Enzyme activity mainly existed in intracellular liquid. The 41 kDa protease was purified using ammonium sulfate precipitation, DEAE-52 ion exchange column and Sephadex G-100 column. Dexamethasone and dexamethasone sodium phosphate degrading rates of the purified enzyme were 36% and 95%, respectively. The 100 kDa protein had a 19% coverage rate to TonB receptor dependent protein, with 11 peptides matching. The 41 kDa protein had a 56% coverage rate to isovaleryl coenzyme A dehydrogenase, with 5 peptides matching. The 41 kDa protein had good degradation between the temperature of 25-40°C and PH value of 6.5-8.5. The enzyme kinetics equation was Ct = C0 e(-0.1769t), in accordance with the first-order kinetic equation. This study laid the foundation for further preparation of bioremediation agents for clearance of dexamethasone pollution in water. PMID:26379892

  3. Effects of arterial blood pressure on rebleeding using Celox and TraumaDEX in a porcine model of lethal femoral injury.

    PubMed

    Burgert, James M; Gegel, Brian T; Austin, Robert; Davila, Alejandro; Deeds, Jacob; Hodges, Lonnie; Hover, Andrew; Lockhart, Cheryl; Roy, John; Simpson, Glenn; Weaver, Stephen; Wolfe, William; Johnson, Don

    2010-06-01

    This study was designed to identify the systolic blood pressure (SBP) and mean arterial pressure (MAP) at which rebleeding occurs when a clot is formed by a hemostatic agent, Celox or TraumaDEX, compared with a standard dressing. Fifteen pigs (5 each) were assigned randomly to 1 of 3 groups: Celox, TraumaDEX, or standard pressure dressing as a control. In all animals, the femoral artery and vein were transected to simulate traumatic injury. Subjects were allowed to hemorrhage 1 minute before treatment. Direct pressure was held 5 minutes followed by application of elastic dressings for 30 minutes. Dressings were removed after 30 minutes, and the wound was observed for rebleeding. Animals demonstrating hemostasis received phenylephrine infusion to increase SBP in 10-mm Hg increments until SBP reached 210 mm Hg or hemorrhage recurred. There were statistically significant differences between Celox (mean SBP, 166.4 mm Hg; mean MAP, 1376 mm Hg) and the control (mean SBP, 88.25 mm Hg; mean MAP, 59.7 mm Hg), and between TraumaDEX (mean SBP, 152.2 mm Hg; mean MAP, 113.2 mm Hg) and the control (P < .05). However, no statistically significant difference existed between Celox and TraumaDEX. Celox and TraumaDEX effectively prevent rebleeding compared with standard dressing.

  4. Inhibition of B7-1 (CD80) by RhuDex® reduces lipopolysaccharide-mediated inflammation in human atherosclerotic lesions

    PubMed Central

    Doesch, Andreas O; Zhao, Li; Gleissner, Christian A; Akhavanpoor, Mohammadreza; Rohde, David; Okuyucu, Deniz; Hakimi, Maani; Dengler, Thomas J; Katus, Hugo A; Erbel, Christian

    2014-01-01

    Background Atherosclerosis is based on a chronic inflammatory process including the innate and adaptive immune response. Costimulatory molecules and their receptors provide decisive signals for antigen-specific cell activation. The contribution of B7-related pathways to atherosclerosis has hardly been explored. Methods In the present study, we investigated the contribution of B7-1 to inflammation and tissue injury in the human plaque microenvironment in order to identify possible target structures of future therapeutic agents ex vivo and in vitro. Results Carotid artery plaque stimulation with lipopolysaccharides (LPS) could be significantly inhibited by RhuDex®, a specific inhibitor of the costimulatory molecule B7-1 ex vivo (P<0.001). Coculture of antigen-presenting cells with T-cells demonstrated that the inhibitory effects of RhuDex® derived from reduced T-cell activation. In addition, incubation of monocytes/macrophages with LPS and RhuDex® resulted in an inhibitory negative feedback on antigen-presenting cells. Signaling pathways affected by RhuDex® seem to be nuclear transcription factor kappa B, activator protein-1, and extracellular signal-regulated kinase 1/2. Conclusion The present data support B7-1 alone as an important costimulatory molecule in the context of LPS-mediated inflammation in atherosclerotic lesions. Due to its marked inhibitory effects, RhuDex® may be a useful therapy to modulate the inflammatory milieu in atherosclerosis. PMID:24872677

  5. Gestational dexamethasone alters fetal neuroendocrine axis.

    PubMed

    Ahmed, R G

    2016-09-01

    This study tested whether the maternal transport of dexamethasone (DEXA) may affect the development of the neuroendocrine system. DEXA (0.2mg/kg b.w., subcutaneous injection) was administered to pregnant rats from gestation day (GD) 1-20. In the DEXA-treated group, a decrease in maternal serum thyroxine (T4), triiodothyronine (T3), and increase in thyrotropin (TSH) levels (hypothyroid status) were observed at GDs 15 & 20 with respect to control group. The reverse pattern (hyperthyroid status) was observed in their fetuses at embryonic days (EDs) 15 & 20. Although the maternal body weight was diminished, the weight of the thyroid gland was increased at studied GDs as compared to the control group. The fetal growth retardation, hyperleptinemia, hyperinsulinism, and cytokines distortions (transforming growth factor-beta; TGF-β, tumor necrosis factor-alpha; TNF-α, and interferon-γ; IFN-γ) were noticed at examined EDs if compared to the control group. Alternatively, the maternofetal thyroid dysfunctions due to the maternal DEXA administration attenuated the levels of fetal cerebral norepinephrine (NE) and epinephrine (E), and elevated the levels of dopamine (DA) and 5-hydroxytryptamine (5-HT) at considered days. These alterations were age-dependent and might damage the nerve transmission. Finally, maternal DEXA might act as neuroendocrine disruptor causing dyshormonogenesis and fetal cerebral dysfunction. PMID:27220267

  6. Dexamethasone-induced immunosuppression: a rabbit model.

    PubMed

    Jeklova, Edita; Leva, Lenka; Jaglic, Zoran; Faldyna, Martin

    2008-04-15

    Rabbits are often used as animal models for experimental purposes; in many cases steroid-induced immunosuppression is necessary. The aim of this study was to characterise a model of immunosuppression in rabbits, based on changes in the lymphocyte subset distribution, changes in proliferative capacity of lymphocytes and activity of neutrophils 1, 3 and 7 days after the administration of 2mg/kg dexamethasone phosphate (DXP) three times at 6-h intervals. In peripheral blood, neutrophilia and lymphopenia together with eosinopenia, monocytopenia and basopenia in the absence of leukocytosis was detected. One day after DXP administration the absolute numbers of all lymphocyte subsets decreased in the blood, whereas in bone marrow, absolute numbers of all lymphocyte subsets increased significantly, except CD79alpha(+) cells that increased only in relative numbers. The effect of DXP on lymphocytes from the spleen, mesenteric and popliteal lymph nodes was less pronounced. In the thymus, DXP led to a marked reduction of the relative and absolute numbers of CD4(+)CD8(+) thymocytes. The proliferative capacity of lymphocytes after concanavalin A stimulation was lower in the peripheral blood and spleen only on day 1, no changes were detected in lymph nodes or in bone marrow. A marked increase in proliferative capacity was detected in the thymus. Spontaneous production of reactive oxygen metabolites by neutrophils was reduced on days 1 and 3 after DXP administration. The present results demonstrate clearly that this DXP application protocol is useful for the experimental induction of relatively short-lasting immunosuppression in rabbits.

  7. Dexamethasone regulates glutamine synthetase expression in rat skeletal muscles

    NASA Technical Reports Server (NTRS)

    Max, Stephen R.; Konagaya, Masaaki; Konagaya, Yoko; Thomas, John W.; Banner, Carl; Vitkovic, Ljubisa

    1986-01-01

    The regulation of glutamine synthetase by glucocorticoids in rat skeletal muscles was studied. Administration of dexamethasone strikingly enhanced glutamine synthetase activity in plantaris and soleus muscles. The dexamethasone-mediated induction of glutamine synthetase activity was blocked to a significant extent by orally administered RU38486, a glucocorticoid antagonist, indicating the involvement of intracellular glucocorticoid receptors in the induction. Northern blot analysis revealed that dexamethasone-mediated enhancement of glutamine synthetase activity involves dramatically increased levels of glutamine synthetase mRNA. The induction of glutamine synthetase was selective in that glutaminase activity of soleus and plantaris muscles was not increased by dexamethasone. Furthermore, dexamethasone treatment resulted in only a small increase in glutamine synthetase activity in the heart. Accordingly, there was only a slight change in glutamine synthetase mRNA level in this tissue. Thus, glucocorticoids regulate glutamine synthetase gene expression in rat muscles at the transcriptional level via interaction with intracellular glutamine production by muscle and to mechanisms underlying glucocorticoid-induced muscle atrophy.

  8. Impaired self-awareness after traumatic brain injury: inter-rater reliability and factor structure of the Dysexecutive Questionnaire (DEX) in patients, significant others and clinicians

    PubMed Central

    McGuire, Brian E.; Morrison, Todd G.; Barker, Lynne A.; Morton, Nicholas; McBrinn, Judith; Caldwell, Sheena; Wilson, Colin F.; McCann, John; Carton, Simone; Delargy, Mark; Walsh, Jane

    2014-01-01

    Aims: This study sought to address two questions: (1) what is the inter-rater reliability of the Dysexecutive Questionnaire (DEX) when completed by patients, their significant others, and clinicians; and (2) does the factor structure of the DEX vary for these three groups? Methods: We obtained DEX ratings for 113 patients with an acquired brain injury from two brain injury services in the UK and two services in Ireland. We gathered data from two groups of raters—“significant others” (DEX-SO) such as partners and close family members and “clinicians” (DEX-C), who were psychologists or rehabilitation physicians working closely with the patient and who were able to provide an opinion about the patient’s level of everyday executive functioning. Intra-class correlation coefficients and their 95% confidence intervals were calculated between each of the three groups (self, significant other, clinician). Principal axis factor (PAF) analyses were also conducted for each of the three groups. Results: The factor analysis revealed a consistent one-factor model for each of the three groups of raters. However, the inter-rater reliability analyses showed a low level of agreement between the self-ratings and the ratings of the two groups of independent raters. We also found low agreement between the significant others and the clinicians. Conclusion: Although there was a consistent finding of a single factor solution for each of the three groups, the low level of agreement between significant others and clinicians raises a question about the reliability of the DEX. PMID:25346668

  9. Lasting effects of developmental dexamethasone treatment on neural cell number and size, synaptic activity, and cell signaling: critical periods of vulnerability, dose-effect relationships, regional targets, and sex selectivity.

    PubMed

    Kreider, Marisa L; Tate, Charlotte A; Cousins, Mandy M; Oliver, Colleen A; Seidler, Frederic J; Slotkin, Theodore A

    2006-01-01

    Glucocorticoids administered to prevent respiratory distress in preterm infants are associated with neurodevelopmental disorders. To evaluate the long-term effects on forebrain development, we treated developing rats with dexamethasone (Dex) at 0.05, 0.2, or 0.8 mg/kg, doses below or spanning the range in clinical use, testing the effects of administration during three different stages: gestational days 17-19, postnatal days 1-3, or postnatal days 7-9. In adulthood, we assessed biomarkers of neural cell number and size, cholinergic presynaptic activity, neurotransmitter receptor expression, and synaptic signaling mediated through adenylyl cyclase (AC), in the cerebral cortex, hippocampus, and striatum. Even at doses that were devoid of lasting effects on somatic growth, Dex elicited deficits in the number and size of neural cells, with the largest effect in the cerebral cortex. Indices of cholinergic synaptic function (choline acetyltransferase, hemicholinium-3 binding) indicated substantial hyperactivity in males, especially in the hippocampus, effectively eliminating the normal sex differences for these parameters. However, the largest effects were seen for cerebrocortical cell signaling mediated by AC, where Dex treatment markedly elevated overall activity while obtunding the function of G-protein-coupled catecholaminergic or cholinergic receptors that stimulate or inhibit AC; uncoupling was noted despite receptor upregulation. Again, the effects on signaling were larger in males and offset the normal sex differences in AC. These results indicate that, during critical developmental periods, Dex administration evokes lasting alterations in neural cell numbers and synaptic function in forebrain regions, even at doses below those used in preterm infants.

  10. Dexamethasone reduces emesis after major gastrointestinal surgery (DREAMS)

    PubMed Central

    2013-01-01

    Background Postoperative nausea and vomiting is one of the most common complications affecting patients after surgery and causes significant morbidity and increased length of hospital stay. It is accepted that patients undergoing surgery on the bowel are at a higher risk. In the current era of minimally invasive colorectal surgery combined with enhanced recovery, reducing the incidence and severity of postoperative nausea and vomiting is particularly important. Dexamethasone is widely, but not universally used. It is known to improve appetite and gastric emptying, thus reduce vomiting. However, this benefit is not established in patients undergoing bowel surgery, and dexamethasone has possible side effects such as increased risk of wound infection and anastomotic leak that could adversely affect recovery. Design DREAMS is a phase III, double-blind, multicenter, randomized controlled trial with the primary objective of determining if preoperative dexamethasone reduces postoperative nausea and vomiting in patients undergoing elective gastrointestinal resections. DREAMS aims to randomize 1,350 patients over 2.5 years. Patients undergoing laparoscopic or open colorectal resections for malignant or benign pathology are randomized between 8 mg intravenous dexamethasone and control (no dexamethasone). All patients are given one additional antiemetic at the time of induction, prior to randomization. Both the patient and their surgeon are blinded as to the treatment arm. Secondary objectives of the DREAMS trial are to determine whether there are other measurable benefits during recovery from surgery with the use of dexamethasone, including quicker return to oral diet and reduced length of stay. Health-related quality of life, fatigue and risks of infections will be investigated. Trial registration ISRCTN21973627 PMID:23938028

  11. Postnatal rat lung retinoic acid receptor (RAR) mRNA expression and effects of dexamethasone on RAR beta mRNA.

    PubMed

    Grummer, M A; Zachman, R D

    1995-10-01

    Retinoids exert multiple effects upon lung differentiation and growth. Although the mechanisms involved are presently poorly understood, increasing evidence points to a central role of nuclear retinoic acid receptors (RAR). The purpose of this study was to determine RAR mRNA expression profile during postnatal alveolarization, compared with the expression in prenatal and adult rat lung, and to describe the effects of dexamethasone (DEX) and oxygen on postnatal lung RAR gene expression. Total RNA was isolated from lungs of Sprague-Dawley rats on prenatal day 19, on postnatal days 1, 3, 7, 10, and 14 of life, and from adults. One subgroup of littermate pups was treated with DEX daily for 3 or 7 days. In a second experiment, rats were exposed to room air or to 95% oxygen for 72 hours, and received either DEX or saline. Northern hybridization showed that the levels of all RAR subtypes in fetal lung were 45% or less of levels at postnatal day 1. The 3.7 kb RAR alpha transcript levels were lower than day 1 on days 10 and 14 (relative to day 1, day 10 = 0.54 +/- 0.05; day 14 = 0.54 +/- 0.08), but there was no change in a 2.7 kb RAR alpha transcript over this time period. By contrast, RAR beta mRNA levels were significantly higher at days 3, 10, and 14 compared with day 1 (day 3 = 1.79 +/- 0.19; day 10 = 1.41 +/- 0.14; day 14 = 1.53 +/- 0.05). Similarly, RAR gamma mRNA expression levels were higher on day 10 (1.45 +/- 0.09), but by day 14 there was no difference from day 1. Adult lung 3.7 kb RAR alpha, 2.7 kb RAR alpha, and RAR gamma were lower than day 1, but RAR beta was significantly greater (3.7 alpha = 0.52 +/- 0.05; 2.7 alpha = 0.49 +/- 0.26; gamma = 0.74 +/- 0.06; beta = 1.63 +/- 0.22). Treatment with DEX prevented the rise in RAR beta mRNA occurring on day 3 and significantly lowered (0.65 +/- 0.06) the amount of RAR beta mRNA in day 7 lung. Exposure of rat pups to oxygen caused an increase in RAR beta mRNA (1.21 +/- 0.03). DEX treatment again decreased RAR beta m

  12. Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis

    PubMed Central

    Beardsley, J.; Wolbers, M.; Kibengo, F.M.; Ggayi, A.-B.M.; Kamali, A.; Cuc, N.T.K.; Binh, T.Q.; Chau, N.V.V.; Farrar, J.; Merson, L.; Phuong, L.; Thwaites, G.; Van Kinh, N.; Thuy, P.T.; Chierakul, W.; Siriboon, S.; Thiansukhon, E.; Onsanit, S.; Supphamongkholchaikul, W.; Chan, A.K.; Heyderman, R.; Mwinjiwa, E.; van Oosterhout, J.J.; Imran, D.; Basri, H.; Mayxay, M.; Dance, D.; Phimmasone, P.; Rattanavong, S.; Lalloo, D.G.; Day, J.N.

    2016-01-01

    BACKGROUND Cryptococcal meningitis associated with human immunodeficiency virus (HIV) infection causes more than 600,000 deaths each year worldwide. Treatment has changed little in 20 years, and there are no imminent new anticryptococcal agents. The use of adjuvant glucocorticoids reduces mortality among patients with other forms of meningitis in some populations, but their use is untested in patients with cryptococcal meningitis. METHODS In this double-blind, randomized, placebo-controlled trial, we recruited adult patients with HIV-associated cryptococcal meningitis in Vietnam, Thailand, Indonesia, Laos, Uganda, and Malawi. All the patients received either dexamethasone or placebo for 6 weeks, along with combination antifungal therapy with amphotericin B and fluconazole. RESULTS The trial was stopped for safety reasons after the enrollment of 451 patients. Mortality was 47% in the dexamethasone group and 41% in the placebo group by 10 weeks (hazard ratio in the dexamethasone group, 1.11; 95% confidence interval [CI], 0.84 to 1.47; P = 0.45) and 57% and 49%, respectively, by 6 months (hazard ratio, 1.18; 95% CI, 0.91 to 1.53; P = 0.20). The percentage of patients with disability at 10 weeks was higher in the dexamethasone group than in the placebo group, with 13% versus 25% having a prespecified good outcome (odds ratio, 0.42; 95% CI, 0.25 to 0.69; P<0.001). Clinical adverse events were more common in the dexamethasone group than in the placebo group (667 vs. 494 events, P = 0.01), with more patients in the dexamethasone group having grade 3 or 4 infection (48 vs. 25 patients, P = 0.003), renal events (22 vs. 7, P = 0.004), and cardiac events (8 vs. 0, P = 0.004). Fungal clearance in cerebrospinal fluid was slower in the dexamethasone group. Results were consistent across Asian and African sites. CONCLUSIONS Dexamethasone did not reduce mortality among patients with HIV-associated cryptococcal meningitis and was associated with more adverse events and disability

  13. Agonist-trafficking and hallucinogens.

    PubMed

    González-Maeso, Javier; Sealfon, Stuart C

    2009-01-01

    Seven transmembrane domain receptors, also termed G protein-coupled receptors (GPCRs), represent the most common molecular target for therapeutic drugs. The generally accepted pharmacological model for GPCR activation is the ternary complex model, in which GPCRs exist in a dynamic equilibrium between the active and inactive conformational states. However, the demonstration that different agonists sometimes elicit a different relative activation of two signaling pathways downstream of the same receptor has led to a revision of the ternary complex model. According to this agonist- trafficking model, agonists stabilize distinct activated receptor conformations that preferentially activate specific signaling pathways. Hallucinogenic drugs and non-hallucinogenic drugs represent an attractive experimental system with which to study agonist-trafficking of receptor signaling. Thus many of the behavioral responses induced by hallucinogenic drugs, such as lysergic acid diethylamide (LSD), psilocybin or mescaline, depend on activation of serotonin 5-HT(2A) receptors (5-HT2ARs). In contrast, this neuropsychological state in humans is not induced by closely related chemicals, such as lisuride or ergotamine, despite their similar in vitro activity at the 5-HT2AR. In this review, we summarize the current knowledge, as well as unresolved questions, regarding agonist-trafficking and the mechanism of action of hallucinogenic drugs.

  14. DEX: Increasing the Capability of Scientific Data Analysis Pipelines by Using Efficient Bitmap Indices to Accelerate Scientific Visualization

    SciTech Connect

    Stockinger, Kurt; Shalf, John; Bethel, Wes; Wu, Kesheng

    2005-02-04

    We describe a new approach to scalable data analysis that enables scientists to manage the explosion in size and complexity of scientific data produced by experiments and simulations. Our approach uses a novel combination of efficient query technology and visualization infrastructure. The combination of bit map indexing, which is a data management technology that accelerates queries on large scientific datasets, with a visualization pipeline for generating images of abstract data results in a tool suitable for use by scientists in fields where data size and complexity poses a barrier to efficient analysis. Our architecture and implementation, which we call DEX (short for dexterous data explorer), directly addresses the problem of ''too much data'' by focusing analysis on data deemed to be ''scientifically interesting'' via a user-specified selection criteria. The architectural concepts and implementation are applicable to wide variety of scientific data analysis and visualization applications. This paper presents an architectural overview of the system along with an analysis showing substantial performance over traditional visualization pipelines. While performance gains are a significant result, even more important is the new functionality not present in any visualization analysis software--namely the ability to perform interactive, multi-dimensional queries to refine regions of interest that are later used as input to analysis or visualization.

  15. Transcription-dependent nucleolar cap localization and possible nuclear function of DExH RNA helicase RHAU

    SciTech Connect

    Iwamoto, Fumiko; Stadler, Michael; Chalupnikova, Katerina; Oakeley, Edward; Nagamine, Yoshikuni

    2008-04-01

    RHAU (RNA helicase associated with AU-rich element) is a DExH protein originally identified as a factor accelerating AU-rich element-mediated mRNA degradation. The discovery that RHAU is predominantly localized in the nucleus, despite mRNA degradation occurring in the cytoplasm, prompted us to consider the nuclear functions of RHAU. In HeLa cells, RHAU was found to be localized throughout the nucleoplasm with some concentrated in nuclear speckles. Transcriptional arrest altered the localization to nucleolar caps, where RHAU is closely localized with RNA helicases p68 and p72, suggesting that RHAU is involved in transcription-related RNA metabolism in the nucleus. To see whether RHAU affects global gene expression transcriptionally or posttranscriptionally, we performed microarray analysis using total RNA from RHAU-depleted HeLa cell lines, measuring both steady-state mRNA levels and mRNA half-lives by actinomycin D chase. There was no change in the half-lives of most transcripts whose steady-state levels were affected by RHAU knockdown, suggesting that these transcripts are subjected to transcriptional regulation. We propose that RHAU has a dual function, being involved in both the synthesis and degradation of mRNA in different subcellular compartments.

  16. Cessation of dexamethasone exacerbates airway responses to methacholine in asthmatic mice.

    PubMed

    Stengel, Peter W; Nickell, Laura E; Wolos, Jeffrey A; Snyder, David W

    2007-06-01

    In asthmatic mice, dexamethasone (30.0 mg/kg) was administered orally once daily on Days 24-27. One hour after dexamethasone on Day 25-27, the mice were exposed to ovalbumin aerosols. Twenty-eight days after the initial ovalbumin immunization, we found that dexamethasone reduced methacholine-induced pulmonary gas trapping and inhibited bronchoalveolar lavage eosinophils and neutrophils. However, five days after the last dose of dexamethasone and last ovalbumin aerosol exposure in other asthmatic mice, the airway obstructive response to methacholine was exacerbated in dexamethasone-treated mice compared to vehicle-treated mice on Day 32. Further, eosinophils, but not neutrophils, were still inhibited after cessation of dexamethasone. Thus, discontinuing dexamethasone worsened methacholine-induced pulmonary gas trapping of asthmatic mice in the absence of eosinophilic airway inflammation.

  17. 21 CFR 522.542 - Dexamethasone-21-isonicotinate suspension.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... intramuscular administration as follows: Dogs—0.25 to 1 milligram; cats—0.125 to 0.5 milligram; horses—5 to 20... suspension contains 1 milligram of dexamethasone-21-isonicotinate. (b) Sponsor. No. 000010 in § 510.600(c) of this chapter. (c) Conditions of use. (1) The drug is used in the treatment of various...

  18. 21 CFR 520.540c - Dexamethasone chewable tablets.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ....25 to 1.25 milligrams per day.1 (2) Indications for use. Supportive therapy in nonspecific dermatosis... crumble over food. Administer 0.25 to 1.25 milligrams daily in single or two divided doses until response... Dexamethasone chewable tablets. (a) Specifications. Each half-scored tablet contains 0.25 milligram...

  19. 21 CFR 520.540c - Dexamethasone chewable tablets.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ....25 to 1.25 milligrams per day.1 (2) Indications for use. Supportive therapy in nonspecific dermatosis... crumble over food. Administer 0.25 to 1.25 milligrams daily in single or two divided doses until response... Dexamethasone chewable tablets. (a) Specifications. Each half-scored tablet contains 0.25 milligram...

  20. 21 CFR 520.540c - Dexamethasone chewable tablets.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ....25 to 1.25 milligrams per day.1 (2) Indications for use. Supportive therapy in nonspecific dermatosis... crumble over food. Administer 0.25 to 1.25 milligrams daily in single or two divided doses until response... Dexamethasone chewable tablets. (a) Specifications. Each half-scored tablet contains 0.25 milligram...

  1. 21 CFR 520.540c - Dexamethasone chewable tablets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ....25 to 1.25 milligrams per day.1 (2) Indications for use. Supportive therapy in nonspecific dermatosis... crumble over food. Administer 0.25 to 1.25 milligrams daily in single or two divided doses until response... Dexamethasone chewable tablets. (a) Specifications. Each half-scored tablet contains 0.25 milligram...

  2. 21 CFR 520.540c - Dexamethasone chewable tablets.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ....25 to 1.25 milligrams per day.1 (2) Indications for use. Supportive therapy in nonspecific dermatosis... crumble over food. Administer 0.25 to 1.25 milligrams daily in single or two divided doses until response... Dexamethasone chewable tablets. (a) Specifications. Each half-scored tablet contains 0.25 milligram...

  3. 21 CFR 522.542 - Dexamethasone-21-isonicotinate suspension.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... intramuscular administration as follows: Dogs—0.25 to 1 milligram; cats—0.125 to 0.5 milligram; horses—5 to 20... suspension contains 1 milligram of dexamethasone-21-isonicotinate. (b) Sponsor. No. 000010 in § 510.600(c) of this chapter. (c) Conditions of use. (1) The drug is used in the treatment of various...

  4. Evaluation of coagulation via thromboelastography in healthy horses administered dexamethasone

    PubMed Central

    Woodman, Jenna; Wagg, Catherine R.; Boysen, Søren R.; Leguillette, Renaud; Mizen, Kyle; Roy, Marie-France

    2015-01-01

    Dexamethasone was administered to healthy horses daily for 7 days. Blood samples were collected at 3 time points from both treatment and non-treatment groups, and analyzed via thromboelastography (TEG). There were no significant differences in TEG parameters between treated and untreated horses, or within treatment groups over time. PMID:26677262

  5. Acute Activation of Metabolic Syndrome Components in Pediatric Acute Lymphoblastic Leukemia Patients Treated with Dexamethasone

    PubMed Central

    Warris, Lidewij T.; van den Akker, Erica L. T.; Bierings, Marc B.; van den Bos, Cor; Zwaan, Christian M.; Sassen, Sebastiaan D. T.; Tissing, Wim J. E.; Veening, Margreet A.; Pieters, Rob; van den Heuvel-Eibrink, Marry M.

    2016-01-01

    Although dexamethasone is highly effective in the treatment of pediatric acute lymphoblastic leukemia (ALL), it can cause serious metabolic side effects. Because studies regarding the effects of dexamethasone are limited by their small scale, we prospectively studied the direct effects of treating pediatric ALL with dexamethasone administration with respect to activation of components of metabolic syndrome (MetS); in addition, we investigated whether these side effects were correlated with the level of dexamethasone. Fifty pediatric patients (3–16 years of age) with ALL were studied during a 5-day dexamethasone course during the maintenance phase of the Dutch Childhood Oncology Group ALL-10 and ALL-11 protocols. Fasting insulin, glucose, total cholesterol, HDL, LDL, and triglycerides levels were measured at baseline (before the start of dexamethasone; T1) and on the fifth day of treatment (T2). Dexamethasone trough levels were measured at T2. We found that dexamethasone treatment significantly increased the following fasting serum levels (P<0.05): HDL, LDL, total cholesterol, triglycerides, glucose, and insulin. In addition, dexamethasone increased insulin resistance (HOMA-IR>3.4) from 8% to 85% (P<0.01). Dexamethasone treatment also significantly increased the diastolic and systolic blood pressure. Lastly, dexamethasone trough levels (N = 24) were directly correlated with high glucose levels at T2, but not with other parameters. These results indicate that dexamethasone treatment acutely induces three components of the MetS. Together with the weight gain typically associated with dexamethasone treatment, these factors may contribute to the higher prevalence of MetS and cardiovascular risk among survivors of childhood leukemia who received dexamethasone treatment. PMID:27362350

  6. Predicting the neurobehavioral side effects of dexamethasone in pediatric acute lymphoblastic leukemia.

    PubMed

    Warris, Lidewij T; van den Akker, Erica L T; Aarsen, Femke K; Bierings, Marc B; van den Bos, Cor; Tissing, Wim J E; Sassen, Sebastiaan D T; Veening, Margreet A; Zwaan, Christian M; Pieters, Rob; van den Heuvel-Eibrink, Marry M

    2016-10-01

    Although dexamethasone is an effective treatment for acute lymphoblastic leukemia (ALL), it can induce a variety of serious neurobehavioral side effects. We hypothesized that these side effects are influenced by glucocorticoid sensitivity at the tissue level. We therefore prospectively studied whether we could predict the occurrence of these side effects using the very low-dose dexamethasone suppression test (DST) or by measuring trough levels of dexamethasone. Fifty pediatric patients (3-16 years of age) with acute lymphoblastic leukemia (ALL) were initially included during the maintenance phase (with dexamethasone) of the Dutch ALL treatment protocol. As a marker of glucocorticoid sensitivity, the salivary very low-dose DST was used. A post-dexamethasone cortisol level <2.0nmol/L was considered a hypersensitive response. The neurobehavioral endpoints consisted of questionnaires regarding psychosocial and sleeping problems administered before and during the course of dexamethasone (6mg/m(2)), and dexamethasone trough levels were measured during dexamethasone treatment. Patients with a hypersensitive response to dexamethasone had more behavioral problems (N=11), sleeping problems, and/or somnolence (N=12) (P<0.05 for all three endpoints). The positive predictive values of the DST for psychosocial problems and sleeping problems were 50% and 30%, respectively. Dexamethasone levels were not associated with neurobehavioral side effects. We conclude that neither the very low-dose DST nor measuring dexamethasone trough levels can accurately predict dexamethasone-induced neurobehavioral side effects. However, patients with glucocorticoid hypersensitivity experienced significantly more symptoms associated with dexamethasone-induced depression. Future studies should elucidate further the mechanisms by which neurobehavioral side effects are influenced by glucocorticoid sensitivity. PMID:27448086

  7. Dexamethasone intravitreal implant in the treatment of diabetic macular edema.

    PubMed

    Dugel, Pravin U; Bandello, Francesco; Loewenstein, Anat

    2015-01-01

    Diabetic macular edema (DME) resembles a chronic, low-grade inflammatory reaction, and is characterized by blood-retinal barrier (BRB) breakdown and retinal capillary leakage. Corticosteroids are of therapeutic benefit because of their anti-inflammatory, antiangiogenic, and BRB-stabilizing properties. Delivery modes include periocular and intravitreal (via pars plana) injection. To offset the short intravitreal half-life of corticosteroid solutions (~3 hours) and the need for frequent intravitreal injections, sustained-release intravitreal corticosteroid implants have been developed. Dexamethasone intravitreal implant provides retinal drug delivery for ≤6 months and recently has been approved for use in the treatment of DME. Pooled findings (n=1,048) from two large-scale, randomized Phase III trials indicated that dexamethasone intravitreal implant (0.35 mg and 0.7 mg) administered at ≥6-month intervals produced sustained improvements in best-corrected visual acuity (BCVA) and macular edema. Significantly more patients showed a ≥15-letter gain in BCVA at 3 years with dexamethasone intravitreal implant 0.35 mg and 0.7 mg than with sham injection (18.4% and 22.2% vs 12.0%). Anatomical assessments showed rapid and sustained reductions in macular edema and slowing of retinopathy progression. Phase II study findings suggest that dexamethasone intravitreal implant is effective in focal, cystoid, and diffuse DME, in vitrectomized eyes, and in combination with laser therapy. Ocular complications of dexamethasone intravitreal implant in Phase III trials included cataract-related events (66.0% in phakic patients), intraocular pressure elevation ≥25 mmHg (29.7%), conjunctival hemorrhage (23.5%), vitreous hemorrhage (10.0%), macular fibrosis (8.3%), conjunctival hyperemia (7.2%), eye pain (6.1%), vitreous detachment (5.8%), and dry eye (5.8%); injection-related complications (eg, retinal tear/detachment, vitreous loss, endophthalmitis) were infrequent (<2

  8. Analysis of renal impairment in MM-003, a phase III study of pomalidomide + low - dose dexamethasone versus high - dose dexamethasone in refractory or relapsed and refractory multiple myeloma

    PubMed Central

    Weisel, Katja C.; Dimopoulos, Meletios A.; Moreau, Philippe; Lacy, Martha Q.; Song, Kevin W.; Delforge, Michel; Karlin, Lionel; Goldschmidt, Hartmut; Banos, Anne; Oriol, Albert; Alegre, Adrian; Chen, Christine; Cavo, Michele; Garderet, Laurent; Ivanova, Valentina; Martinez-Lopez, Joaquin; Knop, Stefan; Yu, Xin; Hong, Kevin; Sternas, Lars; Jacques, Christian; Zaki, Mohamed H.; Miguel, Jesus San

    2016-01-01

    Pomalidomide + low-dose dexamethasone is effective and well tolerated for refractory or relapsed and refractory multiple myeloma after bortezomib and lenalidomide failure. The phase III trial MM-003 compared pomalidomide + low-dose dexamethasone with high-dose dexamethasone. This subanalysis grouped patients by baseline creatinine clearance ≥ 30 − < 60 mL/min (n=93, pomalidomide + low-dose dexamethasone; n=56, high-dose dexamethasone) or ≥ 60 mL/min (n=205, pomalidomide + low-dose dexamethasone; n=93, high-dose dexamethasone). Median progression-free survival was similar for both subgroups and favored pomalidomide + low-dose dexamethasone versus high-dose dexamethasone: 4.0 versus 1.9 months in the group with baseline creatinine clearance ≥ 30 − < 60 mL/min (P<0.001) and 4.0 versus 2.0 months in the group with baseline creatinine clearance ≥ 60 mL/min (P<0.001). Median overall survival for pomalidomide + low-dose dexamethasone versus high-dose dexamethasone was 10.4 versus 4.9 months (P=0.030) and 15.5 versus 9.2 months (P=0.133), respectively. Improved renal function, defined as an increase in creatinine clearance from < 60 to ≥ 60 mL/min, was similar in pomalidomide + low-dose dexamethasone and high-dose dexamethasone patients (42% and 47%, respectively). Improvement in progression-free and overall survival in these patients was comparable with that in patients without renal impairment. There was no increase in discontinuations of therapy, dose modifications, and adverse events in patients with moderate renal impairment. Pomalidomide at a starting dose of 4 mg + low-dose dexamethasone is well tolerated in patients with refractory or relapsed and refractory multiple myeloma, and of comparable efficacy if moderate renal impairment is present. This trial was registered with clinicaltrials.gov identifier 01311687 and EudraCT identifier 2010-019820-30. PMID:27081177

  9. Novel diazabicycloalkane delta opioid agonists.

    PubMed

    Loriga, Giovanni; Lazzari, Paolo; Manca, Ilaria; Ruiu, Stefania; Falzoi, Matteo; Murineddu, Gabriele; Bottazzi, Mirko Emilio Heiner; Pinna, Giovanni; Pinna, Gérard Aimè

    2015-09-01

    Here we report the investigation of diazabicycloalkane cores as potential new scaffolds for the development of novel analogues of the previously reported diazatricyclodecane selective delta (δ) opioid agonists, as conformationally constrained homologues of the reference δ agonist (+)-4-[(αR)-α((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80). In particular, we have simplified the diazatricyclodecane motif of δ opioid agonist prototype 1a with bridged bicyclic cores. 3,6-diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 3,9-diazabicyclo[3.3.1]nonane, 3,9-diazabicyclo[4.2.1]nonane, and 3,10-diazabicyclo[4.3.1]decane were adopted as core motifs of the novel derivatives. The compounds were synthesized and biologically assayed as racemic (3-5) or diastereoisomeric (6,7) mixtures. All the novel compounds 3-7 showed δ agonism behaviour and remarkable affinity to δ receptors. Amongst the novel derivatives, 3,8-diazabicyclo[3.2.1]octane based compound 4 evidenced improved δ affinity and selectivity relative to SNC80.

  10. Favorable Outcome of Ramsay Hunt Syndrome under Dexamethasone

    PubMed Central

    Finsterer, Josef; Bachtiar, Arian; Niedermayr, Anton

    2012-01-01

    A 20-year-old student under chronic stress developed a painful reddish left ear, vesicles on the left ear, severe left-sided peripheral facial-nerve palsy, and hypoesthesia of the left upper lip, after exposure to a ventilator. Ramsay Hunt syndrome was diagnosed. Instead of prednisolone she received dexamethasone (40 mg/d) but nonetheless recovered completely after 12 weeks. PMID:22991518

  11. Effect of Pregabalin and Dexamethasone on Postoperative Analgesia after Septoplasty

    PubMed Central

    Demirhan, Abdullah; Akkaya, Akcan; Tekelioglu, Umit Yasar; Apuhan, Tayfun; Bilgi, Murat; Yurttas, Veysel; Bayir, Hakan; Yildiz, Isa; Gok, Uzeyir; Kocoglu, Hasan

    2014-01-01

    Objectives. The aim of this study was to explore effect of a combination of pregabalin and dexamethasone on pain control after septoplasty operations. Methods. In this study, 90 patients who were scheduled for septoplasty under general anesthesia were randomly assigned into groups that received either placebo (Group C), pregabalin (Group P), or pregabalin and dexamethasone (Group PD). Preoperatively, patients received either pregabalin 300 mg one hour before surgery, dexamethasone 8 mg intravenously during induction, or placebo according to their allocation. Postoperative pain treatment included tramadol and diclofenac sodium 30 minutes before the end of the operation. Numeric rating scale (NRS) for pain assessment, side effects, and consumption of tramadol, pethidine, and ondansetron were recorded. Results. The median NRS score at the postoperative 0 and the 2nd h was significantly higher in Group C than in Group P and Group PD (P ≤ 0.004 for both). The 24 h tramadol and pethidine, consumptions were significantly reduced in Groups P and PD compared to Group C (P < 0.001 and P < 0.001). The incidence of blurred vision was significantly higher in Group PD compared to Group C within both 0–2 h and 0–24 h periods (P = 0.002 and P < 0.001, resp.). Conclusions. We conclude that administration of 300 mg pregabalin preoperatively may be an adequate choice for pain control after septoplasty. Addition of dexamethasone does not significantly reduce pain in these patients. PMID:24876957

  12. Phase II Study of Thalidomide Plus Dexamethasone Induction Followed by Tandem Melphalan-Based Autotransplantation and Thalidomide-Plus-Prednisone Maintenance for Untreated Multiple Myeloma: A Southwest Oncology Group Trial (S0204)

    PubMed Central

    Hussein, Mohamad A.; Bolejack, Vanessa; Zonder, Jeffrey A.; Durie, Brian G.M.; Jakubowiak, Andrzej J.; Crowley, John J.; Barlogie, Bart

    2009-01-01

    Purpose Thalidomide-dexamethasone (THAL-DEX) is standard induction therapy for multiple myeloma (MM). Tandem melphalan-based transplantations have yielded superior results to single transplantations. Phase II trial S0204 was designed to improve survival results reported for the predecessor, phase III trial S9321 by 50%. Patients and Methods Newly diagnosed patients with MM were eligible for S0204 with THAL-DEX induction, tandem melphalan-based tandem transplantation, and THAL-prednisone maintenance. Results Of 143 eligible patients, 142 started induction, 73% completed first transplantation, 58% completed second transplantation, and 56% started maintenance. The quantity of stem cells required for two transplantations was reached in 88% of 111 patients undergoing collection, 74% of whom completed both transplantations. Partial response, very good partial remission, and complete response were documented after 12 months of maintenance therapy in 87%, 72%, and 22% of patients, respectively. During a median follow-up time of 37 months, 4-year estimates of event-free and overall survival were 50% and 64%, respectively. Survival outcomes were superior for International Staging System (ISS) stage 1 disease, when lactate dehydrogenase (LDH) levels were normal and a second transplantation was applied in a timely fashion. Conclusion Both overall survival (P = .0002) and event-free survival (P < .0001) were significantly improved with S0204 compared with S9321 when 121 and 363 patients, respectively, were matched on ISS stage and LDH. PMID:19546405

  13. Metabolism of 2,2′,3,3′,6,6′-Hexachlorobiphenyl (PCB 136) Atropisomers in Tissue Slices from Phenobarbital or Dexamethasone-Induced Rats is Sex-Dependent

    PubMed Central

    Wu, Xianai; Kania-Korwel, Izabela; Chen, Hao; Stamou, Marianna; Dammanahalli, Karigowda J.; Duffel, Michael; Lein, Pamela J.; Lehmler, Hans-Joachim

    2013-01-01

    Chiral polychlorinated biphenyls (PCBs) such as PCB 136 enantioselectively sensitize the ryanodine receptor (RyR). In light of recent evidence that PCBs cause developmental neurotoxicity via RyR-dependent mechanisms, this suggests that enantioselective PCB metabolism may influence the developmental neurotoxicity of chiral PCBs. However, enantioselective disposition of PCBs has not been fully characterized.The effect of sex and cytochrome P450 (P450) enzyme induction on the enantioselective metabolism of PCB 136 was studied using liver tissue slices prepared from naïve control (CTL), phenobarbital (PB; CYP2B inducer) or dexamethasone (DEX; CYP3A inducer) pretreated adult Sprague-Dawley rats. PCB 136 metabolism was also examined in hippocampal slices derived from untreated rat pups.In liver tissue slices, hydroxylated PCB (OH-PCB) profiles depended on sex and inducer pretreatment, and OH-PCB levels followed the rank orders male > female and PB > DEX > CTL. In contrast, the enantiomeric enrichment of PCB 136 and its metabolites was independent of sex and inducer pretreatment. Only small amounts of PCB 136 partitioned into hippocampal tissue slices and no OH-PCB metabolites were detected.Our results suggest that enantioselective metabolism, sex and induction status of P450 enzymes in the liver may modulate the neurotoxic outcomes of developmental exposure to chiral PCBs. PMID:23581876

  14. Thymosin alpha 1 antagonizes dexamethasone and CD3-induced apoptosis of CD4+ CD8+ thymocytes through the activation of cAMP and protein kinase C dependent second messenger pathways.

    PubMed

    Baumann, C A; Badamchian, M; Goldstein, A L

    1997-03-01

    It is well established that glucocorticoid hormones and anti-CD3 monoclonal antibodies induce apoptosis in immature developing thymocytes. This process can be modulated by soluble factors, anti-oxidants and adhesion receptors. Previously we have demonstrated that thymosin alpha 1 (T alpha 1), a 28-amino acid thymic peptide hormone, is a dose and time dependent antagonist of dexamethasone (DEX) and CD# induced DNA fragmentation of murine thymocytes in vitro. To further investigate the mechanism of T alpha 1 action we determined a T alpha 1 sensitive thymocyte population and examined some of the molecular events associated with T alpha 1 anti-apoptotic activity. Phenotypic analysis of the sub-populations of thymocytes, based on CD4 and CD8 expression, revealed that T alpha 1 exerts its effect on CD4+ CD8+ immature thymocytes. T alpha 1 treatment of thymocytes delays the production of free radicals and the subsequent consumption of glutathione, that is observed during both DEX and CD3 induced apoptosis. We further demonstrate that T alpha 1 stimulates the production of cAMP and activates PKC in thymocytes. These data suggest that T alpha 1 exerts an influence on the development of a population of immature T-cells in the thymus by effecting the sensitivity of thymocytes to apoptosis during the pre-selection stages of thymic development. Our studies also suggest that the mechanism of T alpha 1 action involves the induction of both cAMP and PKC dependent second messenger pathways.

  15. Effects of parturition and dexamethasone on DNA methylation patterns of IFN-γ and IL-4 promoters in CD4+ T-lymphocytes of Holstein dairy cows.

    PubMed

    Paibomesai, Marlene; Hussey, Brendan; Nino-Soto, Maria; Mallard, Bonnie A

    2013-01-01

    This study investigated epigenetic mechanisms by which DNA methylation affects the function of bovine adaptive immune system cells, particularly during the peripartum period, when shifts in type 1 and type 2 immune response (IR) biases are thought to occur. Stimulation of CD4+ T-lymphocytes isolated from 5 Holstein dairy cows before and after parturition with concanavalin A (ConA) and stimulation of CD4+ T-lymphocytes isolated from 3 Holstein dairy cows in mid-lactation with ConA alone or ConA plus dexamethasone (Dex) had significant effects on production of the cytokines interferon gamma (IFN-γ, type 1) and interleukin 4 (IL-4, type 2) that were consistent with DNA methylation profiles of the IFN-γ gene promoter region but not consistent for the IL-4 promoter region. ConA stimulation increased the production of both cytokines before and after parturition. It decreased DNA methylation in the IFN-γ promoter region but increased for IL-4 promoter region. Parturition was associated with an increase in IFN-γ production in ConA-stimulated cells that approached significance. Overall, DNA methylation in both promoter regions increased between the prepartum and postpartum periods, although this did not correlate with secreted cytokine concentrations. Dexamethasone treated cells acted in a manner consistent with the glucocorticoid's immunosuppressive activity, which mimicked the change at the IFN-γ promoter region observed during parturition. These results support pregnancy as type 2 IR biased, with increases of IFN-γ occurring after parturition and an increase in IL-4 production before calving. It is likely that these changes may be epigenetically controlled.

  16. Effects of parturition and dexamethasone on DNA methylation patterns of IFN-γ and IL-4 promoters in CD4+ T-lymphocytes of Holstein dairy cows

    PubMed Central

    Paibomesai, Marlene; Hussey, Brendan; Nino-Soto, Maria; Mallard, Bonnie A.

    2013-01-01

    This study investigated epigenetic mechanisms by which DNA methylation affects the function of bovine adaptive immune system cells, particularly during the peripartum period, when shifts in type 1 and type 2 immune response (IR) biases are thought to occur. Stimulation of CD4+ T-lymphocytes isolated from 5 Holstein dairy cows before and after parturition with concanavalin A (ConA) and stimulation of CD4+ T-lymphocytes isolated from 3 Holstein dairy cows in mid-lactation with ConA alone or ConA plus dexamethasone (Dex) had significant effects on production of the cytokines interferon gamma (IFN-γ, type 1) and interleukin 4 (IL-4, type 2) that were consistent with DNA methylation profiles of the IFN-γ gene promoter region but not consistent for the IL-4 promoter region. ConA stimulation increased the production of both cytokines before and after parturition. It decreased DNA methylation in the IFN-γ promoter region but increased for IL-4 promoter region. Parturition was associated with an increase in IFN-γ production in ConA-stimulated cells that approached significance. Overall, DNA methylation in both promoter regions increased between the prepartum and postpartum periods, although this did not correlate with secreted cytokine concentrations. Dexamethasone treated cells acted in a manner consistent with the glucocorticoid’s immunosuppressive activity, which mimicked the change at the IFN-γ promoter region observed during parturition. These results support pregnancy as type 2 IR biased, with increases of IFN-γ occurring after parturition and an increase in IL-4 production before calving. It is likely that these changes may be epigenetically controlled. PMID:23814356

  17. Effects of dexamethasone immunosuppression on turkey clostridial dermatitis.

    PubMed

    Thachil, Anil J; Shaw, Daniel P; Nagaraja, Kakambi V

    2014-09-01

    Clostridia represents a group of anaerobic spore-forming bacteria ubiquitous in the poultry environment. They are widely distributed in soil and survive for many years as highly resistant, inactive spores. They enter the body through wounds and contaminated feed as active bacteria or spores. Multiplication of clostridial bacteria occurs only in the absence of oxygen or in environments with very low concentrations of oxygen. During active multiplication, the clostridial organisms produce several toxins that are responsible for most of the clinical signs seen in clostridial diseases. Immunosuppression is a problem for the poultry industry. In modern, intensive poultry-rearing conditions, stress due to high population densities pose a considerable challenge for the immune system, and infectious agents can exploit this situation to cause disease. Immunosuppression may predispose turkeys to clostridial infection, resulting in clostridial dermatitis and mortality. The purpose of this study was to determine whether immunosuppression predisposes turkeys to clostridial infection and causes clostridial dermatitis. We immunosuppressed 10-wk-old turkey poults with dexamethasone. The birds immunosuppressed and not immunosuppressed were then challenged with Clostridium perfringens, Clostridium septicum, or both and examined for the development of clostridial dermatitis. The dexamethasone-treated birds were found to be more susceptible to C. peifingens/C. septicum challenge and developed clostridial dermatitis than the no-dexamethasone-treated birds through the subcutaneous route. However, oral inoculation of the same agents did not cause any dermatitis lesions in either of the groups.

  18. Zinc and dexamethasone induce metallothionein accumulation by endothelial cells

    SciTech Connect

    Briske-Anderson, M.; Bobilya, D.J.; Reeves, P.G. )

    1991-03-11

    Several tissues increase their metallothionein (MT) concentration when exposed to elevated amounts of plasma Zn. Endothelial cells form the blood vessels that supply all tissues and constitute a barrier between cells of tissues and the blood. This study examined the ability of endothelial cells to synthesize MT and accumulate Zn in response to high amounts of Zn and dexamethasone. Bovine pulmonary endothelial cells were grown to confluence in Minimum Essential Medium with Earle's salts and 10% fetal calf serum. The monolayer was maintained for 2 d prior to use in medium containing EDTA-dialyzed serum. This low Zn medium was replaced with one containing 1, 6, 25, 50, 100, 150, or 200 {mu}M Zn and incubated for 24 hr before harvesting the cells. MT was quantified by the cadmium binding assay. Cellular Zn concentrations were analyzed by atomic absorption after a nitric acid digestion. The MT concentration was elevated in response to Zn concentrations of 100 {mu}M or more. Cellular Zn concentration was elevated when media Zn was 25 {mu}M or more. MT and cellular Zn concentrations were positively correlated. In another study, inclusion of 0.1 {mu}M dexamethasone in the media increased concentration at all Zn concentrations studied. However, the inclusion of 0.3 {mu}M cis-platinum had no effect. In conclusion, endothelial cells in culture respond to elevated amounts of Zn and dexamethasone in the media by accumulating Zn and MT.

  19. Dexamethasone therapy for preventing delayed encephalopathy after carbon monoxide poisoning.

    PubMed

    Li, Q; Song, J J; Zhang, H Y; Fu, K; Lan, H B; Deng, Y

    2015-01-01

    We investigated dexamethasone therapy for preventing delayed encephalopathy after carbon monoxide (CO) poisoning. Eighty healthy male rats were exposed to CO and randomly divided into four groups: hyperbaric oxygen treatment (H), treatment (D), combined hyperbaric and dexamethasone treatment (C), and a control (M) group in which the rats inhaled CO to coma in the hyperbaric oxygen chamber, then were removed without further treatment. Twelve rats were put into the hyperbaric oxygen chamber and treated with air for 60 min (N) group. An eight arm maze was used to evaluate cognitive and memory abilities of these mice. Serum myelin basic protein (MBP) levels were evaluated using ELISA, and magnetic resonance imaging was used to observe brain demyelination and morbidity associated with delayed encephalopathy. A sample of the hippocampus from each group was examined by light microscopy. Cognitive and memory functions decreased in the control group M. Three days after CO poisoning, the serum MBP level of each group increased significantly. On Day 10 after CO poisoning, the MBP levels in groups C and D decreased significantly, but returned to normal on Day 18. MBP levels in the M and H groups were elevated at all time points. Brain MRIs showed significant differences among C, D, H and control M groups. Hematoxylin & eosin staining of the hippocampus showed greater damage in the control M and H groups. Early dexamethasone treatment may be useful for preventing delayed encephalopathy after CO poisoning and may reduce serum MBP levels.

  20. Effects of thyroxine and dexamethasone on rat submandibular glands

    SciTech Connect

    Sagulin, G.B.; Roomans, G.M. )

    1989-08-01

    Glucocorticoids and thyroxine are known to have a marked effect on the flow rate and protein composition of rat parotid saliva in hormonally intact animals. In the present study, the effects of a one-week treatment of male rats with dexamethasone and thyroxine were studied by electron microscopy and x-ray micro-analysis, and by measurement of the flow rate and determination of the chemical composition of pilocarpine-induced submandibular saliva. Thyroxine had the most extensive effects on the submandibular gland. The acinar cells were enlarged and filled with mucus; the cellular calcium concentration was significantly increased. The flow rate of the submandibular saliva was significantly reduced compared with that in saline-injected control animals. Thyroxine caused an increase in the concentrations of protein, total calcium, and potassium in the saliva. Dexamethasone had no significant effects on gland ultrastructure or on the elemental composition of the acinar cells; flow rate was not affected, but the concentrations of protein, calcium, and potassium were significantly increased. The effects of dexamethasone and thyroxine on the flow rate and protein composition of pilocarpine-induced rat submandibular saliva differ from those reported earlier for rat parotid saliva after simultaneous stimulation with pilocarpine and isoproterenol.

  1. In vitro hemocompatibility and cytocompatibility of dexamethasone-eluting PLGA stent coatings

    NASA Astrophysics Data System (ADS)

    Zhang, Jiang; Liu, Yang; Luo, Rifang; Chen, Si; Li, Xin; Yuan, Shuheng; Wang, Jin; Huang, Nan

    2015-02-01

    Drug-eluting stents (DESs) have been an important breakthrough for interventional cardiology applications since 2002. Though successful in reducing restenosis, some adverse clinical problems still emerged, which were mostly caused by the bare-metal stents and non-biodegradable polymer coatings, associated with the delayed endothelialization process. In this study, dexamethasone-loaded poly (lactic-co-glycolic acid) (PLGA) coatings were developed to explore the potential application of dexamethasone-eluting stents. Dexamethasone-eluting PLGA stents were prepared using ultrasonic atomization spray method. For other tests like stability and cytocompatibility and hemocompatibility tests, dexamethasone loaded coatings were deposited on 316L SS wafers. Fourier transform-infrared spectroscopy (FT-IR) results demonstrated that there was no chemical reaction between PLGA and dexamethasone. The balloon expansion experiment and surface morphology observation suggested that the stent coatings were smooth and uniform, and could also withstand the compressive and tensile strains imparted without cracking after stent expansion. The drug release behavior in vitro indicated that dexamethasone existed burst release within 1 day, but it presented linear release characteristics after 6 days. In vitro platelets adhesion, activation test and APTT test were also done, which showed that after blending dexamethasone into PLGA, the hemocompatibility was improved. Besides, dexamethasone and dexamethasone-loaded PLGA coatings could significantly inhibit the attachment and proliferation of smooth muscle cells.

  2. Perineural versus intravenous dexamethasone as adjuncts to local anaesthetic brachial plexus block for shoulder surgery.

    PubMed

    Rosenfeld, D M; Ivancic, M G; Hattrup, S J; Renfree, K J; Watkins, A R; Hentz, J G; Gorlin, A W; Spiro, J A; Trentman, T L

    2016-04-01

    This randomised, double-blind, placebo-controlled study compared the effect of perineural with intravenous dexamethasone, both administered concomitantly with interscalene brachial plexus block for shoulder surgery. Patients received 8 mg dexamethasone mixed with ropivacaine in the block injection (n = 42), 8 mg dexamethasone intravenously at the time of the block (n = 37), or intravenous saline (n = 41) at the time of the block. Perineural and intravenous dexamethasone resulted in prolonged mean (SD) duration of block to 16.9 (5.2) h and 18.2 (6.4) h, respectively, compared with 13.8 (3.8) h for saline (p = 0.001). Mean (SD) opioid consumption (morphine equivalents) during the first 24 h after postanaesthesia recovery arrival was 12.2 (9.3) mg in the perineural dexamethasone, 17.1 (15.9) mg in the intravenous dexamethasone and 24.1 (14.3) mg in the saline groups (p = 0.001). Dexamethasone via either route reduced anti-emetic use (p = 0.046). There was no effect on patient satisfaction. These results suggest that both perineural and intravenous dexamethasone are useful adjuncts to ropivacaine interscalene block, with the intravenous route preferred as this avoids the possibility of neural toxicity of dexamethasone. PMID:26899862

  3. Induction of regulator of G-protein signaling 2 expression by long-acting β2-adrenoceptor agonists and glucocorticoids in human airway epithelial cells.

    PubMed

    Holden, Neil S; George, Tresa; Rider, Christopher F; Chandrasekhar, Ambika; Shah, Suharsh; Kaur, Manminder; Johnson, Malcolm; Siderovski, David P; Leigh, Richard; Giembycz, Mark A; Newton, Robert

    2014-01-01

    In asthma and chronic obstructive pulmonary disease (COPD) multiple mediators act on Gαq-linked G-protein-coupled receptors (GPCRs) to cause bronchoconstriction. However, acting on the airway epithelium, such mediators may also elicit inflammatory responses. In human bronchial epithelial BEAS-2B cells (bronchial epithelium + adenovirus 12-SV40 hybrid), regulator of G-protein signaling (RGS) 2 mRNA and protein were synergistically induced in response to combinations of long-acting β2-adrenoceptor agonist (LABA) (salmeterol, formoterol) plus glucocorticoid (dexamethasone, fluticasone propionate, budesonide). Equivalent responses occurred in primary human bronchial epithelial cells. Concentrations of glucocorticoid plus LABA required to induce RGS2 expression in BEAS-2B cells were consistent with the levels achieved therapeutically in the lungs. As RGS2 is a GTPase-activating protein that switches off Gαq, intracellular free calcium ([Ca(2+)]i) flux was used as a surrogate of responses induced by histamine, methacholine, and the thromboxane receptor agonist U46619 [(Z)-7-[(1S,4R,5R,6S)-5-[(E,3S)-3-hydroxyoct-1-enyl]-3-oxabicyclo[2.2.1]heptan-6-yl]hept-5-enoic acid]. This was significantly attenuated by salmeterol plus dexamethasone pretreatment, or RGS2 overexpression, and the protective effect of salmeterol plus dexamethasone was abolished by RGS2 RNA silencing. Although methacholine and U46619 induced interleukin-8 (IL-8) release and this was inhibited by RGS2 overexpression, the repression of U46619-induced IL-8 release by salmeterol plus dexamethasone was unaffected by RGS2 knockdown. Given a role for Gαq-mediated pathways in inducing IL-8 release, we propose that RGS2 acts redundantly with other effector processes to repress IL-8 expression. Thus, RGS2 expression is a novel effector mechanism in the airway epithelium that is induced by glucocorticoid/LABA combinations. This could contribute to the efficacy of glucocorticoid/LABA combinations in asthma and

  4. In Vitro Inhibition of NFAT5-Mediated Induction of CCL2 in Hyperosmotic Conditions by Cyclosporine and Dexamethasone on Human HeLa-Modified Conjunctiva-Derived Cells

    PubMed Central

    Baudouin, Christophe; Gard, Carole; Brignole-Baudouin, Françoise

    2016-01-01

    Purpose To investigate the pro-inflammatory intracellular mechanisms induced by an in vitro model of dry eye disease (DED) on a Hela-modified conjunctiva-derived cells in hyperosmolarity (HO) stress conditions. This study focused on CCL2 induction and explored the implications of the nuclear factor of activated T-cells 5 (NFAT5) as well as mitogen-activated protein kinases (MAPK) and nuclear factor kappa B (NFĸB). This work was completed by an analysis of the effects of cyclosporine A (CsA), dexamethasone (Dex) and doxycycline (Dox) on HO-induced CCL2 and NFAT5 induction. Methods A human HeLa-modified conjunctiva-derived cell line was cultured in NaCl-hyperosmolar medium for various exposure times. Cellular viability, CCL2 secretion, NFAT5 and CCL2 gene expression, and intracytoplasmic NFAT5 were assessed using the Cell Titer Blue® assay, enzyme-linked immunosorbent assay (ELISA), RT-qPCR and immunostaining, respectively. In selected experiments, inhibitors of MAPKs or NFκB, therapeutic agents or NFAT5 siRNAs were added before the hyperosmolar stimulations. Results HO induced CCL2 secretion and expression as well as NFAT5 gene expression and translocation. Adding NFAT5-siRNA before hyperosmolar stimulation led to a complete inhibition of CCL2 induction and to a decrease in cellular viability. p38 MAPK (p38), c-Jun NH2-terminal kinase (JNK) and NFĸB inhibitors, CsA and Dex induced a partial inhibition of HO-induced CCL2, while Dox and extracellular signal-regulated kinase (ERK) inhibitor did not. Dex also induced a partial inhibition of HO-induced NFAT5 gene expression but not CsA or Dox. Conclusions These in vitro results suggest a potential role of CCL2 in DED and highlight the crucial role of NFAT5 in the pro-inflammatory effect of HO on HeLa-modified conjunctiva-derived cells, a rarely studied cellular type. This inflammatory pathway involving NFAT5 and CCL2 could offer a promising target for developing new therapies to treat DED, warranting further

  5. Kappa Opioid Receptor Agonist and Brain Ischemia

    PubMed Central

    Chunhua, Chen; Chunhua, Xi; Megumi, Sugita; Renyu, Liu

    2014-01-01

    Opioid receptors, especially Kappa opioid receptor (KOR) play an important role in the pathophysiological process of cerebral ischemia reperfusion injury. Previously accepted KOR agonists activity has included anti-nociception, cardiovascular, anti-pruritic, diuretic, and antitussive effects, while compelling evidence from various ischemic animal models indicate that KOR agonist have neuroprotective effects through various mechanisms. In this review, we aimed to demonstrate the property of KOR agonist and its role in global and focal cerebral ischemia. Based on current preclinical research, the KOR agonists may be useful as a neuroprotective agent. The recent discovery of salvinorin A, highly selective non-opioid KOR agonist, offers a new tool to study the role of KOR in brain HI injury and the protective effects of KOR agonist. The unique pharmacological profile of salvinorin A along with the long history of human usage provides its high candidacy as a potential alternative medication for brain HI injury. PMID:25574482

  6. Effects of rifampicin, dexamethasone, St. John's Wort and Thyroxine on maternal and foetal expression of Abcb1 and organ distribution of talinolol in pregnant rats.

    PubMed

    Saljé, Karen; Lederer, Kirstin; Oswald, Stefan; Dazert, Eike; Warzok, Rolf; Siegmund, Werner

    2012-08-01

    It is well accepted that ABCB1 plays a critical role in absorption, distribution and elimination of many xenobiotics and drugs. Only little is known about the regulation and function of ABCB1 during pregnancy. Thus, the aim of this study is to investigate maternal, placental and foetal Abcb1 expression and function in pregnant rats after induction with rifampicin, dexamethasone, St. John's wort (SJW) or thyroxine. Wistar rats were orally treated with rifampicin (250 mg/kg), SJW (1.0 g/kg), thyroxine (9 μg/kg), dexamethasone (1 mg/kg) or 0.5% methylcellulose suspension (control) for 9 days during late pregnancy (each N = 5). Afterwards, organ mRNA expression and protein content of Abcb1a were determined. Tissue concentrations of the ABCB1 probe drug talinolol were measured after repeated administration of the drug (100 mg/kg, 9 days) and after induction with oral rifampicin (250 mg/kg, 9 days, N = 5). Abcb1 expression was substantially lower in foetal than in maternal organs. Abcb1 was significantly induced by SJW in the maternal jejunum and placenta, by dexamethasone in foetal brain and liver and by thyroxine in the placenta and maternal and foetal brain. Rifampicin induced Abcb1 in all maternal and foetal organs. However, organ distribution of talinolol was not influenced by comedication of rifampicin. In conclusion, maternal and foetal Abcb1 organ expression in pregnant rats is inducible by nuclear receptor agonists. Although rifampicin regulates maternal and foetal Abcb1 expression, organ distribution of talinolol remains unchanged most likely caused by the known inhibitory effect of rifampicin on Abcb1 function.

  7. Antileukemic Efficacy of Continuous vs Discontinuous Dexamethasone in Murine Models of Acute Lymphoblastic Leukemia

    PubMed Central

    Ramsey, Laura B.; Janke, Laura J.; Payton, Monique A.; Cai, Xiangjun; Paugh, Steven W.; Karol, Seth E.; Kamdem, Landry Kamdem; Cheng, Cheng; Williams, Richard T.; Jeha, Sima; Pui, Ching-Hon; Evans, William E.; Relling, Mary V.

    2015-01-01

    Osteonecrosis is one of the most common, serious, toxicities resulting from the treatment of acute lymphoblastic leukemia. In recent years, pediatric acute lymphoblastic leukemia clinical trials have used discontinuous rather than continuous dosing of dexamethasone in an effort to reduce the incidence of osteonecrosis. However, it is not known whether discontinuous dosing would compromise antileukemic efficacy of glucocorticoids. Therefore, we tested the efficacy of discontinuous dexamethasone against continuous dexamethasone in murine models bearing human acute lymphoblastic leukemia xenografts (n = 8 patient samples) or murine BCR-ABL+ acute lymphoblastic leukemia. Plasma dexamethasone concentrations (7.9 to 212 nM) were similar to those achieved in children with acute lymphoblastic leukemia using conventional dosages. The median leukemia-free survival ranged from 16 to 59 days; dexamethasone prolonged survival from a median of 4 to 129 days in all seven dexamethasone-sensitive acute lymphoblastic leukemias. In the majority of cases (7 of 8 xenografts and the murine BCR-ABL model) we demonstrated equal efficacy of the two dexamethasone dosing regimens; whereas for one acute lymphoblastic leukemia sample, the discontinuous regimen yielded inferior antileukemic efficacy (log-rank p = 0.002). Our results support the clinical practice of using discontinuous rather than continuous dexamethasone dosing in patients with acute lymphoblastic leukemia. PMID:26252865

  8. Measurement of pulmonary status and surfactant protein levels during dexamethasone treatment of neonatal respiratory distress syndrome.

    PubMed Central

    Wang, J. Y.; Yeh, T. F.; Lin, Y. C.; Miyamura, K.; Holmskov, U.; Reid, K. B.

    1996-01-01

    BACKGROUND: Early postnatal use of dexamethasone in infants with respiratory distress syndrome (RDS) has been shown effectively to improve pulmonary status and to allow early weaning off mechanical ventilation. However, the mechanisms to explain the beneficial effects of dexamethasone in ventilatory dependent preterm infants remain unclear. METHODS: A double blind, placebo controlled study was performed to determine the change in pulmonary ventilation of premature infants with RDS as a result of dexamethasone treatment, and to evaluate the effect of dexamethasone on the levels of surfactant-associated proteins A (SP-A) and D (SP-D) in the tracheal fluid from 34 premature infants with RDS and 29 control subjects. RESULTS: Dexamethasone treatment decreased fractional inspired oxygen concentration (FIO2), arterial carbon dioxide tension (PCO2), mean airway pressure (MAP), and facilitated successful weaning from mechanical ventilation. SP-A concentrations in the tracheal aspirates were increased at days 7 and 14, and SP-D concentrations were increased during the period from days 3 to 14 in the dexamethasone treated group compared with the control group. However, albumin levels in the tracheal aspirate samples were decreased after dexamethasone treatment over the period from days 3 to 14. There was an inverse correlation between PCO2 values and SP-A concentrations. CONCLUSIONS: These results suggest that early use of dexamethasone can improve pulmonary status and also increase SP-A and SP-D levels in the tracheal fluid in premature infants with RDS. PMID:8984701

  9. Dexamethasone increases aquaporin-2 protein expression in ex vivo inner medullary collecting duct suspensions.

    PubMed

    Chen, Minguang; Cai, Hui; Klein, Janet D; Laur, Oskar; Chen, Guangping

    2015-01-01

    Aquaporin-2 (AQP2) is the vasopressin-regulated water channel that controls renal water reabsorption and plays an important role in the maintenance of body water homeostasis. Excessive glucocorticoid as often seen in Cushing's syndrome causes water retention. However, whether and how glucocorticoid regulates AQP2 remains unclear. In this study, we examined the direct effect of dexamethasone on AQP2 protein expression and activity. Dexamethasone increased AQP2 protein abundance in rat inner medullary collecting duct (IMCD) suspensions. This was confirmed in HEK293 cells transfected with AQP2 cDNA. Cell surface protein biotinylation showed an increase of dexamethasone-induced cell membrane AQP2 expression and this effect was blocked by glucocorticoid receptor antagonist RU486. Functionally, dexamethasone treatment of oocytes injected with an AQP2 cRNA increased water transport activity as judged by cell rupture time in a hypo-osmotic solution (66 ± 13 s in dexamethasone vs. 101 ± 11 s in control, n = 15). We further found that dexamethasone treatment reduced AQP2 protein degradation, which could result in an increase of AQP2 protein. Interestingly, dexamethasone promoted cell membrane AQP2 moving to less buoyant lipid raft submicrodomains. Taken together, our data demonstrate that dexamethasone promotes AQP2 protein expression and increases water permeability mainly via inhibition of AQP2 protein degradation. The increase in AQP2 activity promotes water reabsorption, which may contribute to glucocorticoid-induced water retention and hypertension. PMID:26578982

  10. 21 CFR 524.1484g - Neomycin sulfate-thiabendazole-dexamethasone solution.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... solution. 524.1484g Section 524.1484g Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND... NEW ANIMAL DRUGS § 524.1484g Neomycin sulfate-thiabendazole-dexamethasone solution. (a) Specifications. Each cubic centimeter of neomycin sulfate-thiabendazole-dexamethasone solution contains: 40...

  11. Carfilzomib, pomalidomide, and dexamethasone for relapsed or refractory myeloma

    PubMed Central

    Stadtmauer, Edward A.; Abonour, Rafat; Cohen, Adam D.; Bensinger, William I.; Gasparetto, Cristina; Kaufman, Jonathan L.; Lentzsch, Suzanne; Vogl, Dan T.; Gomes, Christina L.; Pascucci, Natalia; Smith, David D.; Orlowski, Robert Z.; Durie, Brian G. M.

    2015-01-01

    Treatment options for patients with heavily pretreated relapsed and/or refractory multiple myeloma remain limited. We evaluated a novel therapeutic regimen consisting of carfilzomib, pomalidomide, and dexamethasone (CPD) in an open-label, multicenter, phase 1, dose-escalation study. Patients who relapsed after prior therapy or were refractory to the most recently received therapy were eligible. All patients were refractory to prior lenalidomide. Patients received carfilzomib IV on days 1, 2, 8, 9, 15, and 16 (starting dose of 20/27 mg/m2), pomalidomide once daily on days 1 to 21 (4 mg as the initial dose level), and dexamethasone (40 mg oral or IV) on days 1, 8, 15, and 22 of 28-day cycles. The primary objective was to evaluate the safety and determine the maximum tolerated dose (MTD) of the regimen. A total of 32 patients were enrolled. The MTD of the regimen was dose level 1 (carfilzomib 20/27 mg/m2, pomalidomide 4 mg, dexamethasone 40 mg). Hematologic adverse events (AEs) occurred in ≥60% of all patients, including 11 patients with grade ≥3 anemia. Dyspnea was limited to grade 1/2 in 10 patients. Peripheral neuropathy was uncommon and limited to grade 1/2. Eight patients had dose reductions during therapy, and 7 patients discontinued treatment due to AEs. Two deaths were noted on study due to pneumonia and pulmonary embolism (n = 1 each). The combination of CPD is well-tolerated and highly active in patients with relapsed/refractory multiple myeloma. This trial was registered at www.clinicaltrials.gov as #NCT01464034. PMID:26384354

  12. Apoptosis Induced by Metal Complexes and Interaction with Dexamethasone

    PubMed Central

    Kim, Jung Sun; Barros, José Carlos Almeida

    2002-01-01

    Apoptosis induced by rhodium II amidate, rhodium II propionate, cisplatin and interactions with dexamethaxone were studied on some human leukemia cell lines Raji, Jurkat and U937. Apoptosis was studied by flow cytometry, agarose gel electrophoresis and morphological analysis. Rhodium II propionate induced apoptosis in all the three cell lines, Rhodium II amidate, in the lymphoid cell lines Jurkat and Raji, and cisplatin, only in the Jurkat, a T lymphoid cell line. It has also been observed that the addition of dexamethasone enhances the apoptosis index only in U937, a monocytic line with a glucocorticoid receptor bearing. PMID:18476001

  13. Beta-agonists and animal welfare

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The use of beta-agonists in animal feed is a high profile topic within the U.S. as consumers and activist groups continue to question its safety. The only beta-agonist currently available for use in swine is ractopamine hydrochloride (RAC). This is available as Paylean™ (Elanco Animal Health – FDA a...

  14. [Adrenergic beta-agonist intoxication].

    PubMed

    Carrola, Paulo; Devesa, Nuno; Silva, José Manuel; Ramos, Fernando; Alexandrino, Mário B; Moura, José J

    2003-01-01

    The authors describe two clinical cases (father and daughter), observed in the Hospital Urgency with distal tremors, anxiety, palpitations, nausea, headaches and dizziness, two hours after ingestión of cow liver. They also had leucocytosis (with neutrophylia), hypokalemia and hyperglycaemia. After treatment with potassium i.v. and propranolol, the symptoms disappeared. The symptoms recurred at home because the patients didn't take the prescribed medication and persisted for five days, with spontaneous disappearance. The serum of both patients revealed the presence of clenbuterol (65 hg/ml - father and 58 hg/ml - daughter). The animal's liver had a concentration of 1,42 mg/kg. Clenbuterol is a ß-adrenergic agonist with low specificity, with some veterinary indications. However, this substance has been illegally used as a growth's promotor. We intend to alert doctors for this problem, particularly those that work in the Urgency.

  15. Cortisol and ACTH response to oral dexamethasone in obesity and effects of sex, body fat distribution, and dexamethasone concentrations: a dose-response study.

    PubMed

    Pasquali, Renato; Ambrosi, Bruno; Armanini, Decio; Cavagnini, Francesco; Uberti, Ettore Degli; Del Rio, Graziano; de Pergola, Giovanni; Maccario, Mauro; Mantero, Franco; Marugo, Mario; Rotella, Carlo Maria; Vettor, Roberto

    2002-01-01

    There is increasing evidence that the abdominal obesity phenotype may be associated with multiple alterations of the hypothalamic-pituitary-adrenocortical (HPA) axis activity in both sexes. Our hypothesis is that the lack of adequate cortisol suppression after the dexamethasone test may constitute an indirect marker of HPA axis hyperactivity in the presence of the abdominal obesity phenotype. A total of 34 normal-weight (13 men and 21 women) and 87 obese (36 men and 51 women), healthy, nondepressed subjects therefore underwent four different dexamethasone suppression tests randomly performed at varying intervals of at least 1 wk between each test. After a standard overnight 1-mg dexamethasone test, which served as a reference, three other tests were randomly performed at 1-wk intervals by administering 0.0035, 0.0070, and 0.015 mg oral dexamethasone per kilogram of body weight overnight. Blood samples were obtained for cortisol, ACTH, and dexamethasone. Results were analyzed separately in men and women as well as in normal-weight [body mass index (BMI) < or = 25 kg/m(2)] and overweight or obese (BMI > 25 kg/m(2)) subjects. The waist circumference and the waist to hip ratio (WHR) were used as markers of body fat distribution. After the standard 1-mg test, cortisol suppression was greater than 90% in all subjects. However, after each test, obese women had significantly higher values of percent cortisol and percent ACTH suppression than normal-weight women without any difference between obese and normal-weight men. Considering the response to the three variable-dose tests, a clear dose- response pattern (P < 0.001 for trend analysis) in percent cortisol and percent ACTH suppression was found in all subjects. After each test men had significantly higher dexamethasone levels than women, regardless of BMI. However, obese women, but not men, had significantly higher dexamethasone levels after each test than their normal-weight counterpart. Plasma dexamethasone

  16. β2-agonist therapy in lung disease.

    PubMed

    Cazzola, Mario; Page, Clive P; Rogliani, Paola; Matera, M Gabriella

    2013-04-01

    β2-Agonists are effective bronchodilators due primarily to their ability to relax airway smooth muscle (ASM). They exert their effects via their binding to the active site of β2-adrenoceptors on ASM, which triggers a signaling cascade that results in a number of events, all of which contribute to relaxation of ASM. There are some differences between β2-agonists. Traditional inhaled short-acting β2-agonists albuterol, fenoterol, and terbutaline provide rapid as-needed symptom relief and short-term prophylactic protection against bronchoconstriction induced by exercise or other stimuli. The twice-daily β2-agonists formoterol and salmeterol represent important advances. Their effective bronchodilating properties and long-term improvement in lung function offer considerable clinical benefits to patients. More recently, a newer β2-agonist (indacaterol) with a longer pharmacodynamic half-life has been discovered, with the hopes of achieving once-daily dosing. In general, β2-agonists have an acceptable safety profile, although there is still controversy as to whether long-acting β2-agonists may increase the risk of asthma mortality. In any case, they can induce adverse effects, such as increased heart rate, palpitations, transient decrease in PaO2, and tremor. Desensitization of β2-adrenoceptors that occurs during the first few days of regular use of β2-agonist treatment may account for the commonly observed resolution of the majority of these adverse events after the first few doses. Nevertheless, it can also induce tolerance to bronchoprotective effects of β2-agonists and has the potential to reduce bronchodilator sensitivity to them. Some novel once-daily β2-agonists (olodaterol, vilanterol, abediterol) are under development, mainly in combination with an inhaled corticosteroid or a long-acting antimuscarinic agent. PMID:23348973

  17. Budesonide epimer R or dexamethasone selectively inhibit platelet-activating factor-induced or interleukin 1β-induced DNA binding activity of cis-acting transcription factors and cyclooxygenase-2 gene expression in human epidermal keratinocytes

    PubMed Central

    Lukiw, Walter J.; Pelaez, Ricardo Palacios; Martinez, Jorge; Bazan, Nicolas G.

    1998-01-01

    To further understand the molecular mechanism of glucocorticoid action on gene expression, DNA-binding activities of the cis-acting transcription factors activator protein 1 (AP1), AP2, Egr1 (zif268), NF-κB, the signal transducers and activators of transcription proteins gamma interferon activation site (GAS), Sis-inducible element, and the TATA binding protein transcription factor II D (TFIID) were examined in human epidermal keratinocytes. The cytokine interleukin 1β (IL-1β) and platelet-activating factor (PAF), both potent mediators of inflammation, were used as triggers for gene expression. Budesonide epimer R (BUDeR) and dexamethasone (DEX) were studied as potential antagonists. BUDeR or DEX before IL-1β- or PAF-mediated gene induction elicited strong inhibition of AP1-, GAS-, and in particular NF-κB-DNA binding (P < 0.001, ANOVA). Only small effects were noted on AP2, Egr1 (zif268), and Sis-inducible element-DNA binding (P > 0.05). No significant effect was noted on the basal transcription factor TFIID recognition of TATA-containing core promoter sequences (P > 0.68). To test the hypothesis that changing cis-acting transcription factor binding activity may be involved in inflammatory-response related gene transcription, RNA message abundance for human cyclooxygenase (COX)-1 and -2 (E.C.1.14.99.1) was assessed in parallel by using reverse transcription–PCR. Although the COX-1 gene was found to be expressed at constitutively low levels, the TATA-containing COX-2 gene, which contains AP1-like, GAS, and NF-κB DNA-binding sites in its immediate promoter, was found to be strongly induced by IL-1β or PAF (P < 0.001). BUDeR and DEX both suppressed COX-2 RNA message generation; however, no correlation was associated with TFIID–DNA binding. These results suggest that on stimulation by mediators of inflammation, although the basal transcription machinery remains intact, modulation of cis-activating transcription factor AP1, GAS, and NF-κB-DNA binding by the

  18. Uptake of dexamethasone incorporated into liposomes by macrophages and foam cells and its inhibitory effect on cellular cholesterol ester accumulation.

    PubMed

    Chono, Sumio; Morimoto, Kazuhiro

    2006-09-01

    To confirm the efficacy of dexamethasone incorporated into liposomes in the treatment of atherosclerosis, the uptake of dexamethasone-liposomes by macrophages and foam cells and its inhibitory effect on cellular cholesterol ester accumulation in these cells were investigated in-vitro. Dexamethasone-liposomes were prepared with egg yolk phosphatidylcholine, cholesterol and dicetylphosphate in a lipid molar ratio of 7/2/1 by the hydration method. This was adjusted to three different particle sizes to clarify the influence of particle size on the uptake by the macrophages and foam cells, and the inhibitory effect on cellular cholesterol ester accumulation. The distribution of particle sizes of dexamethasone-liposomes were 518.7+/-49.5 nm (L500), 202.2+/-23.1 nm (L200), and 68.6+/-6.5 nm (L70), respectively. For each size, dexamethasone concentration and dexamethasone/lipid molar ratio in dexamethasone-liposome suspension were 1 mg dexamethasone mL-1 and 0.134 mol dexamethasone mol-1 total lipids, respectively. The zeta potential was approximately -70 mV for all sizes. Dexamethasone-liposomes or free dexamethasone were added to the macrophages in the presence of oxidized low density lipoprotein (oxLDL) and foam cells, and then incubated at 37 degrees C. The uptake amount of dexamethasone by the macrophages and foam cells after a 24-h incubation was L500>L200>free dexamethasone>L70. The macrophages in the presence of oxLDL and foam cells were incubated with dexamethasone-liposomes or free dexamethasone for 24 h at 37 degrees C to evaluate the inhibitory effect on the cellular cholesterol ester accumulation. The cellular cholesterol ester level in the macrophages treated with oxLDL was significantly increased compared with that in macrophages without additives. L500, L200 and free dexamethasone significantly inhibited this cholesterol ester accumulation. L500, L200 and free dexamethasone also significantly reduced cellular cholesterol ester accumulation in foam cells. In

  19. Dexamethasone and Acetate Modulate Cytoplasmic Leptin in Bovine Preadipocytes

    PubMed Central

    Yonekura, Shinichi; Hirota, Shohei; Tokutake, Yukako; Rose, Michael T.; Katoh, Kazuo; Aso, Hisashi

    2014-01-01

    Hormonal and nutrient signals regulate leptin synthesis and secretion. In rodents, leptin is stored in cytosolic pools of adipocytes. However, not much information is available regarding the regulation of intracellular leptin in ruminants. Recently, we demonstrated that leptin mRNA was expressed in bovine intramuscular preadipocyte cells (BIP cells) and that a cytoplasmic leptin pool may be present in preadipocytes. In the present study, we investigated the expression of cytoplasmic leptin protein in BIP cells during differentiation as well as the effects of various factors added to the differentiation medium on its expression in BIP cells. Leptin mRNA expression was observed only at 6 and 8 days after adipogenic induction, whereas the cytoplasmic leptin concentration was the highest on day 0 and decreased gradually thereafter. Cytoplasmic leptin was detected at 6 and 8 days after adipogenic induction, but not at 4 days after adipogenic induction. The cytoplasmic leptin concentration was reduced in BIP cells at 4 days after treatment with dexamethasone, whereas cytoplasmic leptin was not observed at 8 days after treatment. In contrast, acetate significantly enhanced the cytoplasmic leptin concentration in BIP cells at 8 days after treatment, although acetate alone did not induce adipocyte differentiation in BIP cells. These results suggest that dexamethasone and acetate modulate the cytoplasmic leptin concentration in bovine preadipocytes. PMID:25049989

  20. Multiple Antenatal Dexamethasone Treatment Alters Brain Vessel Differentiation in Newborn Mouse Pups.

    PubMed

    Neuhaus, Winfried; Schlundt, Marian; Fehrholz, Markus; Ehrke, Alexander; Kunzmann, Steffen; Liebner, Stefan; Speer, Christian P; Förster, Carola Y

    2015-01-01

    Antenatal steroid treatment decreases morbidity and mortality in premature infants through the maturation of lung tissue, which enables sufficient breathing performance. However, clinical and animal studies have shown that repeated doses of glucocorticoids such as dexamethasone and betamethasone lead to long-term adverse effects on brain development. Therefore, we established a mouse model for antenatal dexamethasone treatment to investigate the effects of dexamethasone on brain vessel differentiation towards the blood-brain barrier (BBB) phenotype, focusing on molecular marker analysis. The major findings were that in total brains on postnatal day (PN) 4 triple antenatal dexamethasone treatment significantly downregulated the tight junction protein claudin-5, the endothelial marker Pecam-1/CD31, the glucocorticoid receptor, the NR1 subunit of the N-methyl-D-aspartate receptor, and Abc transporters (Abcb1a, Abcg2 Abcc4). Less pronounced effects were found after single antenatal dexamethasone treatment and in PN10 samples. Comparisons of total brain samples with isolated brain endothelial cells together with the stainings for Pecam-1/CD31 and claudin-5 led to the assumption that the morphology of brain vessels is affected by antenatal dexamethasone treatment at PN4. On the mRNA level markers for angiogenesis, the sonic hedgehog and the Wnt pathway were downregulated in PN4 samples, suggesting fundamental changes in brain vascularization and/or differentiation. In conclusion, we provided a first comprehensive molecular basis for the adverse effects of multiple antenatal dexamethasone treatment on brain vessel differentiation. PMID:26274818

  1. Dexamethasone Release from Within Engineered Cartilage as a Chondroprotective Strategy Against Interleukin-1α.

    PubMed

    Roach, Brendan L; Kelmendi-Doko, Arta; Balutis, Elaine C; Marra, Kacey G; Ateshian, Gerard A; Hung, Clark T

    2016-04-01

    While significant progress has been made toward engineering functional cartilage constructs with mechanical properties suitable for in vivo loading, the impact on these grafts of inflammatory cytokines, chemical factors that are elevated with trauma or osteoarthritis, is poorly understood. Previous work has shown dexamethasone to be a critical compound for cultivating cartilage with functional properties, while also providing chondroprotection from proinflammatory cytokines. This study tested the hypothesis that the incorporation of poly(lactic-co-glycolic acid) (PLGA) (75:25) microspheres that release dexamethasone from within chondrocyte-seeded agarose hydrogel constructs would promote development of constructs with functional properties and protect constructs from the deleterious effects of interleukin-1α (IL-1α). After 28 days of growth culture, experimental groups were treated with IL-1α (10 ng/mL) for 7 days. Reaching native equilibrium moduli and proteoglycan levels, dexamethasone-loaded microsphere constructs exhibited tissue properties similar to microsphere-free control constructs cultured in dexamethasone-supplemented culture media and were insensitive to IL-1α exposure. These findings are in stark contrast to constructs containing dexamethasone-free microspheres or no microspheres, cultured without dexamethasone, where IL-1α exposure led to significant tissue degradation. These results support the use of dexamethasone delivery from within engineered cartilage, through biodegradable microspheres, as a strategy to produce mechanically functional tissues that can also combat the deleterious effects of local proinflammatory cytokine exposure. PMID:26956216

  2. The evolution of beta2-agonists.

    PubMed

    Sears, M R

    2001-08-01

    Beta-agonists have been widely used in the treatment of asthma for many years Although concerns have been expressed over their safety based largely upon epidemics of increased mortality in asthmatics associated with high doses of isoprenaline in the 1960s and fenoterol in the 1970s and 1980s, the specific beta2-agonists are vital drugs in asthma management. The short-acting beta2-agonists have an important prophylactic role in the prevention of exercise-induced bronchoconstriction, and are essential in the emergency treatment of severe asthma. However, little if any benefit seems to be derived from regular use of short-acting beta2-agonists and regular or frequent use can increase the severity of the condition. The development of beta2-agonists with long-acting properties, such as salmeterol and formoterol, has provided advantages over short-acting beta-agonists, such as prolonged bronchodilation, reduced day- and night-time symptoms and improved quality of sleep, and has reduced the requirement for short-acting beta2-agonists as relief medication. Both drugs are well tolerated and, when added to inhaled corticosteroids, produce greater mprovement in lung function than increased steroid dose alone. Because of its rapid onset of action, formoterol also has the potential to be used for as-needed bronchodilator therapy in asthma.

  3. Aspirin metabolites are GPR35 agonists.

    PubMed

    Deng, Huayun; Fang, Ye

    2012-07-01

    Aspirin is widely used as an anti-inflammatory, anti-platelet, anti-pyretic, and cancer-preventive agent; however, the molecular mode of action is unlikely due entirely to the inhibition of cyclooxygenases. Here, we report the agonist activity of several aspirin metabolites at GPR35, a poorly characterized orphan G protein-coupled receptor. 2,3,5-Trihydroxybenzoic acid, an aspirin catabolite, was found to be the most potent GPR35 agonist among aspirin metabolites. Salicyluric acid, the main metabolite of aspirin, was also active. These results suggest that the GPR35 agonist activity of certain aspirin metabolites may contribute to the clinical features of aspirin. PMID:22526472

  4. [Influence of UV-light and dexamethasone on functional properties of lymphocytes and neutrophils].

    PubMed

    Artiukhov, V G; Basharina, O V; Lialina, I E; Maslov, O V

    2005-01-01

    UV-light and dexamethasone influence on functional properties of lymphocytes and neutrophils of peripherical donors' blood was studied. An increase of phagocytic activity of neutrophils was observed after their incubation with photomodified lymphocytes. It was found that UV-irradiation of lymphocytes activated synthesis of interleukines 1beta and 2. Dexamethasone presence in lymphocyte suspension inhibited the synthesis of the studied cytokines, especially by the incubation with photomodified cells. It was shown by the method of fluorescent labels that UV-irradiation improved interaction between dexamethasone and cell membrane.

  5. The effect of antenatal dexamethasone on maternal and fetal retinol-binding protein.

    PubMed

    Hustead, V A; Zachman, R D

    1986-01-01

    Sixteen rhesus monkeys received 0.1 to 15 mg/kg of antenatal dexamethasone at 132 days' gestation; seven control animals received placebo. At 135 days' gestation they underwent cesarean section, and maternal and fetal serum was assayed for retinol-binding protein. Fetal and maternal concentrations of retinol-binding protein increased after dexamethasone (p less than 0.05) and there was a trend for fetal levels of retinol-binding protein to increase with increasing dosage (p less than 0.01). Whether the elevation of retinol-binding protein in response to antenatal dexamethasone is a desirable side effect is not clear at this time. PMID:3946495

  6. Intravitreal Controlled Release of Dexamethasone from Engineered Microparticles of Porous Silicon Dioxide

    PubMed Central

    Wang, Chengyun; Hou, Huiyuan; Nan, Kaihui; Sailor, Michael J; Freeman, William R.; Cheng, Lingyun

    2014-01-01

    Dexamethasone is a glucocorticoid that is widely used in the ophthalmic arena. The recent FDA approved dexamethasone implant can provide a three month efficacy but with high rate of drug related cataract and high intraocular pressure (IOP). It seems that higher steroid in aqueous humor and around lens may be associated with these complications based on clinical fact that higher IOP was observed with intravitreal triamcinolone acetonide (TA) than with subtenon TA. We hypothesize that placing a sustained dexamethasone release system near back of the eye through a fine needle can maximize efficacy while mitigate higher rate of IOP rise and cataract. To develop a sustained intravitreal dexamethasone delivery system, porous silicon dioxide (pSiO2) microparticles were fabricated and functionalized with amines as well as carboxyl groups. Dexamethasone was conjugated to pSiO2 through the Steglich Esterificaion Reaction between hydroxyl of dexamethasone and carboxyl groups on the pSiO2. The drug loading was confirmed by Fourier transform infrared spectroscopy (FTIR) and loading efficiency was quantitated using thermogravimetric analysis (TGA). In vitro release was conducted for three months and dexamethasone was confirmed in the released samples using liquid chromatography-tandem mass spectrometry (LC/MS/MS). A pilot ocular safety and determination of vitreous drug level was performed in rabbit eyes. The drug loading study demonstrated that loading efficiency was from 5.96% to 10.77% depending on the loading reaction time, being higher with longer loading reaction time before reaching saturation around 7 days. In vitro drug release study revealed that dexamethasone release from pSiO2 particles was sustainable for over 90 days and was 80 days longer than free dexamethasone or infiltration-loaded pSiO2 particle formulation in the same setting. Pilot in vivo study demonstrated no sign of ocular adverse reaction in rabbit eyes following a single 3 mg intravitreal injection and

  7. Intravitreal controlled release of dexamethasone from engineered microparticles of porous silicon dioxide.

    PubMed

    Wang, Chengyun; Hou, Huiyuan; Nan, Kaihui; Sailor, Michael J; Freeman, William R; Cheng, Lingyun

    2014-12-01

    Dexamethasone is a glucocorticoid that is widely used in the ophthalmic arena. The recent FDA approved dexamethasone implant can provide a three month efficacy but with high rate of drug related cataract and high intraocular pressure (IOP). It seems that higher steroid in aqueous humor and around lens may be associated with these complications based on clinical fact that higher IOP was observed with intravitreal triamcinolone acetonide (TA) than with subtenon TA. We hypothesize that placing a sustained dexamethasone release system near back of the eye through a fine needle can maximize efficacy while mitigate higher rate of IOP rise and cataract. To develop a sustained intravitreal dexamethasone delivery system, porous silicon dioxide (pSiO2) microparticles were fabricated and functionalized with amines as well as carboxyl groups. Dexamethasone was conjugated to pSiO2 through the Steglich Esterification Reaction between hydroxyl of dexamethasone and carboxyl groups on the pSiO2. The drug loading was confirmed by Fourier transform infrared spectroscopy (FTIR) and loading efficiency was quantitated using thermogravimetric analysis (TGA). In vitro release was conducted for three months and dexamethasone was confirmed in the released samples using liquid chromatography-tandem mass spectrometry (LC/MS/MS). A pilot ocular safety and determination of vitreous drug level was performed in rabbit eyes. The drug loading study demonstrated that loading efficiency was from 5.96% to 10.77% depending on the loading reaction time, being higher with longer loading reaction time before reaching saturation around 7 days. In vitro drug release study revealed that dexamethasone release from pSiO2 particles was sustainable for over 90 days and was 80 days longer than free dexamethasone or infiltration-loaded pSiO2 particle formulation in the same setting. Pilot in vivo study demonstrated no sign of ocular adverse reaction in rabbit eyes following a single 3 mg intravitreal injection and

  8. Apoptosis of murine BW 5147 thymoma cells induced by dexamethasone and gamma-irradiation.

    PubMed

    Kruman, I I; Matylevich, N P; Beletsky, I P; Afanasyev, V N; Umansky, S R

    1991-08-01

    The mode and the kinetics of the death of T-thymoma cells upon dexamethasone treatment and gamma-irradiation (10Gy) have been studied using flow cytometry and biochemical analysis. It has been shown that the hormone and gamma-irradiation induce cell death by apoptosis. In both cases the cells are initially blocked in G2/M and die only after overcoming the blockage and cytokinesis. A short exposure to dexamethasone results in a cytostatic effect, whereas a cytotoxic effect is absent. Reducing serum concentration to 2% causes more rapid death both following gamma-irradiation and dexamethasone. These results are discussed in relation to cell death and proliferation.

  9. Monoterpenoid agonists of TRPV3

    PubMed Central

    Vogt-Eisele, A K; Weber, K; Sherkheli, M A; Vielhaber, G; Panten, J; Gisselmann, G; Hatt, H

    2007-01-01

    Background and purpose: Transient receptor potential (TRP) V3 is a thermosensitive ion channel expressed predominantly in the skin and neural tissues. It is activated by warmth and the monoterpene camphor and has been hypothesized to be involved in skin sensitization. A selection of monoterpenoid compounds was tested for TRPV3 activation to establish a structure-function relationship. The related channel TRPM8 is activated by cool temperatures and a number of chemicals, among them the monoterpene (-)-menthol. The overlap of the receptor pharmacology between the two channels was investigated. Experimental approach: Transfected HEK293 cells were superfused with the test substances. Evoked currents were measured in whole cell patch clamp measurements. Dose-response curves for the most potent agonists were obtained in Xenopus laevis oocytes. Key results: Six monoterpenes significantly more potent than camphor were identified: 6-tert-butyl-m-cresol, carvacrol, dihydrocarveol, thymol, carveol and (+)-borneol. Their EC50 is up to 16 times lower than that of camphor. All of these compounds carry a ring-located hydroxyl group and neither activates TRPM8 to a major extent. Conclusions and implications: Terpenoids have long been recognized as medically and pharmacologically active compounds, although their molecular targets have only partially been identified. TRPV3 activation may be responsible for several of the described effects of terpenoids. We show here that TRPV3 is activated by a number of monoterpenes and that a secondary hydroxyl-group is a structural requirement. PMID:17420775

  10. The giant Dexing porphyry Cu-Mo-Au deposit in east China: product of melting of juvenile lower crust in an intracontinental setting

    NASA Astrophysics Data System (ADS)

    Hou, Zengqian; Pan, Xiaofei; Li, Qiuyun; Yang, Zhiming; Song, Yucai

    2013-12-01

    The Dexing porphyry Cu-Mo-Au deposit in east China (1,168 Mt at 0.45 % Cu) is located in the interior of the South China Craton (SCC), made up of two lithospheric blocks, the Yangtze and Cathaysia blocks. The Cu-Mo-Au mineralization is associated with mid-Jurassic granodioritic porphyries with three high-level intrusive centers, controlled by a series of lineaments at the southeastern edge of the Yangtze block. Available age data define a short duration (172-170 Ma) of the felsic magmatism and the mineralization (171 ± 1 Ma). The deposit shows broad similarities with deposits in volcanoplutonic arcs, although it was formed in an intracontinental setting. Porphyries associated with mineralization are mainly granodiorites, which contain abundant phenocrysts (40-60 %) and carry contemporaneous microgranular mafic enclaves (MMEs). They are mainly high-K calc-alkaline and show geochemical affinities with adakite, characterized by relatively high MgO, Cr, Ni, Th, and Th/Ce ratios. The least-altered porphyries yielded relatively uniform ɛ Nd( t) values from -0.9 to +0.6, and wide (87Sr/86Sr)i range between 0.7046 and 0.7058 partially overlapping with the Sr-Nd isotopic compositions of the MMEs and mid-Jurassic mafic rocks in the SCC. Zircons from the porphyries have positive ɛ Hf( t) values (3.4 to 6.9), and low δ18O values (4.7 to 6.3 ‰), generally close to those of depleted mantle. All data suggest an origin by partial melting of a thickened juvenile lower crust involving mantle components (e.g., Neoproterozoic mafic arc magmas), triggered by invasion of contemporaneous mafic melts at Dexing. The MMEs show textural, mineralogical, and chemical evidence for an origin as xenoliths formed by injection of mafic melts into the felsic magmas. These MMEs usually contain magmatic chalcopyrite, and have original, variable contents of Cu (up to 500 ppm). Their geochemical characteristics suggest that they were derived from an enriched mantle source, metasomatized by

  11. [Safety of beta-agonists in asthma].

    PubMed

    Oscanoa, Teodoro J

    2014-01-01

    Beta 2 agonist bronchodilators (β2A) are very important part in the pharmacotherapy of bronchial asthma, a disease that progresses in the world in an epidemic way. The β2A are prescribed to millions of people around the world, therefore the safety aspects is of public interest. Short-Acting β2 Agonists (SABAs), such as albuterol inhaler, according to current evidence, confirming its safety when used as a quick-relief or rescue medication. The long-acting β2 agonists (LABAs) The long-acting bronchodilators β2A (Long acting β2 Agonists or LABAs) are used associated with inhaled corticosteroids as controller drugs for asthma exacerbationsaccess, for safety reasons LABAs are not recommended for use as monotherapy.

  12. DExD-box RNA-helicases in Listeria monocytogenes are important for growth, ribosomal maturation, rRNA processing and virulence factor expression

    PubMed Central

    Bäreclev, Caroline; Vaitkevicius, Karolis; Netterling, Sakura; Johansson, Jörgen

    2014-01-01

    RNA-helicases are proteins required for the unwinding of occluding secondary RNA structures, especially at low temperatures. In this work, we have deleted all 4 DExD-box RNA helicases in various combinations in the Gram-positive pathogen Listeria monocytogenes. Our results show that 3 out of 4 RNA-helicases were important for growth at low temperatures, whereas the effect was less prominent at 37°C. Over-expression of one RNA-helicase, Lmo1450, was able to overcome the reduced growth of the quadruple mutant strain at temperatures above 26°C, but not at lower temperatures. The maturation of ribosomes was affected in different degrees in the various strains at 20°C, whereas the effect was marginal at 37°C. This was accompanied by an increased level of immature 23S rRNA precursors in some of the RNA-helicase mutants at low temperatures. Although the expression of the PrfA regulated virulence factors ActA and LLO decreased in the quadruple mutant strain, this strain showed a slightly increased infection ability. Interestingly, even though the level of the virulence factor LLO was decreased in the quadruple mutant strain as compared with the wild-type strain, the hly-transcript (encoding LLO) was increased. Hence, our results could suggest a role for the RNA-helicases during translation. In this work, we show that DExD-box RNA-helicases are involved in bacterial virulence gene-expression and infection of eukaryotic cells. PMID:25590644

  13. Effect of antenatal dexamethasone on neonatal leukocyte count.

    PubMed

    Zachman, R D; Bauer, C R; Boehm, J; Korones, S B; Rigatto, H; Rao, A V

    1988-01-01

    The leukocyte count and differential white blood cell count during the first hour of life was determined in 164 neonates born of mothers receiving antenatal steroids and compared to 171 neonates of mothers randomly assigned to a placebo group. A leukemoid reaction (greater than 40,000 WBC/mm3) was seen only once each in the neonates born of placebo or steroid treated mothers. In addition, maternal steroid treatment had no general effect, except in a small subgroup of neonates born 3 to 7 days after the mother had been treated with 20 mg dexamethasone, where the total leukocyte and the absolute neutrophil counts were higher than the placebo group and other subgroups. PMID:3057139

  14. Alopecia areata treated with phenolisation and intravenous dexamethasone pulses.

    PubMed

    Kar, Sumit; Singh, Neha

    2013-01-01

    Phenol is an aromatic hydrocarbon derived from coal tar or manufactured from monochlorobenzene. Alopecia areata is a common non scarring autoimmune condition characterised by patchy loss of hair without atrophy. Various treatment modalities have been proposed and used for the treatment of alopecia areata, which is indeed a difficult condition to treat. Variable results have been documented using intralesional corticosteroid injections, topical minoxidil, topical anthralin ointment, topical contact sensitizers like diphencyprone, dinitrochlorobenzene or squaric acid dibutyl ester, and oral mini pulse with betamethasone. The use of 88% phenol for the treatment of alopecia areata has been documented in literature, but it has failed to secure a place in the priority list. Herein we have reported a case of a young girl who was treated with short-time aggressive therapy using 88% phenol and dexamethasone pulse therapy and who responded well to the treatment with no recurrence in the last 6 months of follow-up. PMID:23960401

  15. Dexamethasone and infection in preterm babies: a controlled study.

    PubMed Central

    Ng, P C; Thomson, M A; Dear, P R

    1990-01-01

    To find out if the use of steroids affected the incidence of infection in babies who were nursed in the neonatal intensive care unit for nine weeks or more, 24 preterm babies who had received a three weeks course of dexamethasone (0.6 mg/kg/day, reducing to 0.3 mg/kg/day after a week, and 0.15 mg/kg/day after two weeks) were compared with 18 preterm babies who had not been so treated. No differences were found in the incidence or pattern of septicaemia or other bacteriologically proved infections between the groups. Of 57 episodes of septicaemia, 44 (77%) were caused by coagulase negative staphylococci. PMID:2306135

  16. Amniotic fluid phospholipids after maternal administration of dexamethasone.

    PubMed

    Farrell, P M; Engle, M J; Zachman, R D; Curet, L B; Morrison, J C; Rao, A V; Poole, W K

    1983-02-15

    The administration of corticosteroids to pregnant women in premature labor can accelerate fetal lung development and potentially prevent neonatal respiratory distress syndrome (RDS). Controversy exists, however, as to whether amniotic fluid phospholipid indices of lung maturation are influenced by such treatment. Without a suitable test for evaluating the fetal response to corticosteroids, there is no method of recognizing whether and when lung development has been stimulated. In an attempt to resolve this issue, we carried out a study of amniotic fluid phospholipids as part of the National Institutes of Health multicenter trial of prenatal corticosteroids. Amniocenteses were performed before the administration of either steroid hormone or placebo and approximately 1 week after a series of four injections was initiated. Analysis of the ratio of lecithin (phosphatidylcholine) to sphingomyelin (L/S ratio) revealed nearly identical values initially and no significant difference in the posttreatment means when 25 steroid-treated pregnancies were compared to 20 control pregnancies. Although there were significant increases in both groups during the interval between amniocenteses, no statistical difference was found in the extent of change in L/S ratios between the two groups, when pretreatment values were compared with those obtained an average of 1 week later. In addition to evaluating L/S ratios, we performed an assessment of phospholipid concentrations in 17 pregnancies before and after administration of dexamethasone. This revealed no detectable phosphatidylglycerol. There were increases in the absolute concentrations of phosphatidylcholine and disaturated phosphatidylcholine, but these changes were relatively modest in magnitude and could be attributable to either advanced gestational age or dexamethasone. Our results demonstrate that current tests of fetal lung maturity do not provide a routine means for prenatal detection of pulmonary maturational responses to

  17. Induction of taxol metabolism in the rat by dexamethasone

    SciTech Connect

    Anderson, C.D.; Gondi, K.N.; Walle, T.

    1994-12-31

    The antitumor drug taxol was metabolized to two major metabolites (RM1 and RM2) in adult male and female rat liver microsomes. The male rats produced RM1 2.6 fold faster than the females, and they produced RM2 3 fold faster than the females. This correlated well with the sex differences noticed in liver microsomal cytochrome P450 (CYP) 3A content (4.4 fold greater in male) and 6{beta}-hydroxylation of testosterone (2.4 fold greater in male). Taxol was metabolized to three major metabolites (RM1, RM2, and RM3) in adult male and female rat liver microsomes from rats pretreated with dexamethasone. Production of RM1 and RM2 was increased in these rats (2.3 and 3.3 fold respectively in males; 6.5 and 8.7 fold respectively in females) as compared to the untreated rats. These results compared well with the induction of CYP 3A proteins (3.5 fold in male, 10 fold in female) and induction of 6{beta}-hydroxylation (1.9 fold in males, 3.8 fold in females). RM3, which was produced only by the rats pretreated with dexamethasone, had a retention time of 0.58 relative to taxol which corresponds to 6{alpha}- hydroxytaxol, the major human metabolite of taxol. This study indicates that taxol metabolism in the rat is likely due to CYP 3A enzymes. Although the evidence points toward CYP 3A1 as the major isoform involved, it does not rule out others. The findings also suggest that CYP 3A1 is responsible for the induced metabolite, RM3.

  18. Dopamine receptor partial agonists and addiction.

    PubMed

    Moreira, Fabricio A; Dalley, Jeffrey W

    2015-04-01

    Many drugs abused by humans acutely facilitate, either directly or indirectly, dopamine neurotransmission in the mesolimbic pathway. As a consequence dopamine receptor agonists and antagonists have been widely investigated as putative pharmacological therapies for addiction. This general strategy, however, has had only limited success due in part to poor treatment adherence and efficacy and the significant adverse effects of dopaminergic medications. In this perspective, we discuss the potential therapeutic use of dopamine receptor partial agonists in addiction, developed initially as antipsychotic agents. Recent research indicates that the dopamine D2 receptor partial agonists, such as aripiprazole, also shows useful ancillary efficacy in several animal models of psychostimulant and opioid addiction. Notably, these findings suggest that unlike full dopamine receptor agonists and antagonists these compounds have low abuse liability and are generally well tolerated. Indeed, partial dopamine agonists attenuate the rewarding properties of opioids without interfering with their analgesic effects. Herein we discuss the utility and potential of dopamine receptor partial agonists as treatments for both stimulant and non-stimulant drug addiction.

  19. PPAR Agonists and Cardiovascular Disease in Diabetes.

    PubMed

    Calkin, Anna C; Thomas, Merlin C

    2008-01-01

    Peroxisome proliferators activated receptors (PPARs) are ligand-activated nuclear transcription factors that play important roles in lipid and glucose homeostasis. To the extent that PPAR agonists improve diabetic dyslipidaemia and insulin resistance, these agents have been considered to reduce cardiovascular risk. However, data from murine models suggests that PPAR agonists also have independent anti-atherosclerotic actions, including the suppression of vascular inflammation, oxidative stress, and activation of the renin angiotensin system. Many of these potentially anti-atherosclerotic effects are thought to be mediated by transrepression of nuclear factor-kB, STAT, and activator protein-1 dependent pathways. In recent clinical trials, PPARalpha agonists have been shown to be effective in the primary prevention of cardiovascular events, while their cardiovascular benefit in patients with established cardiovascular disease remains equivocal. However, the use of PPARgamma agonists, and more recently dual PPARalpha/gamma coagonists, has been associated with an excess in cardiovascular events, possibly reflecting unrecognised fluid retention with potent agonists of the PPARgamma receptor. Newer pan agonists, which retain their anti-atherosclerotic activity without weight gain, may provide one solution to this problem. However, the complex biologic effects of the PPARs may mean that only vascular targeted agents or pure transrepressors will realise the goal of preventing atherosclerotic vascular disease.

  20. PPAR Agonists and Cardiovascular Disease in Diabetes

    PubMed Central

    Calkin, Anna C.; Thomas, Merlin C.

    2008-01-01

    Peroxisome proliferators activated receptors (PPARs) are ligand-activated nuclear transcription factors that play important roles in lipid and glucose homeostasis. To the extent that PPAR agonists improve diabetic dyslipidaemia and insulin resistance, these agents have been considered to reduce cardiovascular risk. However, data from murine models suggests that PPAR agonists also have independent anti-atherosclerotic actions, including the suppression of vascular inflammation, oxidative stress, and activation of the renin angiotensin system. Many of these potentially anti-atherosclerotic effects are thought to be mediated by transrepression of nuclear factor-kB, STAT, and activator protein-1 dependent pathways. In recent clinical trials, PPARα agonists have been shown to be effective in the primary prevention of cardiovascular events, while their cardiovascular benefit in patients with established cardiovascular disease remains equivocal. However, the use of PPARγ agonists, and more recently dual PPARα/γ coagonists, has been associated with an excess in cardiovascular events, possibly reflecting unrecognised fluid retention with potent agonists of the PPARγ receptor. Newer pan agonists, which retain their anti-atherosclerotic activity without weight gain, may provide one solution to this problem. However, the complex biologic effects of the PPARs may mean that only vascular targeted agents or pure transrepressors will realise the goal of preventing atherosclerotic vascular disease. PMID:18288280

  1. Use of the Dexamethasone Suppression Test with Mentally Retarded Persons: Review and Recommendations.

    ERIC Educational Resources Information Center

    Wolkowitz, Owen M.

    1990-01-01

    Studies on the use of the Dexamethasone Suppression Test to detect depression are described, with special emphasis on use of the test with children, demented elderly persons, and mentally retarded persons. (Author/JDD)

  2. Gastrointestinal tract obstruction secondary to post-operative oedema: does dexamethasone administration help?

    PubMed Central

    Atie, M.; Khoma, O.; Dunn, G.; Falk, G.L.

    2016-01-01

    Oedema can occur in handled tissues following upper gastrointestinal surgery with anastomosis formation. Obstruction of the lumen may result in delayed return of enteric function. Intravenous steroid use may be beneficial. Three cases of delayed emptying following fundoplication, gastro-enteric and entero-enteric anastomoses are reviewed. Conservative management with supportive measures failed. Dexamethasone was administered to treat the oedematous obstruction. A literature review in PubMed, Cochrane database and Medline for English language publications on the use of dexamethasone in the treatment of acute post surgical oedema of the upper gastrointestinal was conducted. Administration of dexamethasone led to resolution of symptoms and successful outcome. No reports on the use of steroids in this context were identified in the literature. The use of dexamethasone may effectively treat intestinal obstruction due to inflammatory or oedematous cause in the early post-operative period. PMID:27554826

  3. REDD1 Is a Major Target of Testosterone Action in Preventing Dexamethasone-Induced Muscle Loss

    PubMed Central

    Wu, Yong; Zhao, Weidong; Zhao, Jingbo; Zhang, Yuanfei; Qin, Weiping; Pan, Jiangping; Bauman, William A.; Blitzer, Robert D.; Cardozo, Christopher

    2010-01-01

    Glucocorticoids are a well-recognized and common cause of muscle atrophy that can be prevented by testosterone. However, the molecular mechanisms underlying such protection have not been described. Thus, the global effects of testosterone on dexamethasone-induced changes in gene expression were evaluated in rat gastrocnemius muscle using DNA microarrays. Gene expression was analyzed after 7-d administration of dexamethasone, dexamethasone plus testosterone, or vehicle. Dexamethasone changed expression of 876 probe sets by at least 2-fold. Among these, 474 probe sets were changed by at least 2-fold in the opposite direction in the dexamethasone plus testosterone group (genes in opposition). Major biological themes represented by genes in opposition included IGF-I signaling, myogenesis and muscle development, and cell cycle progression. Testosterone completely prevented the 22-fold increase in expression of the mammalian target of rapamycin (mTOR) inhibitor regulated in development and DNA damage responses 1 (REDD1), and attenuated dexamethasone induced increased expression of eIF4E binding protein 1, Forkhead box O1, and the p85 regulatory subunit of the IGF-I receptor but prevented decreased expression of IRS-1. Testosterone attenuated increases in REDD1 protein in skeletal muscle and L6 myoblasts and prevented dephosphorylation of p70S6 kinase at the mTOR-dependent site Thr389 in L6 myoblast cells. Effects of testosterone on REDD1 mRNA levels occurred within 1 h, required the androgen receptor, were blocked by bicalutamide, and were due to inhibition of transcriptional activation of REDD1 by dexamethasone. These data suggest that testosterone blocks dexamethasone-induced changes in expression of REDD1 and other genes that collectively would otherwise down-regulate mTOR activity and hence also down-regulate protein synthesis. PMID:20032058

  4. The sequential appearance of sperm abnormalities after scrotal insulation or dexamethasone treatment in bulls.

    PubMed Central

    Barth, A D; Bowman, P A

    1994-01-01

    Scrotal insulation and dexamethasone treatment were used as a model to compare the effect of testicular heating and stress on spermatogenesis. Insulation was applied to the scrotum of eight bulls (insulated) for a period of four days, eight bulls were treated daily for seven days with 20 mg dexamethasone injected intramuscularly, and four bulls were untreated controls. Semen from four bulls in each group was collected and evaluated over a six-week period after treatment. Blood samples for testosterone analysis were taken hourly for eight hours at the beginning and the end of the six-week period from the control bulls and before and after treatment from the four insulated and four dexamethasone-treated bulls that were not used for semen collection. At the end of the last blood sampling period, the four bulls in each group were castrated for the collection of testicular tissue for the determination of testosterone concentrations. Basal, peak episodic, and mean serum testosterone concentrations among control bulls, pre and postinsulated bulls, and pretreatment samples of dexamethasone-treated bulls were not different (p > 0.05); however, bulls that had received dexamethasone treatments had significantly lower basal, peak episodic, and mean testosterone concentrations (p < 0.05). Tissue concentrations of testosterone in control, insulated, and dexamethasone-treated bulls were not significantly different but tended to be lower in dexamethasone-treated bulls (p > 0.13). The spermiograms of the control bulls varied insignificantly over the six-week sampling period; however, there was a marked increase in sperm defects in insulated and dexamethasone-treated bulls. The types of sperm defects and the temporal relationships of rises and declines of sperm defects were quite similar for both treatments. All bulls recovered to approximately pretreatment levels of sperm defects by six weeks after the initiation of treatment. Results indicate that two of the most common types of

  5. Dexamethasone acutely down-regulates genes involved in steroidogenesis in stallion testes.

    PubMed

    Ing, Nancy H; Forrest, David W; Riggs, Penny K; Loux, Shavahn; Love, Charlie C; Brinsko, Steven P; Varner, Dickson D; Welsh, Thomas H

    2014-09-01

    In rodents, livestock and primate species, a single dose of the synthetic glucocorticoid dexamethasone acutely lowers testosterone biosynthesis. To determine the mechanism of decreased testosterone biosynthesis, stallions were treated with 0.1mg/kg dexamethasone 12h prior to castration. Dexamethasone decreased serum concentrations of testosterone by 60% compared to saline-treated control stallions. Transcriptome analyses (microarrays, northern blots and quantitative PCR) of testes discovered that dexamethasone treatment decreased concentrations of glucocorticoid receptor alpha (NR3C1), alpha actinin 4 (ACTN4), luteinizing hormone receptor (LHCGR), squalene epoxidase (SQLE), 24-dehydrocholesterol reductase (DHCR24), glutathione S-transferase A3 (GSTA3) and aromatase (CYP19A1) mRNAs. Dexamethasone increased concentrations of NFkB inhibitor A (NFKBIA) mRNA in testes. SQLE, DHCR24 and GSTA3 mRNAs were predominantly expressed by Leydig cells. In man and livestock, the GSTA3 protein provides a major 3-ketosteroid isomerase activity: conversion of Δ(5)-androstenedione to Δ(4)-androstenedione, the immediate precursor of testosterone. Consistent with the decrease in GSTA3 mRNA, dexamethasone decreased the 3-ketosteroid isomerase activity in testicular extracts. In conclusion, dexamethasone acutely decreased the expression of genes involved in hormone signaling (NR3C1, ACTN4 and LHCGR), cholesterol synthesis (SQLE and DHCR24) and steroidogenesis (GSTA3 and CYP19A1) along with testosterone production. This is the first report of dexamethasone down-regulating expression of the GSTA3 gene and a very late step in testosterone biosynthesis. Elucidation of the molecular mechanisms involved may lead to new approaches to modulate androgen regulation of the physiology of humans and livestock in health and disease. PMID:25010478

  6. Treatment of Dexamethasone-Induced Hiccup in Chemotherapy Patients by Methylprednisolone Rotation

    PubMed Central

    Lee, Gyeong-Won; Oh, Sung Yong; Kang, Myoung Hee; Park, Se Hoon; Hwang, In Gyu; Yi, Seong Yoon; Choi, Young Jin; Ji, Jun Ho; Lee, Ha Yeon; Bruera, Eduardo

    2013-01-01

    Background. Dexamethasone-induced hiccup (DIH) is an underrecognized symptom in patients with cancer, and little information is available about its treatment. The aims of this study were to investigate the feasibility of methylprednisolone rotation as treatment and to confirm the male predominance among those with cancer who experienced DIH during chemotherapy. Methods. Persons with cancer who experienced hiccups during chemotherapy treatment and who were receiving treatment with dexamethasone were presumed to have DIH. The following algorithmic practice was implemented for antiemetic corticosteroid use: rotation from dexamethasone to methylprednisolone in the next cycle and dexamethasone re-administration in the second cycle of chemotherapy after recognition of hiccups to confirm DIH. All other antiemetics except corticosteroid remained unchanged. Patients (n = 40) were recruited from eight cancer centers in Korea from September 2012 to April 2013. Data were collected retrospectively. Results. Hiccup intensity (numeric rating scale [NRS]: 5.38 vs. 0.53) and duration (68.44 minutes vs. 1.79 minutes) were significantly decreased after rotation to methylprednisolone, while intensity of emesis was not increased (NRS: 2.63 vs. 2.08). Median dose of dexamethasone and methylprednisolone were 10 mg and 50 mg, respectively. Thirty-four (85%) of 40 patients showed complete resolution of hiccups after methylprednisolone rotation in the next cycle. Of these 34 patients, 25 (73.5%) had recurrence of hiccups after dexamethasone re-administration. Compared with baseline values, hiccup intensity (NRS: 5.24 vs. 2.44) and duration (66.43 minutes vs. 22.00 minutes) were significantly attenuated after dexamethasone re-administration. Of the 40 eligible patients, 38 (95%) were male. Conclusion. DIH during chemotherapy could be controlled without losing antiemetic potential by replacing dexamethasone with methylprednisolone. We also identified a male predominance of DIH. Further

  7. Antagonistic interactions between dexamethasone and fluoxetine modulate morphodynamics and expression of cytokines in astrocytes.

    PubMed

    Henkel, A W; Alali, H; Devassy, A; Alawadi, M M; Redzic, Z B

    2014-11-01

    The "plasticity hypothesis" proposes that major depression is caused by morphological and biochemical modifications in neurons and astrocytes and those beneficial pharmacological effects of selective-serotonin-reuptake-inhibitors (SSRI) are at least partially associated with modifications of cellular communications between these cells. In this study we examined effects of the antidepressant fluoxetine on cultured astrocytes that were, in some cases, pretreated with dexamethasone, a cortisol analog known to trigger depressive disorder. Primary rat astrocytes were purified and treated with dexamethasone and the SSRI fluoxetine in physiological concentrations so that both drugs did not affect cell viability. Expression of interleukin-2 (IL-2) and glia-derived-neurotrophic-factor (GDNF) were analyzed and monitored and cell viability, apoptosis, cluster formation, particle-removing capacity and cell mobility were also monitored. Pre-studies without any drugs on mixed neuron-astrocyte co-cultures suggested that astrocytes interacted with neurons and other brain cells in vitro by actively assembling them into clusters. Treatment of purified astrocytes with dexamethasone significantly decreased their mobility compared to controls but had no effect on cluster formation. Dexamethasone-treated cells removed fewer extracellular particles derived from dead cells and cell debris. Both effects were abolished by simultaneous application of fluoxetine. Intracellular IL-2 increased, while GDNF amount expression was diminished following dexamethasone treatment. Simultaneous administration of fluoxetine reversed dexamethasone-triggered IL-2 elevation but had no effect on decreased GDNF concentration. These results suggest that mobility and growth factor equilibrium of astrocytes are affected by dexamethasone and by fluoxetine and that fluoxetine could reverse some changes induced by dexamethasone. PMID:25242644

  8. Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma.

    PubMed

    Mai, E K; Bertsch, U; Dürig, J; Kunz, C; Haenel, M; Blau, I W; Munder, M; Jauch, A; Schurich, B; Hielscher, T; Merz, M; Huegle-Doerr, B; Seckinger, A; Hose, D; Hillengass, J; Raab, M S; Neben, K; Lindemann, H-W; Zeis, M; Gerecke, C; Schmidt-Wolf, I G H; Weisel, K; Scheid, C; Salwender, H; Goldschmidt, H

    2015-08-01

    We aimed at demonstrating non-inferiority of bortezomib/cyclophosphamide/dexamethasone (VCD) compared to bortezomib/doxorubicin/dexamethasone (PAd) induction therapy with respect to very good partial response rates or better (⩾VGPR) in 504 newly diagnosed, transplant-eligible multiple myeloma patients. VCD was found to be non-inferior to PAd with respect to ⩾VGPR rates (37.0 versus 34.3%, P=0.001). The rates of progressive disease (PD) were 0.4% (VCD) versus 4.8% (PAd; P=0.003). In the PAd arm, 11 of 12 patients with PD had either renal impairment (creatinine ⩾2 mg/dl) at diagnosis or the cytogenetic abnormality gain 1q21, whereas no PD was observed in these subgroups in the VCD arm. Leukocytopenia/neutropenia (⩾3°) occurred more frequently in the VCD arm (35.2% versus 11.3%, P<0.001). Neuropathy rates (⩾2°) were higher in the PAd group (14.9 versus 8.4%, P=0.03). Serious adverse events, both overall and those related to thromboembolic events, were higher in the PAd group (32.7 versus 24.0%, P=0.04 and 2.8 versus 0.4%, P=0.04). Stem cell collection was not impeded by VCD. VCD is as effective as PAd in terms of achieving ⩾VGPR rates with fewer PD and has a favorable toxicity profile. Therefore, VCD is preferable to PAd as induction therapy. PMID:25787915

  9. Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM

    PubMed Central

    Offidani, Massimo; Pégourie, Brigitte; De La Rubia, Javier; Garderet, Laurent; Laribi, Kamel; Bosi, Alberto; Marasca, Roberto; Laubach, Jacob; Mohrbacher, Ann; Carella, Angelo Michele; Singhal, Anil K.; Tsao, L. Claire; Lynch, Mark; Bleickardt, Eric; Jou, Ying-Ming; Robbins, Michael; Palumbo, Antonio

    2016-01-01

    In this proof-of-concept, open-label, phase 2 study, patients with relapsed/refractory multiple myeloma (RRMM) received elotuzumab with bortezomib and dexamethasone (EBd) or bortezomib and dexamethasone (Bd) until disease progression/unacceptable toxicity. Primary endpoint was progression-free survival (PFS); secondary/exploratory endpoints included overall response rate (ORR) and overall survival (OS). Two-sided 0.30 significance level was specified (80% power, 103 events) to detect hazard ratio (HR) of 0.69. Efficacy and safety analyses were performed on all randomized patients and all treated patients, respectively. Of 152 randomized patients (77 EBd, 75 Bd), 150 were treated (75 EBd, 75 Bd). PFS was greater with EBd vs Bd (HR, 0.72; 70% confidence interval [CI], 0.59-0.88; stratified log-rank P = .09); median PFS was longer with EBd (9.7 months) vs Bd (6.9 months). In an updated analysis, EBd-treated patients homozygous for the high-affinity FcγRIIIa allele had median PFS of 22.3 months vs 9.8 months in EBd-treated patients homozygous for the low-affinity allele. ORR was 66% (EBd) vs 63% (Bd). Very good partial response or better occurred in 36% of patients (EBd) vs 27% (Bd). Early OS results, based on 40 deaths, revealed an HR of 0.61 (70% CI, 0.43-0.85). To date, 60 deaths have occurred (28 EBd, 32 Bd). No additional clinically significant adverse events occurred with EBd vs Bd. Grade 1/2 infusion reaction rate was low (5% EBd) and mitigated with premedication. In patients with RRMM, elotuzumab, an immunostimulatory antibody, appears to provide clinical benefit without added clinically significant toxicity when combined with Bd vs Bd alone. Registered to ClinicalTrials.gov as NCT01478048. PMID:27091875

  10. The effect of combination treatment using palonosetron and dexamethasone for the prevention of postoperative nausea and vomiting versus dexamethasone alone in women receiving intravenous patient-controlled analgesia

    PubMed Central

    Ryoo, Seung-hwa; Yoo, Jae Hwa; Kim, Mun Gyu; Lee, Ki Hoon

    2015-01-01

    Background The purpose of this study was to evaluate the effect of palonosetron combined with dexamethasone for the prevention of PONV compared to dexamethasone alone in women who received intravenous patient-controlled analgesia (IV-PCA) using fentanyl. Methods In this randomized, double-blinded, placebo-controlled study, 204 healthy female patients who were scheduled to undergo elective surgery under general anesthesia followed by IV-PCA for postoperative pain control were enrolled. Patients were divided into two groups: the PD group (palonosetron 0.075 mg and dexamethasone 5 mg IV; n = 102) and the D group (dexamethasone 5 mg IV; n = 102). The treatments were given after the induction of anesthesia. The incidence of nausea, vomiting, severity of nausea, and the use of rescue anti-emetics during the first 48 hours after surgery were evaluated. Results The incidence of PONV was significantly lower in the PD group compared with the D group during the 0-24 hours (43 vs. 59%) and 0-48 hours after surgery (45 vs. 63%) (P < 0.05). The severity of nausea during the 6-24 hours after surgery was significantly less in the PD group compared with the D group (P < 0.05). The incidence of rescue antiemetic used was significantly lower in the PD group than in the D group during the 0-6 hours after surgery (13.1 vs. 24.5%) (P < 0.05). Conclusions Palonosetron combined with dexamethasone was more effective in preventing PONV compared to dexamethasone alone in women receiving IV-PCA using fentanyl. PMID:26045930

  11. Kinetics and control of oxidative phosphorylation in rat liver mitochondria after dexamethasone treatment

    PubMed Central

    2004-01-01

    The present investigation was undertaken in order to evaluate the contributions of ATP synthesis and proton leak reactions to the rate of active respiration of liver mitochondria, which is altered following dexamethasone treatment (1.5 mg/kg per day for 5 days). We applied top-down metabolic control analysis and its extension, elasticity analysis, to gain insight into the mechanisms of glucocorticoid regulation of mitochondrial bioenergetics. Liver mitochondria were isolated from dexamethasone-treated, pair-fed and control rats when in a fed or overnight fasted state. Injection of dexamethasone for 5 days resulted in an increase in the fraction of the proton cycle of phosphorylating liver mitochondria, which was associated with a decrease in the efficiency of the mitochondrial oxidative phosphorylation process in liver. This increase in proton leak activity occurred with little change in the mitochondrial membrane potential, despite a significant decrease in the rate of oxidative phosphorylation. Regulation analysis indicates that mitochondrial membrane potential homoeostasis is achieved by equal inhibition of the mitochondrial substrate oxidation and phosphorylation reactions in rats given dexamethasone. Our results also suggest that active liver mitochondria from dexamethasone-treated rats are capable of maintaining phosphorylation flux for cellular purposes, despite an increase in the energetic cost of mitochondrial ATP production due to increased basal proton permeability of the inner membrane. They also provide a complete description of the effects of dexamethasone treatment on liver mitochondrial bioenergetics. PMID:15175015

  12. “Magic Bullet”: Eccentric Macular Hole as a Complication from Dexamethasone Implant Insertion

    PubMed Central

    Sanders, Riley; Olson, Jeffrey

    2016-01-01

    Introduction. Intravitreal drug injections and implants are generally safe but do carry some risk, from both the procedure itself and adverse effects of the medications. We report a case of an eccentric macular hole after dexamethasone implant (Ozurdex®) administration. Ex vitro force testing was performed to evaluate dexamethasone implant injection force. Methods. Five dexamethasone implant (Ozurdex) applicators were placed 16 mm from a force plate and the force of the injected dexamethasone pellet was recorded in Newtons. Four dexamethasone implant applicators were placed 16 mm from a force plate in a basic saline solution and the force of the pellet was recorded. Results. Average maximum force in air was 0.77 N and 0.024 N in a basic saline solution (BSS). Conclusion. We present a case report of an eccentric macular hole after dexamethasone implant administration. We hypothesize a mechanical injury to the retina during insertion caused the macular hole. Force testing done in air demonstrated sufficient force from the pellet injection to cause retinal damage though injections done in BSS showed reduced forces.

  13. Open randomised controlled trial of inhaled nitric oxide and early dexamethasone in high risk preterm infants

    PubMed Central

    Subhedar, N; Ryan, S; Shaw, N

    1997-01-01

    AIM—To determine whether treatment with inhaled nitric oxide (NO) and/or dexamethasone reduces the incidence of chronic lung disease (CLD) and/or death in high risk preterm infants.
METHODS—Infants below 32 weeks of gestation were recruited at 96 hours of age if they were deemed to be at high risk of developing CLD. Infants were randomly assigned to one of four treatment groups using a factorial design: (1) 5-20 parts per million inhaled NO for 72 hours; (2) 0.5-1 mg/kg/day intravenous dexamethasone for 6 days; (3) both drugs together; (4) continued conventional management.
RESULTS—Forty two infants were randomised: 10 infants received inhaled NO alone; 11 dexamethasone alone; 10 both treatments; and 11 neither treatment. There was no difference in the combined incidence of CLD and/or death before discharge from hospital between either infants treated with inhaled NO and controls (RR 1.05, 95% CI 0.84-1.25), or those treated with dexamethasone and controls (RR 0.95, 95% CI 0.79-1.18).
CONCLUSIONS—At 96 hours of age, neither treatment with inhaled NO nor dexamethasone prevented CLD or death.

 Keywords: randomised controlled trial; nitric oxide; dexamethasone; chronic lung disease PMID:9462187

  14. Dexamethasone acutely regulates endocrine parameters in stallions and subsequently affects gene expression in testicular germ cells.

    PubMed

    Ing, N H; Brinsko, S P; Curley, K O; Forrest, D W; Love, C C; Hinrichs, K; Vogelsang, M M; Varner, D D; Welsh, T H

    2015-01-01

    Testicular steroidogenesis and spermatogenesis are negatively impacted by stress-related hormones such as glucocorticoids. The effects of two injections of a therapeutic dose of dexamethasone (a synthetic glucocorticoid, 0.1mg/kg; i.v.) given 24h apart to each of three stallions were investigated and compared to three saline-injected control stallions. Dexamethasone decreased circulating concentrations of cortisol by 50% at 24h after the initial injection. Serum testosterone decreased by a maximum of 94% from 4 to 20h after the initial injection of dexamethasone. Semen parameters of the dexamethasone-treated stallions were unchanged in the subsequent two weeks. Two weeks after treatment, stallions were castrated. Functional genomic analyses of the testes revealed that, of eight gene products analyzed, dexamethasone depressed concentrations of heat shock protein DNAJC4 and sperm-specific calcium channel CATSPER1 mRNAs by more than 60%. Both genes are expressed in germ cells during spermiogenesis and have been related to male fertility in other species, including humans. This is the first report of decreased DNAJC4 and CATSPER1 mRNA concentrations in testes weeks after dexamethasone treatment. Concentrations of these mRNAs in sperm may be useful as novel markers of fertility in stallions. PMID:25487569

  15. Efficacy of epidural local anesthetic and dexamethasone in providing postoperative analgesia: A meta-analysis

    PubMed Central

    Jebaraj, B; Khanna, P; Baidya, DK; Maitra, S

    2016-01-01

    Background: Dexamethasone is a potent anti-inflammatory, analgesic, and antiemetic drug. Individual randomized controlled trials found a possible benefit of epidural dexamethasone. The purpose of this meta-analysis is to estimate the benefit of epidural dexamethasone on postoperative pain and opioid consumption and to formulate a recommendation for evidence-based practice. Materials and Methods: Prospective, randomized controlled trials comparing the analgesic efficacy of epidural local anesthetic and dexamethasone combination, with local anesthetic alone for postoperative pain management after abdominal surgery, were planned to be included in this meta-analysis. PubMed, PubMed Central, Scopus, and Central Register of Clinical Trials of the Cochrane Collaboration (CENTRAL) databases were searched for eligible controlled trials using the following search words: “Epidural”, “dexamethasone”, and “postoperative pain”, until February 20, 2015. Results: Data from five randomized control trials have been included in this meta-analysis. Epidural dexamethasone significantly decreased postoperative morphine consumption (mean difference −7.89 mg; 95% confidence interval [CI]: −11.66 to −3.71) and number of patients required postoperative rescue analgesic boluses (risk ratio: 0.51; 95% CI: 0.41-0.63). Conclusion: The present data shows that the addition of dexamethasone to local anesthetic in epidural is beneficial for postoperative pain management. PMID:27375389

  16. In vitro Osteogenic impulse effect of Dexamethasone on periodontal ligament stem cells

    PubMed Central

    Roozegar, Mohamad Ali; Mohammadi, Tayebeh Malek; Havasian, Mohamad Reza; Panahi, Jafar; Hashemian, Amirreza; Amraei, Mansur; Hoshmand, Behzad

    2015-01-01

    Periodontium is a complex organ composed of mineralized epithelial and connective tissue. Dexamethasone could stimulate proliferation of osteoblast and fibroblasts. This study aimed to assess the osteogenic effect of dexamethasone on periodental ligament (PDL) stem cells. PDL stem cells were collected from periodontal ligament tissue of root of extracted premolar of young and healthy people. The stem cells were cultured in α-MEM Medium in three groups, one group with basic medium contains (α- MEM and FBS 10 % and 50 mmol of β_ gelisrophosphat and L_ ascorbic acid µg/ml), the second group: basic medium with dexamethasone and the third one: basic medium without any osteogenic stimulant. Mineralization of cellular layer was analyzed with Alizarin red stain method. Osteogenic analysis was done by Alkaline phosphates and calcium test. These analysis indicated that the amount of intra-cellular calcium and alkaline phosphates in the Dexamethasone group was far more than the control and basic group (P<0.05). The results of Alizarin red stain indicated more mineralization of cultured cells in Dexamethasone group (P<0.05). The study results showed that Dexamethasone has significant osteogenic effect on PDL stem cells and further studies are recommended to evaluate its effect on treatment of bone disorders. PMID:25848170

  17. Dexamethasone prevents long-lasting learning impairment following neonatal hypoxic-ischemic brain insult in rats.

    PubMed

    Ikeda, Tomoaki; Mishima, Kenichi; Yoshikawa, Tetsuya; Iwasaki, Katsunori; Fujiwara, Michihiro; Xia, Yi X; Ikenoue, Tsuyomu

    2002-10-17

    We examined for 18 weeks the effect of dexamethasone treatment on learning and memory impairment produced by hypoxic-ischemic stress at postnatal day 7 in rat in addition to brain histological study. Dexamethasone of 0.5 mg/kg was injected i.p. 4 h before hypoxic-ischemic stress, in which the left carotid artery was ligated followed by 2 h hypoxia (8% oxygen). Dexamethasone treatment improved behavior in each learning task: in choice reaction time tasks relating to the attention process, in 8-arm radial maze task examining working and reference memory, and in water maze task relating to reference memory. Improvement to the extent of the sham-control level was observed. Dexamethasone treatment also completely prevented histological brain damage. No adverse effect in learning and memory tests was observed in the animals treated with dexamethasone without hypoxic-ischemic stress. It is concluded that dexamethasone treatment is significantly effective in prevention not only of histological brain damage but also of learning and memory impairment occasioned by subsequent hypoxic-ischemic insult, warranting further clinical investigation.

  18. Exercise training prevents hyperinsulinemia, muscular glycogen loss and muscle atrophy induced by dexamethasone treatment.

    PubMed

    Barel, Matheus; Perez, Otávio André Brogin; Giozzet, Vanessa Aparecida; Rafacho, Alex; Bosqueiro, José Roberto; do Amaral, Sandra Lia

    2010-03-01

    This study investigated whether exercise training could prevent the negative side effects of dexamethasone. Rats underwent a training period and were either submitted to a running protocol (60% physical capacity, 5 days/week for 8 weeks) or kept sedentary. After this training period, the animals underwent dexamethasone treatment (1 mg/kg per day, i.p., 10 days). Glycemia, insulinemia, muscular weight and muscular glycogen were measured from blood and skeletal muscle. Vascular endothelial growth factor (VEGF) protein was analyzed in skeletal muscles. Dexamethasone treatment evoked body weight loss (-24%), followed by muscular atrophy in the tibialis anterior (-25%) and the extensor digitorum longus (EDL, -15%). Dexamethasone also increased serum insulin levels by 5.7-fold and glucose levels by 2.5-fold compared to control. The exercise protocol prevented atrophy of the EDL and insulin resistance. Also, dexamethasone-treated rats showed decreased muscular glycogen (-41%), which was further attenuated by the exercise protocol. The VEGF protein expression decreased in the skeletal muscles of dexamethasone-treated rats and was unaltered by the exercise protocol. These data suggest that exercise attenuates hyperglycemia and may also prevent insulin resistance, muscular glycogen loss and muscular atrophy, thus suggesting that exercise may have some benefits during glucocorticoid treatment.

  19. Dexamethasone and Long-Term Outcome of Tuberculous Meningitis in Vietnamese Adults and Adolescents

    PubMed Central

    Török, M. Estée; Bang, Nguyen Duc; Chau, Tran Thi Hong; Yen, Nguyen Thi Bich; Thwaites, Guy E.; Thi Quy, Hoang; Dung, Nguyen Huy; Hien, Tran Tinh; Chinh, Nguyen Tran; Thi Thanh Hoang, Hoang; Wolbers, Marcel; Farrar, Jeremy J.

    2011-01-01

    Background Dexamethasone has been shown to reduce mortality in patients with tuberculous meningitis but the long-term outcome of the disease is unknown. Methods Vietnamese adults and adolescents with tuberculous meningitis recruited to a randomised, double-blind, placebo-controlled trial of adjunctive dexamethasone were followed-up at five years, to determine the effect of dexamethasone on long-term survival and neurological disability. Results 545 patients were randomised to receive either dexamethasone (274 patients) or placebo (271 patients). 50 patients (9.2%) were lost to follow-up at five years. In all patients two-year survival, probabilities tended to be higher in the dexamethasone arm (0.63 versus 0.55; p = 0.07) but five-year survival rates were similar (0.54 versus 0.51, p = 0.51) in both groups. In patients with grade 1 TBM, but not with grade 2 or grade 3 TBM, the benefit of dexamethasone treatment tended to persist over time (five-year survival probabilities 0.69 versus 0.55, p = 0.07) but there was no conclusive evidence of treatment effect heterogeneity by TBM grade (p = 0.36). The dexamethasone group had a similar proportion of severely disabled patients among survivors at five years as the placebo group (17/128, 13.2% vs. 17/116, 14.7%) and there was no significant association between dexamethasone treatment and disability status at five years (p = 0.32). Conclusions Adjunctive dexamethasone appears to improve the probability of survival in patients with TBM, until at least two years of follow-up. We could not demonstrate a five-year survival benefit of dexamethasone treatment which may be confined to patients with grade 1 TBM. Trial Registration ClinicalTrials.gov NCT01317654 NCT01317654?term = tuberculous+meningitis&rank = 3 PMID:22174748

  20. beta2-Agonists at the Olympic Games.

    PubMed

    Fitch, Kenneth D

    2006-01-01

    The different approaches that the International Olympic Committee (IOC) had adopted to beta2-agonists and the implications for athletes are reviewed by a former Olympic team physician who later became a member of the Medical Commission of the IOC (IOC-MC). Steadily increasing knowledge of the effects of inhaled beta2-agonists on health, is concerned with the fact that oral beta2-agonists may be anabolic, and rapid increased use of inhaled beta2-agonists by elite athletes has contributed to the changes to the IOC rules. Since 2001, the necessity for athletes to meet IOC criteria (i.e., that they have asthma and/or exercise-induced asthma [EIA]) has resulted in improved management of athletes. The prevalence of beta2-agonist use by athletes mirrors the known prevalence of asthma symptoms in each country, although athletes in endurance events have the highest prevalence. The age-of-onset of asthma/EIA in elite winter athletes may be atypical. Of the 193 athletes at the 2006 Winter Olympics who met th IOC's criteria, only 32.1% had childhood asthma and 48.7% of athletes reported onset at age 20 yr or older. These findings lead to speculation that years of intense endurance training may be a causative factor in bronchial hyperreactivity. The distinction between oral (prohibited in sports) and inhaled salbutamol is possible, but athletes must be warned that excessive use of inhaled salbutamol can lead to urinary concentrations similar to those observed after oral administration. This article provides justification that athletes should provide evidence of asthma or EIA before being permitted to use inhaled beta2-agonists. PMID:17085798

  1. Dexamethasone exacerbates cerebral edema and brain injury following lithium-pilocarpine induced status epilepticus.

    PubMed

    Duffy, B A; Chun, K P; Ma, D; Lythgoe, M F; Scott, R C

    2014-03-01

    Anti-inflammatory therapies are the current most plausible drug candidates for anti-epileptogenesis and neuroprotection following prolonged seizures. Given that vasogenic edema is widely considered to be detrimental for outcome following status epilepticus, the anti-inflammatory agent dexamethasone is sometimes used in clinic for alleviating cerebral edema. In this study we perform longitudinal magnetic resonance imaging in order to assess the contribution of dexamethasone on cerebral edema and subsequent neuroprotection following status epilepticus. Lithium-pilocarpine was used to induce status epilepticus in rats. Following status epilepticus, rats were either post-treated with saline or with dexamethasone sodium phosphate (10mg/kg or 2mg/kg). Brain edema was assessed by means of magnetic resonance imaging (T2 relaxometry) and hippocampal volumetry was used as a marker of neuronal injury. T2 relaxometry was performed prior to, 48 h and 96 h following status epilepticus. Volume measurements were performed between 18 and 21 days after status epilepticus. Unexpectedly, cerebral edema was worse in rats that were treated with dexamethasone compared to controls. Furthermore, dexamethasone treated rats had lower hippocampal volumes compared to controls 3 weeks after the initial insult. The T2 measurements at 2 days and 4 days in the hippocampus correlated with hippocampal volumes at 3 weeks. Finally, the mortality rate in the first week following status epilepticus increased from 14% in untreated rats to 33% and 46% in rats treated with 2mg/kg and 10mg/kg dexamethasone respectively. These findings suggest that dexamethasone can exacerbate the acute cerebral edema and brain injury associated with status epilepticus.

  2. Intratympanic dexamethasone injection vs methylprednisolone for the treatment of refractory sudden sensorineural hearing loss

    PubMed Central

    Berjis, Nezamoddin; Soheilipour, Saeed; Musavi, Alireza; Hashemi, Seyed Mostafa

    2016-01-01

    Background: During the past years various drugs have been used for sudden sensorineural hearing loss (SSNHL) treatment including steroids that are shown to be beneficial. Directed delivery of high doses of steroids into the inner ear is suggested for its potential and known as intratympanic steroids therapy (IST). Despite the use of dexamethasone and methylprednisolone as the traditional treatments, there are still debates about the optimal dosage, preferred drug, and the route of administration. Materials and Methods: We performed a randomized clinical trial study in which 50 patients suffering from SSNHL and resistant to standard therapy were employed. Each patient took 0.5 ml methylprednisolone (40 mg/mg) along with bicarbonate or dexamethasone (4 mg/mL) through direct intratympanic injection. This method was performed and scheduled once every 2 days for three times only for the dexamethasone receiving group. Hearing test was carried out and the results were analyzed according to a four-frequency (0.5, 1.0, 2.0, 3.0 kHz) pure tone average (PTA) and Siegel's criteria. Results: According to Siegel's criteria, three out of 25 (12%) dexamethasone receiving patients were healed in 1 and 4 (16%), 9 (32%) were respectively recovered in Siegel's criteria 2, 3, and 9 (32%) showed no recovery. In the group receiving methylprednisolone, recovery was found in 6 (24%), 8 (32%), 7 (28%) patients in the Siegel's criteria 1, 2, 3, respectively, and in 4 (16%) patients no recovery was recorded. In methylprednisolone group, hearing was significantly improved compared to the dexamethasone group (P < 0.05). The general hearing improvement rate was 84% in methylprednisolone receiving patients showing a significantly higher improvement than 64% in the dexamethasone group. Conclusions: Topical intratympanic treatment with methylprednisolone is safe and an effective treatment approach for those SSNHL cases that are refractory to the common therapies by Dexamethasone. PMID:27403406

  3. Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala.

    PubMed

    Sawamura, Takehito; Klengel, Torsten; Armario, Antonio; Jovanovic, Tanja; Norrholm, Seth D; Ressler, Kerry J; Andero, Raül

    2016-02-01

    Posttraumatic stress disorder (PTSD) is both a prevalent and debilitating trauma-related disorder associated with dysregulated fear learning at the core of many of its signs and symptoms. Improvements in the currently available psychological and pharmacological treatments are needed in order to improve PTSD treatment outcomes and to prevent symptom relapse. In the present study, we used a putative animal model of PTSD that included presentation of immobilization stress (IMO) followed by fear conditioning (FC) a week later. We then investigated the acute effects of GR receptor activation on the extinction (EXT) of conditioned freezing, using dexamethasone administered systemically which is known to result in suppression of the HPA axis. In our previous work, IMO followed by tone-shock-mediated FC was associated with impaired fear EXT. In this study, we administered dexamethasone 4 h before EXT training and then examined EXT retention (RET) 24 h later to determine whether dexamethasone suppression rescued EXT deficits. Dexamethasone treatment produced dose-dependent enhancement of both EXT and RET. Dexamethasone was also associated with reduced amygdala Fkbp5 mRNA expression following EXT and after RET. Moreover, DNA methylation of the Fkbp5 gene occurred in a dose-dependent and time course-dependent manner within the amygdala. Additionally, we found dynamic changes in epigenetic regulation, including Dnmt and Tet gene pathways, as a function of both fear EXT and dexamethasone suppression of the HPA axis. Together, these data suggest that dexamethasone may serve to enhance EXT by altering Fkbp5-mediated glucocorticoid sensitivity via epigenetic regulation of Fkbp5 expression.

  4. miR-216a rescues dexamethasone suppression of osteogenesis, promotes osteoblast differentiation and enhances bone formation, by regulating c-Cbl-mediated PI3K/AKT pathway.

    PubMed

    Li, H; Li, T; Fan, J; Li, T; Fan, L; Wang, S; Weng, X; Han, Q; Zhao, R C

    2015-12-01

    Osteoporosis is a disease marked by reduced bone mass, leading to an increased risk of fractures or broken bones. Bone formation is mediated by recruiting mesenchymal stem cells (MSCs). Elucidation of the molecular mechanisms that regulate MSC differentiation into osteoblasts is of great importance for the development of anabolic therapies for osteoporosis and other bone metabolism-related diseases. microRNAs (miRNAs) have been reported to have crucial roles in bone development, osteogenic differentiation and osteoporosis pathophysiology. However, to date, only a few miRNAs have been reported to enhance osteogenesis and regulate the suppressive effect of glucocorticoids on osteogenic differentiation. In this study, we discovered that miR-216a, a pancreatic-specific miRNA, was significantly upregulated during osteogenic differentiation in human adipose-derived MSCs (hAMSCs). The expression of miR-216a was positively correlated with the expression of bone formation marker genes in clinical osteoporosis samples. Functional analysis demonstrated that miR-216a can markedly promote osteogenic differentiation of hAMSCs, rescue the suppressive effect of dexamethasone (DEX) on osteogenic differentiation in vitro and enhance bone formation in vivo. c-Cbl, a gene that encodes a RING finger E3 ubiquitin ligase, was identified as a direct target of miR-216a. Downregulation of c-Cbl by short hairpin RNAs can mimic the promotion effects of miR-216a and significantly rescue the suppressive effects of DEX on osteogenesis. Pathway analysis indicated that miR-216a regulation of osteogenic differentiation occurs via the c-Cbl-mediated phosphatidylinositol 3 kinase (PI3K)/AKT pathway. The recovery effects of miR-216a on the inhibition of osteogenesis by DEX were attenuated after blocking the PI3K pathway. Thus, our findings suggest that miR-216a may serve as a novel therapeutic agent for the prevention and treatment of osteoporosis and other bone metabolism-related diseases. PMID

  5. Dexamethasone-suppression adrenal scintigraphy in hyperandrogenism: concise communication

    SciTech Connect

    Gross, M.D.; Freitas, J.E.; Swanson, D.P.; Woodbury, M.C.; Schteingart, D.E.; Beierwaltes, W.H.

    1981-01-01

    To assess the contribution of adrenal-derived androgens in women with hirsutism, adrenal scintigrams under dexamethasone suppression (DS) were performed on 35 women with increasing facial or body hair and irregular or absent menses. Based upon the DS regimen chosen (8 mg/d for 2 days or 4 md/d for 7 days before the injection of 6..beta..-(/sup 131/I)iodomethylnorcholesterol), three imaging patterns were identified. The first was the absence of uptake before 3 days (8-mg DS) or before 5 days (4-mg DS) after injection. This imaging pattern was seen in 17 of the 35 patients studied and was considered normal. The second pattern was bilateral uptake earlier than 3 days (8-mg DS regimen) or 5 days (4-mg DS) after injection. This was seen in 13 of the 35 patients and was interpreted as bilateral early visualization. Adrenal-vein catheterization performed on six patients with this pattern showed increased adrenal-vein testosterone. The third pattern, observed in five patients, was unilateral early visualization, which in four cases investigated to date was the result of an adrenocortical adenoma. This study confirms the adrenal cortex as a source of androgens in women with hirsutism and hyperandrogenism and demonstrates that DS adrenal scintigraphy can be utilized to identify those women in whom adrenal-derived androgens contribute to their hyperandrogenism.

  6. DEXAMETHASONE PROMOTES CPPD CRYSTAL FORMATION BY ARTICULAR CHONDROCYTES

    PubMed Central

    Fahey, Mark; Mitton, Elizabeth; Muth, Emily; Rosenthal, Ann K.

    2008-01-01

    Objective Calcium pyrophosphate dihydrate crystals (CPPD) are commonly found in osteoarthritic joints and correlate with a poor prognosis. Intra-articular corticosteroids, such as dexamethasone (Dxm), are commonly used therapies for osteoarthritis with or without CPPD deposition. Dxm has variable effects in mineralization models. We investigated the effects of Dxm on CPPD crystal formation in a well established tissue culture model. Methods Porcine articular chondrocytes were incubated with ATP to generate CPPD crystals. Chondrocytes incubated with or without ATP were exposed to 1–100 nM Dxm in the presence of 45Ca. Mineralization was measured by 45Ca uptake in the cell layer. We also investigated the effect of Dxm on mineralization-regulating enzymes such as alkaline phosphatase, NTPPPH and transglutaminase. Results Dxm significantly increased ATP-induced mineralization by articular chondrocytes. While alkaline phosphatase and NTPPPH activities were unchanged by Dxm, transglutaminase activity increased in a clear dose responsive manner. Levels of factor XIIIA mRNA and protein were increased by Dxm, while type II Tgase protein was unchanged. Transglutaminase inhibitors suppressed Dxm-induced increases in CPPD crystal formation. Conclusion These findings suggest a potential for Dxm to contribute to pathologic mineralization in cartilage and reinforce a central role for the transglutaminase enzymes in CPPD crystal formation. PMID:19132782

  7. Effect of autophagy induced by dexamethasone on senescence in chondrocytes

    PubMed Central

    Xue, Enxing; Zhang, Yu; Song, Bing; Xiao, Jun; Shi, Zhanjun

    2016-01-01

    The aim of the current study was to explore the effects of dexamethasone (DXM) on autophagy and senescence in chondrocytes. Collagen II and aggrecan were examined in normal chondrocytes isolated from Sprague-Dawley rats. Following stimulation with DXM, LysoTracker Red staining, monodansylcadaverine (MDC) staining, green fluorescent protein-red fluorescent protein-light chain 3 (LC3) and western blotting were used to detect autophagy levels in the chondrocytes. Mechanistic target of rapamycin (mTOR) pathway-associated molecules were investigated by western blotting. Cell senescence was analyzed by senescence-associated (SA)-β-galactosidase (β-gal) staining. A dose-dependent increase in the number of autophagic vacuoles was observed in the DXM-treated chondrocytes, as demonstrated by LysoTracker Red and MDC staining. A dose-dependent increase in autophagosome formation was observed in the DXM-treated chondrocytes. Expression of LC3-II and beclin-1 was increased by DXM, in particular in the cells treated with DXM for 4 days. However, P62 expression was reduced as a result of treatment. SA-β-gal staining indicated that DXM increased cell senescence. Notably, DXM-induced cell senescence was exacerbated by the autophagic inhibitor 3-MA. Autophagy induced by DXM protected chondrocytes from senescence, and it is suggested that the mTOR pathway may be involved in the activation of DXM-induced autophagy. PMID:27572674

  8. Dexamethasone Suppresses Oxysterol-Induced Differentiation of Monocytic Cells

    PubMed Central

    Son, Yonghae; Kim, Bo-Young; Eo, Seong-Kug; Park, Young Chul; Kim, Koanhoi

    2016-01-01

    Oxysterol like 27-hydroxycholesterol (27OHChol) has been reported to induce differentiation of monocytic cells into a mature dendritic cell phenotype. We examined whether dexamethasone (Dx) affects 27OHChol-induced differentiation using THP-1 cells. Treatment of monocytic cells with Dx resulted in almost complete inhibition of transcription and surface expression of CD80, CD83, and CD88 induced by 27OHChol. Elevated surface levels of MHC class I and II molecules induced by 27OHChol were reduced to basal levels by treatment with Dx. A decreased endocytosis ability caused by 27OHChol was recovered by Dx. We also examined effects of Dx on expression of CD molecules involved in atherosclerosis. Increased levels of surface protein and transcription of CD105, CD137, and CD166 by treatment with 27OHChol were significantly inhibited by cotreatment with Dx. These results indicate that Dx inhibits 27OHChol-induced differentiation of monocytic cells into a mature dendritic cell phenotype and expression of CD molecules whose levels are associated with atherosclerosis. In addition, we examined phosphorylation of AKT induced by 27OHChol and effect of Dx, where cotreatment with Dx inhibited the phosphorylation of AKT. The current study reports that Dx regulates oxysterol-mediated dendritic cell differentiation of monocytic cells. PMID:27340507

  9. Evaluation of thymus morphology and serum cortisol concentration as indirect biomarkers to detect low-dose dexamethasone illegal treatment in beef cattle

    PubMed Central

    2012-01-01

    Background Corticosteroids are illegally used in several countries as growth promoters in veal calves and beef cattle, either alone or in association with sex steroids and β-agonists, especially at low dosages and primarily through oral administration, in order to enhance carcasses and meat quality traits. The aim of the present study is to evaluate the reliability of the histological evaluation of the thymus, as well as the serum cortisol determination, in identifying beef cattle, treated with two different dexamethasone-based growth-promoting protocols and the application of different withdrawal times before slaughter. Results Our findings demonstrate that low dosages of dexamethasone (DXM), administered alone or in association with clenbuterol as growth promoter in beef cattle, induce morphologic changes in the thymus, resulting in increase fat infiltration with concurrent cortical atrophy and reduction of the cortex/medulla ratio (C/M). In fact, the C/M value was significantly lower in treated animals than in control ones, with both the protocols applied. The cut off value of 0.93 for the cortex/medulla ratio resulted to be highly effective to distinguish control and treated animals. The animals treated with DXM showed inhibition of cortisol secretion during the treatment period, as well as at the slaughterhouse, 3 days after treatment suspension. The animals treated with lower doses of DXM in association with clenbuterol, showed inhibition of cortisol secretion during the treatment period, but serum cortisol concentration was restored to physiological levels at slaughterhouse, 8 days after treatment suspension. Conclusions The histological evaluation of thymus morphology, and particularly of the C/M may represent a valuable and reproducible method applicable to large-scale screening programs, due to the easy sampling procedures at slaughterhouse, as well as time and cost-saving of the analysis. Serum cortisol determination could be considered as an useful in

  10. The Mineralocorticoid Agonist Fludrocortisone Promotes Survival and Proliferation of Adult Hippocampal Progenitors

    PubMed Central

    Gesmundo, Iacopo; Villanova, Tania; Gargantini, Eleonora; Arvat, Emanuela; Ghigo, Ezio; Granata, Riccarda

    2016-01-01

    Glucocorticoid receptor (GR) activation has been shown to reduce adult hippocampal progenitor cell proliferation and neurogenesis. By contrast, mineralocorticoid receptor (MR) signaling is associated with neuronal survival in the dentate gyrus of the hippocampus, and impairment of hippocampal MR has been linked to pathological conditions, such as depression or neurodegenerative disorders. Here, we aimed to further clarify the protective role of MR in adult hippocampal neurons by studying the survival and proliferative effects of the highly potent MR agonist fludrocortisone (Fludro) in adult rat hippocampal progenitor cells (AHPs), along with the associated signaling mechanisms. Fludro, which upregulated MR but not GR expression, increased survival and proliferation and prevented apoptosis in AHPs cultured in growth factor-deprived medium. These effects were blunted by the MR antagonist spironolactone and by high doses of the GR agonist dexamethasone. Moreover, they involved signaling through cAMP/protein kinase A (PKA)/cAMP response element-binding protein, phosphoinositide 3-kinase (PI3K)/Akt and its downstream targets glycogen synthase kinase-3β (GSK-3β) and mammalian target of rapamycin. Furthermore, Fludro attenuated the detrimental effects of amyloid-β peptide 1–42 (Aβ1–42) on cell survival, proliferation, and apoptosis in AHPs, and increased the phosphorylation of both PI3K/Akt and GSK-3β, which was reduced by Aβ1–42. Finally, Fludro blocked Aβ1–42-induced hyperphosphorylation of Tau protein, which is a main feature of Alzheimer’s disease. Overall, these results are the first to show the protective and proliferative role of Fludro in AHPs, suggesting the potential therapeutic importance of targeting MR for increasing hippocampal neurogenesis and for treating neurodegenerative diseases. PMID:27379018

  11. Fetal dexamethasone exposure accelerates development of renal function: relationship to dose, cell differentiation and growth inhibition.

    PubMed

    Slotkin, T A; Seidler, F J; Kavlock, R J; Gray, J A

    1992-02-01

    Fetal exposure to high doses of glucocorticoids slows cellular development and impairs organ performance, in association with growth retardation. Nevertheless, low doses of glucocorticoids may enhance cell differentiation and accelerate specific functions. The current study examined this apparent paradox in the developing rat kidney, using doses of dexamethasone that span the threshold for growth impairment: 0.05 or 0.2 mg/kg given on gestational days 17, 18 and 19. At the lower dose, which did not significantly retard body growth, the postnatal development of tubular reabsorptive capabilities for sodium, potassium, osmotic particles, water and urea was accelerated. These effects were less notable at the higher dose, which caused initial body growth impairment. The selectivity toward promotion of tubular function was evidenced by the absence of effect of either dose of dexamethasone on development of glomerular filtration rate. Because of the wide spectrum of dexamethasone's effects on tubular function, we also assessed fetal kidney adenylate cyclase as a means of detecting altered cell differentiation in the prenatal period during which dexamethasone was given. Either glucocorticoid dose increased the total adenylate cyclase catalytic activity (assessed with forskolin). Thus, the net effect of fetal dexamethasone exposure on development of renal excretory capabilities probably represents the summation of promoted cell differentiation and slowed development consequent to growth retardation. At low dose levels, the former effect predominates, leading to enhanced functional development, whereas higher doses that interfere with general growth and development can offset the direct promotional effect.

  12. Gene Expression Pattern after Insertion of Dexamethasone-Eluting Electrode into the Guinea Pig Cochlea

    PubMed Central

    Mugridge, Kenneth; Oguchi, Tomohiro; Hashimoto, Shigenari; Suzuki, Nobuyoshi; Iwasaki, Satoshi; Jolly, Claude; Usami, Shin-ichi

    2014-01-01

    A cochlear implant is an indispensable apparatus for a profound hearing loss patient. But insertion of the electrode entails a great deal of stress to the cochlea, and may cause irreversible damage to hair cells and related nerve structure. Although damage prevention effects of dexamethasone have been reported, long-term administration is difficult. In this study, we used a dexamethasone-eluting electrode in the guinea pig cochlea, and compared the gene expression after 7 days insertion with that of a normal electrode and non-surgically treated control by microarray. 40 genes were up-regulated 2-fold or more in the normal electrode group compared to the non-surgically treated group. Most of the up-regulated genes were associated with immune response and inflammation. In the dexamethasone-eluting group, compared to the normal electrode group, 7 of the 40 genes were further up-regulated, while 12 of them were down-regulated and there was a tendency to return to the non-surgical condition. 9 genes were down-regulated 2-fold or less with normal electrode insertion, and 4 of the 9 tended to return to the non-surgical condition in the dexamethasone-eluting group. These genes are certainly involved in the maintenance of the physiological functions of the cochlea. Our results indicate that the dexamethasone-eluting electrode will have an effect on the normalization of homeostasis in the cochlea. PMID:25329543

  13. Impairment of wound healing after operative treatment of mandibular fractures, and the influence of dexamethasone.

    PubMed

    Snäll, Johanna; Kormi, Eeva; Lindqvist, Christian; Suominen, Anna Liisa; Mesimäki, Karri; Törnwall, Jyrki; Thorén, Hanna

    2013-12-01

    Our aim was to clarify the incidence of impaired wound healing after open reduction and ostheosynthesis of mandibular fractures, and to find out whether the use of dexamethasone during the operation increased the risk. Patients were drawn from a larger group of healthy adult dentate patients who had participated in a single-blind, randomised study, the aim of which was to clarify the benefits of operative dexamethasone after treatment of facial fractures. The present analysis comprised 41 patients who had had open reduction and fixation of mandibular fractures with titanium miniplates and monocortical screws through one or 2 intraoral approaches. The outcome variable was impaired healing of the wound. The primary predictive variable was the perioperative use of dexamethasone; other potential predictive variables were age, sex, smoking habit, type of fracture, delay in treatment, and duration of operation. Wound healing was impaired in 13/41 patients (32%) (13/53 of all fractures). The incidence among patients who were given dexamethasone and those who were not did not differ significantly. Only age over 25 was significantly associated with delayed healing (p=0.02). The use of dexamethasone 30 mg perioperatively did not significantly increase the risk of impaired wound healing in healthy patients with clinically uninfected mandibular fractures fixed with titanium miniplates through an intraoral approach. Older age is a significant predictor of impaired healing, which emphasises the importance of thorough anti-infective care in these patients during and after the operation.

  14. Simultaneous determination of chlorpheniramine maleate and dexamethasone in a tablet dosage form by liquid chromatography.

    PubMed

    Moyano, María A; Rosasco, María A; Pizzorno, María T; Segall, Adriana I

    2005-01-01

    An accurate, simple, reproducible, and sensible liquid chromatographic method was developed and validated for the determination of chlorpheniramine maleate and dexamethasone in a tablet formulation. The analysis was performed at room temperature on a reversed-phase C18 column with UV detection at 254 nm. The mobile phase consisted of 7.5 mM monobasic potassium phosphate in methanol-water (62.5 + 37.5) at a constant flow rate of 1 mL/min. The method was validated in terms of linearity, precision, accuracy, and specificity by forced decomposition of chlorpheniramine maleate and dexamethasone initiated by using acid, base, water, hydrogen peroxide, heat, and light. The response was linear in the ranges of 0.04-0.12 and 0.006-0.016 mg/mL for chlorpheniramine maleate (r2 = 0.9999) and dexamethasone (r2 = 0.9994), respectively. The relative standard deviation values for intra- and interday precision studies were 2.39 and 2.02, respectively, for chlorpheniramine maleate and 2.39 and 1.25, respectively, for dexamethasone. Recoveries ranged from 95.07 to 101.95% for chlorpheniramine maleate and from 97.75 to 102.10% for dexamethasone.

  15. Intratympanic injection of dexamethasone for treatment of tinnitus in patients with sudden sensorineural hearing loss.

    PubMed

    Yoshida, Tadao; Teranishi, Masaaki; Iwata, Tomoyuki; Otake, Hironao; Nakashima, Tsutomu

    2012-01-01

    The purpose of this study is to test the effectiveness of intratympanic dexamethasone injections as a treatment for severe tinnitus in idiopathic sudden sensorineural hearing loss (SNHL). We studied 37 patients who received intratympanic dexamethasone injections and 14 control patients who did not receive it, with severe tinnitus after onset of unilateral sudden SNHL. Hearing level did not change during this study in any patient. The relationship between the duration of tinnitus and effectiveness of treatment was investigated in sudden SNHL. We used a visual analogue scale to evaluate 51 patients with severe tinnitus at the stage of stable hearing level after idiopathic sudden sensorineural hearing loss. Forty-one per cent of patients showed significant improvement after treatment. The average period between onset of sudden sensorineural hearing loss and initiation of intratympanic dexamethasone injection was significantly shorter (207 days) in the improved group than in the unchanged group (482 days) (P<0.001). In control group, one of 14 patients presented significant improvement spontaneously. Intratympanic dexamethasone treatment may be effective in treatment of severe tinnitus after sudden SNHL at the stage of stable hearing level, and the shorter the period from onset of sudden deafness to the start of intratympanic dexamethasone treatment, the greater the improvement in tinnitus that can be expected.

  16. Development of a dexamethasone intravitreal implant for the treatment of noninfectious posterior segment uveitis.

    PubMed

    Whitcup, Scott M; Robinson, Michael R

    2015-11-01

    Uveitis is a group of ocular inflammatory disorders that can lead to severe vision loss. Despite advances in anti-inflammatory therapy, many patients are resistant to or intolerant of existing treatments. A biodegradable, sustained-release implant, dexamethasone intravitreal implant 0.7 mg (Ozurdex), has been developed to deliver dexamethasone to target tissues in the posterior segment of the eye, minimizing systemic drug exposure and limiting side effects. The implant releases dexamethasone over a period of up to 6 months as the poly(D,L-lactide-co-glycolide) polymer matrix of the implant is metabolized to carbon dioxide and water. The implant is placed in the vitreous of the eye with a single-use applicator in a sutureless, office-based procedure. Treatment with a single dexamethasone intravitreal implant in patients with noninfectious intermediate or posterior uveitis has been shown to produce significant improvements in intraocular inflammation and best-corrected visual acuity with treatment benefit sustained for 6 months. Dexamethasone intravitreal implant has also been shown to reduce central retinal thickness and improve best-corrected visual acuity in patients with macular edema of various etiologies. The implant has been approved for treatment of noninfectious uveitis involving the posterior segment, diabetic macular edema, and macular edema associated with branch and central retinal vein occlusion.

  17. Identification of Selective ERRγ Inverse Agonists.

    PubMed

    Kim, Jina; Im, Chun Young; Yoo, Eun Kyung; Ma, Min Jung; Kim, Sang-Bum; Hong, Eunmi; Chin, Jungwook; Hwang, Hayoung; Lee, Sungwoo; Kim, Nam Doo; Jeon, Jae-Han; Lee, In-Kyu; Jeon, Yong Hyun; Choi, Hueng-Sik; Kim, Seong Heon; Cho, Sung Jin

    2016-01-12

    GSK5182 (4) is currently one of the lead compounds for the development of estrogen-related receptor gamma (ERRγ) inverse agonists. Here, we report the design, synthesis, pharmacological and in vitro absorption, distribution, metabolism, excretion, toxicity (ADMET) properties of a series of compounds related to 4. Starting from 4, a series of analogs were structurally modified and their ERRγ inverse agonist activity was measured. A key pharmacophore feature of this novel class of ligands is the introduction of a heterocyclic group for A-ring substitution in the core scaffold. Among the tested compounds, several of them are potent ERRγ inverse agonists as determined by binding and functional assays. The most promising compound, 15g, had excellent binding selectivity over related subtypes (IC50 = 0.44, >10, >10, and 10 μM at the ERRγ, ERRα, ERRβ, and ERα subtypes, respectively). Compound 15g also resulted in 95% transcriptional repression at a concentration of 10 μM, while still maintaining an acceptable in vitro ADMET profile. This novel class of ERRγ inverse agonists shows promise in the development of drugs targeting ERRγ-related diseases.

  18. Multiple tyrosine metabolites are GPR35 agonists

    PubMed Central

    Deng, Huayun; Hu, Haibei; Fang, Ye

    2012-01-01

    Both kynurenic acid and 2-acyl lysophosphatidic acid have been postulated to be the endogenous agonists of GPR35. However, controversy remains whether alternative endogenous agonists exist. The molecular targets accounted for many nongenomic actions of thyroid hormones are mostly unknown. Here we report the agonist activity of multiple tyrosine metabolites at the GPR35. Tyrosine metabolism intermediates that contain carboxylic acid and/or catechol functional groups were first selected. Whole cell dynamic mass redistribution (DMR) assays enabled by label-free optical biosensor were then used to characterize their agonist activity in native HT-29. Molecular assays including β-arrestin translocation, ERK phosphorylation and receptor internalization confirmed that GPR35 functions as a receptor for 5,6-dihydroxyindole-2-carboxylic acid, 3,3′,5′-triiodothyronine, 3,3′,5-triiodothyronine, gentisate, rosmarinate, and 3-nitrotyrosine. These results suggest that multiple tyrosine metabolites are alternative endogenous ligands of GPR35, and GPR35 may represent a druggable target for treating certain diseases associated with abnormality of tyrosine metabolism. PMID:22523636

  19. FXR agonist activity of conformationally constrained analogs of GW 4064

    SciTech Connect

    Akwabi-Ameyaw, Adwoa; Bass, Jonathan Y.; Caldwell, Richard D.; Caravella, Justin A.; Chen, Lihong; Creech, Katrina L.; Deaton, David N.; Madauss, Kevin P.; Marr, Harry B.; McFadyen, Robert B.; Miller, Aaron B.; Navas, III, Frank; Parks, Derek J.; Spearing, Paul K.; Todd, Dan; Williams, Shawn P.; Wisely, G. Bruce

    2010-09-27

    Two series of conformationally constrained analogs of the FXR agonist GW 4064 1 were prepared. Replacement of the metabolically labile stilbene with either benzothiophene or naphthalene rings led to the identification of potent full agonists 2a and 2g.

  20. FXR agonist activity of conformationally constrained analogs of GW 4064.

    PubMed

    Akwabi-Ameyaw, Adwoa; Bass, Jonathan Y; Caldwell, Richard D; Caravella, Justin A; Chen, Lihong; Creech, Katrina L; Deaton, David N; Madauss, Kevin P; Marr, Harry B; McFadyen, Robert B; Miller, Aaron B; Navas, Frank; Parks, Derek J; Spearing, Paul K; Todd, Dan; Williams, Shawn P; Bruce Wisely, G

    2009-08-15

    Two series of conformationally constrained analogs of the FXR agonist GW 4064 1 were prepared. Replacement of the metabolically labile stilbene with either benzothiophene or naphthalene rings led to the identification of potent full agonists 2a and 2g.

  1. The suppression of radiation-induced NF-{kappa}B activity by dexamethasone correlates with increased cell death in vivo

    SciTech Connect

    Nam, Seon Young; Chung, Hee-Yong . E-mail: hychung@hanyang.ac.kr

    2005-10-21

    In this study, we show that dexamethasone treatment increases ionizing radiation-induced cell death by inducing the inhibitory {kappa}B{alpha} (I{kappa}B{alpha}) pathway in mice. The effect of dexamethasone on radiation-induced cell death was assessed by changes in total spleen cellularity and bone marrow colony-forming unit-granulocyte-macrophage (CFU-GM) contents after total body irradiation. While in vivo treatment of mice with dexamethasone alone (1 mg/kg/day, for 2 days) failed to elicit cell death in spleen cells, the combined treatment with dexamethasone (1 mg/kg/day, for 2 days) and {gamma}-rays (1 or 5 Gy) caused a 50-80% reduction in total cellularity in spleen and CFU-GM contents in bone marrow. These results demonstrate that dexamethasone has a synergistic effect on radiation-induced cellular damages in vivo. Immunoblot analysis showed that dexamethasone treatment significantly increases I{kappa}B{alpha} expression in the spleens of irradiated mice. In addition, the dexamethasone treatment significantly reduced radiation-induced nuclear translocation of the nucleus factor-{kappa}B in the spleens of irradiated mice. These results indicate that dexamethasone treatment in vivo may increase radiation-induced cell damages by increasing I{kappa}B{alpha} expression in hematopoietic organs such as spleen and bone marrow.

  2. Depot delivery of dexamethasone and cediranib for the treatment of brain tumor associated edema in an intracranial rat glioma model.

    PubMed

    Ong, Qunya; Hochberg, Fred H; Cima, Michael J

    2015-11-10

    Treatments of brain tumor associated edema with systemically delivered dexamethasone, the standard of care, and cediranib, a novel anti-edema agent, are associated with systemic toxicities in brain tumor patients. A tunable, reservoir-based drug delivery device was developed to investigate the effects of delivering dexamethasone and cediranib locally in the brain in an intracranial 9L gliosarcoma rat model. Reproducible, sustained releases of both dexamethasone and solid dispersion of cediranib in polyvinylpyrrolidone (AZD/PVP) from these devices were achieved. The water-soluble AZD/PVP, which exhibited similar bioactivity as cediranib, was developed to enhance the release of cediranib from the device. Local and systemic administration of both dexamethasone and cediranib was equally efficacious in alleviating edema but had no effect on tumor growth. Edema reduction led to modest but significant improvement in survival. Local delivery of dexamethasone prevented dexamethasone-induced weight loss, an adverse effect seen in animals treated with systemic dexamethasone. Local deliveries of dexamethasone and cediranib via these devices used only 2.36% and 0.21% of the systemic doses respectively, but achieved similar efficacy as systemic drug deliveries without the side effects associated with systemic administration. Other therapeutic agents targeting brain tumor can be delivered locally in the brain to provide similar improved treatment outcomes.

  3. Remelting of Neoproterozoic relict volcanic arcs in the Middle Jurassic: Implication for the formation of the Dexing porphyry copper deposit, Southeastern China

    NASA Astrophysics Data System (ADS)

    Liu, Xuan; Fan, Hong-Rui; Santosh, M.; Hu, Fang-Fang; Yang, Kui-Feng; Li, Qiu-Li; Yang, Yue-Heng; Liu, Yongsheng

    2012-10-01

    The Dexing copper deposit in southeastern China is a typical non-arc porphyry deposit, the origin of which has been a topic of debate for several decades. Here we present new results from U-Pb geochronology, whole-rock chemistry and Sr-Nd-Hf-O isotopic investigations on the ore-forming granodioritic porphyry. LA-ICPMS zircon U-Pb data suggest that the granodioritic porphyry was formed in the Middle Jurassic (ca. 172.5 Ma) probably associated with lithospheric thinning driven by either sub-continental lithospheric mantle delamination or asthenospheric upwelling. The porphyry displays both arc-like and adakitic trace element signatures. The adakitic features suggest that HREE (heavy rare earth elements)-rich minerals such as garnet and hornblende, in the absence of plagioclase resided in the source region. The arc-like signatures are broadly comparable with those of the proximal Neoproterozoic island arc rocks including the keratophyre from Shuangxiwu Group and associated granitoids indicating a potential genetic relationship. The porphyry has chondritic ɛNd(t) of - 0.28 to 0.25 and radiogenic ɛHf(t) of 2 to 7, and correspondingly, uniform two stage depleted mantle Nd model ages of 940-980 Ma and Hf model ages of 800-1100 Ma (mean ~ 920 Ma). On Nd and Hf isotopic evolution diagrams, these values are markedly similar to those of the adjacent Neoproterozoic arc rocks when calculated forward to the Mid-Jurassic. Zircons of the porphyry show mantle-like oxygen isotope characters with δ18O values clustering in the range of 4.7-5.9‰, similar to the values for the Neoproterozoic arc rocks mentioned above. The geochemical and isotopic features recorded in our study suggest mantle-derived magmas with no significant supracrustal input for the source of the porphyry. With regard to the source of the Cu ore, we consider a model involving the remelting of sulfide-bearing arc-related lower crustal source. Furthermore, the occurrence of a Neoproterozoic VMS (volcanic massive

  4. Competitive inhibition of (TH)dexamethasone binding to mammary glucocorticoid receptor by leupeptin

    SciTech Connect

    Hsieh, L.C.C.; Su, C.; Markland, F.S. Jr.

    1987-03-01

    The inhibitory effect of leupeptin on (TH)dexamethasone binding to the glucocorticoid receptor from lactating goat mammary cytosol has been studied. Leupeptin (10 mM) caused a significant (about 35%) inhibition of (TH)dexamethasone binding to glucocorticoid receptor. Binding inhibition is further increased following filtration of unlabeled cytosolic receptor through a Bio-Gel A 0.5-m column. Binding inhibition was partially reversed by monothioglycerol at 10 mM concentration. A double reciprocal plot revealed that leupeptin appears to be a competitive inhibitor of (TH)dexamethasone binding to the glucocorticoid receptor. Low salt sucrose density gradient centrifugation revealed that the leupeptin-treated sample formed a slightly larger (approximately 9 S) receptor complex (leupeptin-free complex sediments at 8 S).

  5. The effect of phenytoin, phenobarbitone, dexamethasone and flurbiprofen on misonidazole neurotoxicity in mice.

    PubMed Central

    Sheldon, P. W.; Clarke, C.; Dawson, K. B.

    1984-01-01

    Using a quantitative cytochemical technique for measuring beta-glucuronidase activity in the peripheral nerves of mice, we have investigated the effectiveness of four potential adjuncts for reducing the dose limiting neurotoxicity of misonidazole (MISO) in the clinic. Under the conditions used, the most effective adjunct was the steroid anti-inflammatory agent dexamethasone. When given over the week previous to MISO treatment, this agent almost completely eliminated the MISO neurotoxicity as determined at week 4 after commencement of MISO dosing. The second most effective adjunct was phenytoin, the third flurbiprofen and the last adjunct, phenobarbitone, was ineffective. Dexamethasone, phenytoin and phenobarbitone all reduced the clearance half-life of MISO and hence the drug exposure dose calculated as the area under the curve of MISO tissue concentration against time. However, no correlation was evident with these parameters and MISO neurotoxicity in the mouse. Dexamethasone, whilst affording protection against MISO toxicity, did not alter the radiosensitivity of the anaplastic MT tumour. PMID:6696821

  6. Adrenocorticotrophic hormone and dexamethasone failed to affect milk yield in dairy goats: comparative aspects.

    PubMed

    Shamay; Mabjeesh; Shapiro; Silanikove

    2000-11-01

    The ability of adrenocorticotrophic hormone (ACTH; single i.v. injection of 2.5IU/kg BW) and dexamethasone (single i.m. injection of 36mg/kg BW) to affect milk production was studied in mid-lactating Israeli Saanen goats. None of these treatments produced changes in milk yield and composition of the goats. The effects of ACTH on blood cortisol levels, and the effects of ACTH and dexamethasone on blood plasma concentrations of glucose, however, were consistent with previous reports in goats and cows. These responses suggest that ACTH and dexamethasone treatments produced their expected glucocorticoid effects. It is suggested that obstructing the axis: stress-ACTH-glucocorticoid-down regulation of milk yield, which was demonstrated in dairy cows, reflects the adaptation of goats to harsh conditions, and the selection pressure to produce milk under conditions which are considered stressful for other ruminants. PMID:11024343

  7. Insulin and dexamethasone stimulation of cardiac lipoprotein lipase activity involves the actin-based cytoskeleton.

    PubMed Central

    Ewart, H S; Severson, D L

    1999-01-01

    Lipoprotein lipase (LPL) activity in cultured ventricular cardiomyocytes from adult rat hearts was stimulated by the combination of insulin (100 nM) and dexamethasone (100 nM) during an overnight (16 h) incubation. Wortmannin (100 nM), rapamycin (30 ng/ml) or PD98059 (50 microM) did not prevent this stimulation, suggesting that phosphatidylinositol 3-kinase, p70 S6 kinase and the mitogen-activated protein kinase cascade are not involved in transducing the hormonal signal. In contrast, cytochalasin D (2 microM) completely abolished the stimulatory effect of insulin and dexamethasone on both heparin-releasable LPL and total cellular LPL activities. The potential role of the actin cytoskeleton in the stimulation of LPL activity by insulin and dexamethasone appears to be distal to the initial signalling events since cytochalasin D is still effective in preventing the stimulation when added 2 h after the hormones. PMID:10333493

  8. Variable effects of dexamethasone on protein synthesis in clonal rat osteosarcoma cells

    SciTech Connect

    Hodge, B.O.; Kream, B.E.

    1988-05-01

    We examined the effects of dexamethasone on protein synthesis in clonal rat osteoblastic osteosarcoma (ROS) cell lines by measuring the incorporation of (/sup 3/H)proline into collagenase-digestible and noncollagen protein in the cell layer and medium of the cultures. In ROS 17/2 and subclone C12 of ROS 17/2.8, dexamethasone decreased collagen synthesis with no change in DNA content of the cultures. In ROS 17/2.8 and its subclone G2, dexamethasone stimulated collagen and noncollagen protein synthesis, with a concomitant decrease in the DNA content of the cells. These data indicate that ROS cell lines are phenotypically heterogeneous and suggest that in normal bone there may be distinct subpopulations of osteoblasts with varying phenotypic traits with respect to the regulation of protein synthesis.

  9. Autoradiographic localization of specific [3H]dexamethasone binding in fetal lung.

    PubMed

    Beer, D G; Butley, M S; Cunha, G R; Malkinson, A M

    1984-10-01

    The cellular and subcellular localization of specific [3H]dexamethasone binding was examined in fetal mouse lung at various stages of development and in human fetal lung at 8 weeks of gestation using a rapid in vitro steroid incubation technique followed by thaw-mount autoradiography. Competition studies with unlabeled steroids demonstrate the specificity of [3H]dexamethasone labeling, and indicate that fetal lung mesenchyme is a primary glucocorticoid target during lung development. Quantitative binding studies, involving incubation of intact tissue with competing ligand and subsequent subcellular fractionation, show this to be specific, nuclear binding characteristic of glucocorticoid receptors. Autoradiographs of [3H]dexamethasone binding in lung tissue at early stages of development demonstrate that the mesenchyme directly adjacent to the more proximal portions of the bronchiolar network is heavily labeled. In contrast, the epithelium which will later differentiate into bronchi and bronchioles, is relatively unlabeled. Distal portions of the growing epithelium, destined to become alveolar ducts and alveoli, do show nuclear localization of [3H]dexamethasone. Because of the known importance of the mesenchyme in controlling lung development and the ability of glucocorticoids to stimulate lung development, these results suggest that many of the growth-promoting effects of glucocorticoids may be mediated through the mesenchyme. In addition, by utilizing a technique which allows the simultaneous examination of extracellular matrix components and [3H]dexamethasone binding, a relationship is observed between extensive mesenchymal [3H]dexamethasone binding and extensive extracellular matrix accumulation. Since glucocorticoids stimulate the synthesis of many extracellular matrix components, these results suggest a role for these hormones in affecting mesenchymal-epithelial interactions during lung morphogenesis.

  10. Preoperative dexamethasone reduces postoperative pain, nausea and vomiting following mastectomy for breast cancer

    PubMed Central

    2010-01-01

    Background Dexamethasone has been reported to reduce postoperative symptoms after different surgical procedures. We evaluated the efficacy of preoperative dexamethasone in ameliorating postoperative nausea and vomiting (PONV), and pain after mastectomy. Methods In this prospective, double-blind, placebo-controlled study, 70 patients scheduled for mastectomy with axillary lymph node dissection were analyzed after randomization to treatment with 8 mg intravenous dexamethasone (n = 35) or placebo (n = 35). All patients underwent standardized procedures for general anesthesia and surgery. Episodes of PONV and pain score were recorded on a visual analogue scale. Analgesic and antiemetic requirements were also recorded. Results Demographic and medical variables were similar between groups. The incidence of PONV was lower in the dexamethasone group at the early postoperative evaluation (28.6% vs. 60%; p = 0.02) and at 6 h (17.2% vs. 45.8%; p = 0.03). More patients in the placebo group required additional antiemetic medication (21 vs. 8; p = 0.01). Dexamethasone treatment significantly reduced postoperative pain just after surgery (VAS score, 4.54 ± 1.55 vs. 5.83 ± 2.00; p = 0.004), at 6 h (3.03 ± 1.20 vs. 4.17 ± 1.24; p < 0.0005) and at 12 h (2.09 ± 0.85 vs. 2.54 ± 0.98; p = 0.04). Analgesics were required in more patients of the control group (21 vs. 10; p = 0.008). There were no adverse events, morbidity or mortality. Conclusions Preoperative intravenous dexamethasone (8 mg) can significantly reduce the incidence of PONV and pain in patients undergoing mastectomy with axillary dissection for breast cancer. Trial registration number NCT01116713 PMID:21182781

  11. Cortisol secretion after adrenocorticotrophin (ACTH) and Dexamethasone tests in healthy female and male dogs

    PubMed Central

    Pessina, Paula; Fernández-Foren, Andrea; Cueto, Enrique; Delucchi, Luis; Castillo, Victor; Meikle, Ana

    2009-01-01

    Background For the conclusive diagnosis of Cushing's Syndrome, a stimulating ACTH test or a low suppressive Dexamethasone test is used. Reports in other species than the dog indicate that plasma cortisol concentration after ACTH administration is affected by gender. We investigated the effect of gender on the cortisol response to ACTH and Dexamethasone tests in dogs. Methods Seven healthy adult Cocker Spaniels (4 females and 3 males) were assigned to a two by two factorial design: 4 dogs (2 females and 2 males) received IV Dexamethasone 0.01 mg/kg, while the other 3 dogs received an IV saline solution (control group). Two weeks later the treatments were reversed. After one month, ACTH was given IV (250 μg/animal) to 4 dogs (2 female and 2 males) while the rest was treated with saline solution (control group). Cortisol concentrations were determined by a direct solid-phase radioimmunoassay and cholesterol and triglycerides by commercial kits. Results and Discussion No effect of treatment was observed in metabolite concentrations, but females presented higher cholesterol concentrations. ACTH-treated dogs showed an increase in cortisol levels in the first hour after sampling until 3 hours post injection. Cortisol concentrations in Dexamethasone-treated dogs decreased one hour post injection and remained low for 3 hours, thereafter cortisol concentrations increased. The increase in cortisol levels from one to two hours post ACTH injection was significantly higher in females than males. In Dexamethasone-treated males cortisol levels decreased one hour post injection up to 3 hours; in females the decrease was more pronounced and prolonged, up to 5 hours post injection. Conclusion We have demonstrated that cortisol response to ACTH and Dexamethasone treatment in dogs differs according to sex. PMID:19686591

  12. Dexamethasone induces caveolin-1 in vascular endothelial cells: implications for attenuated responses to VEGF.

    PubMed

    Igarashi, Junsuke; Hashimoto, Takeshi; Shoji, Kazuyo; Yoneda, Kozo; Tsukamoto, Ikuko; Moriue, Tetsuya; Kubota, Yasuo; Kosaka, Hiroaki

    2013-04-15

    Steroids exert direct actions on cardiovascular cells, although underlying molecular mechanisms remain incompletely understood. We examined if steroids modulate abundance of caveolin-1, a regulatory protein of cell-surface receptor pathways that regulates the magnitudes of endothelial response to vascular endothelial growth factor (VEGF). Dexamethasone, a synthetic glucocorticoid, induces caveolin-1 at both levels of protein and mRNA in a time- and dose-dependent manner in pharmacologically relevant concentrations in cultured bovine aortic endothelial cells. Aldosterone, a mineralocorticoid, but not the sex steroids 17β-estradiol, testosterone, or progesterone, elicits similar caveolin-1 induction. Caveolin-1 induction by dexamethasone and that by aldosterone were abrogated by RU-486, an inhibitor of glucocorticoid receptor, and by spironolactone, a mineralocorticoid receptor inhibitor, respectively. Dexamethasone attenuates VEGF-induced responses at the levels of protein kinases Akt and ERK1/2, small-G protein Rac1, nitric oxide production, and migration. When induction of caveolin-1 by dexamethasone is attenuated either by genetically by transient transfection with small interfering RNA or pharmacologically by RU-486, kinase responses to VEGF are rescued. Dexamethasone also increases expression of caveolin-1 protein in cultured human umbilical vein endothelial cells, associated with attenuated tube formation responses of these cells when cocultured with normal fibroblasts. Immunohistochemical analyses revealed that intraperitoneal injection of dexamethasone induces endothelial caveolin-1 protein in thoracic aorta and in lung artery in healthy male rats. Thus steroids functionally attenuate endothelial responses to VEGF via caveolin-1 induction at the levels of signal transduction, migration, and tube formation, identifying a novel point of cross talk between nuclear and cell-surface receptor signaling pathways. PMID:23426970

  13. Prenatal Dexamethasone Augments the Neurobehavioral Teratology of Chlorpyrifos: Significance for Maternal Stress and Preterm Labor

    PubMed Central

    Levin, Edward D.; Cauley, Marty; Johnson, Joshua E.; Cooper, Ellen M.; Stapleton, Heather M.; Ferguson, P. Lee; Seidler, Frederic J.; Slotkin, Theodore A.

    2014-01-01

    Glucocorticoids are the consensus treatment given in preterm labor and are also elevated by maternal stress; organophosphate exposures are virtually ubiquitous, so human developmental coexposures to these two agents are common. This study explores how prenatal dexamethasone exposure modifies the neurobehavioral teratology of chlorpyrifos, one of the most widely used organophosphates. We administered dexamethasone to pregnant rats on gestational days 17-19 at a standard therapeutic dose (0.2 mg/kg); offspring were then given chlorpyrifos on postnatal days 1-4, at a dose (1 mg/kg) that produces barely-detectable (<10%) inhibition of brain cholinesterase activity. Dexamethasone did not alter brain chlorpyrifos concentrations, nor did either agent alone or in combination affect brain thyroxine levels. Assessments were carried out from adolescence through adulthood encompassing T-maze alternation, Figure-8 maze (locomotor activity, habituation), novelty-suppressed feeding and novel object recognition tests. For behaviors where chlorpyrifos or dexamethasone individually had small effects, the dual exposure produced larger, significant effects that reflected additivity (locomotor activity, novelty-suppressed feeding, novel object recognition). Where the individual effects were in opposite directions or were restricted to only one agent, we found enhancement of chlorpyrifos’ effects by prenatal dexamethasone (habituation). Finally, for behaviors where controls displayed a normal sex difference in performance, the combined treatment either eliminated or reversed the difference (locomotor activity, novel object recognition). Combined exposure to dexamethasone and chlorpyrifos results in a worsened neurobehavioral outcome, providing a proof-of-principle that prenatal glucocorticoids can create a subpopulation with enhanced vulnerability to environmental toxicants. PMID:24177596

  14. Prenatal dexamethasone augments the neurobehavioral teratology of chlorpyrifos: significance for maternal stress and preterm labor.

    PubMed

    Levin, Edward D; Cauley, Marty; Johnson, Joshua E; Cooper, Ellen M; Stapleton, Heather M; Ferguson, P Lee; Seidler, Frederic J; Slotkin, Theodore A

    2014-01-01

    Glucocorticoids are the consensus treatment given in preterm labor and are also elevated by maternal stress; organophosphate exposures are virtually ubiquitous, so human developmental coexposures to these two agents are common. This study explores how prenatal dexamethasone exposure modifies the neurobehavioral teratology of chlorpyrifos, one of the most widely used organophosphates. We administered dexamethasone to pregnant rats on gestational days 17-19 at a standard therapeutic dose (0.2 mg/kg); offspring were then given chlorpyrifos on postnatal days 1-4, at a dose (1 mg/kg) that produces barely-detectable (<10%) inhibition of brain cholinesterase activity. Dexamethasone did not alter brain chlorpyrifos concentrations, nor did either agent alone or in combination affect brain thyroxine levels. Assessments were carried out from adolescence through adulthood encompassing T-maze alternation, Figure 8 maze (locomotor activity, habituation), novelty-suppressed feeding and novel object recognition tests. For behaviors where chlorpyrifos or dexamethasone individually had small effects, the dual exposure produced larger, significant effects that reflected additivity (locomotor activity, novelty-suppressed feeding, novel object recognition). Where the individual effects were in opposite directions or were restricted to only one agent, we found enhancement of chlorpyrifos' effects by prenatal dexamethasone (habituation). Finally, for behaviors where controls displayed a normal sex difference in performance, the combined treatment either eliminated or reversed the difference (locomotor activity, novel object recognition). Combined exposure to dexamethasone and chlorpyrifos results in a worsened neurobehavioral outcome, providing a proof-of-principle that prenatal glucocorticoids can create a subpopulation with enhanced vulnerability to environmental toxicants.

  15. Plasma concentration-dependent suppression of endogenous hydrocortisone in the horse after intramuscular administration of dexamethasone-21-isonicotinate.

    PubMed

    Ekstrand, C; Bondesson, U; Gabrielsson, J; Hedeland, M; Kallings, P; Olsén, L; Ingvast-Larsson, C

    2015-06-01

    Detection times and screening limits (SL) are methods used to ensure that the performance of horses in equestrian sports is not altered by drugs. Drug concentration-response relationship and knowledge of concentration-time profiles in both plasma and urine are required. In this study, dexamethasone plasma and urine concentration-time profiles were investigated. Endogenous hydrocortisone plasma concentrations and their relationship to dexamethasone plasma concentrations were also explored. A single dose of dexamethasone-21-isonicotinate suspension (0.03 mg/kg) was administered intramuscularly to six horses. Plasma was analysed for dexamethasone and hydrocortisone and urine for dexamethasone, using UPLC-MS/MS. Dexamethasone was quantifiable in plasma for 8.3 ± 2.9 days (LLOQ: 0.025 μg/L) and in urine for 9.8 ± 3.1 days (LLOQ: 0.15 μg/L). Maximum observed dexamethasone concentration in plasma was 0.61 ± 0.12 μg/L and in urine 4.2 ± 0.9 μg/L. Terminal plasma half-life was 38.7 ± 19 h. Hydrocortisone was significantly suppressed for 140 h. The plasma half-life of hydrocortisone was 2.7 ± 1.3 h. Dexamethasone potency, efficacy and sigmoidicity factor for hydrocortisone suppression were 0.06 ± 0.04 μg/L, 0.95 ± 0.04 and 6.2 ± 4.6, respectively. Hydrocortisone suppression relates to the plasma concentration of dexamethasone. Thus, determination of irrelevant plasma concentrations and SL is possible. Future research will determine whether hydrocortisone suppression can be used as a biomarker of the clinical effect of dexamethasone.

  16. Attenuation of dexamethasone-induced cell death in multiple myeloma is mediated by miR-125b expression

    PubMed Central

    Murray, Megan Y.; Rushworth, Stuart A.; Zaitseva, Lyubov; Bowles, Kristian M.; MacEwan, David J.

    2013-01-01

    Dexamethasone is a key front-line chemotherapeutic for B-cell malignant multiple myeloma (MM). Dexamethasone modulates MM cell survival signaling but fails to induce marked cytotoxicity when used as a monotherapy. We demonstrate here the mechanism behind this insufficient responsiveness of MM cells toward dexamethasone, revealing in MM a dramatic anti-apoptotic role for microRNA (miRNA)-125b in the insensitivity toward dexamethasone-induced apoptosis. MM cells responding to dexamethasone exhibited enhanced expression of oncogenic miR-125b. Dexamethasone also induced expression of miR-34a, which acts to suppress SIRT1 deacetylase, and thus allows maintained acetylation and inactivation of p53. p53 mRNA is also suppressed by miR-125b targeting. Reporter assays showed that both these dexamethasone-induced miRNAs act downstream of their target genes to prevent p53 tumor suppressor actions and, ultimately, resist cytotoxic responses in MM. Use of antisense miR-125b transcripts enhanced expression of pro-apoptotic p53, repressed expression of anti-apoptotic SIRT1 and, importantly, significantly enhanced dexamethasone-induced cell death responses in MM. Pharmacological manipulations showed that the key regulation enabling complete dexamethasone sensitivity in MM cells lies with miR-125b. In summary, dexamethasone-induced miR-125b induces cell death resistance mechanisms in MM cells via the p53/miR-34a/SIRT1 signaling network and provides these cells with an enhanced level of resistance to cytotoxic chemotherapeutics. Clearly, such anti-apoptotic mechanisms will need to be overcome to more effectively treat nascent, refractory and relapsed MM patients. These mechanisms provide insight into the role of miRNA regulation of apoptosis and their promotion of MM cell proliferative mechanisms. PMID:23759586

  17. Dexamethasone inhibits human interleukin 2 but not interleukin 2 receptor gene expression in vitro at the level of nuclear transcription.

    PubMed Central

    Boumpas, D T; Anastassiou, E D; Older, S A; Tsokos, G C; Nelson, D L; Balow, J E

    1991-01-01

    Glucocorticosteroids have an inhibitory effect on the expression of interleukin 2 (IL-2) and interleukin 2 receptor (IL-2R) genes. To determine the mechanisms of this inhibition, human T lymphocytes were stimulated with mitogens in the presence of dexamethasone. Nuclear transcription run-off assays showed that high doses of dexamethasone inhibited the transcription of the IL-2 gene but not that of the IL-2R gene. Post-transcriptionally, high doses of dexamethasone (10(-4) M) were required to inhibit IL-2R mRNA levels by 50%, whereas lower doses (10(-6) M) inhibited by greater than 70% the accumulation of IL-2 mRNA. IL-2 mRNA half-life decreased in the presence of dexamethasone (10(-6) M) by approximately 50%. At the protein product level, dexamethasone inhibited both IL-2 production, as well as cell surface and soluble forms of IL-2R. IL-2R gene expression was inhibited for at least 72 h after exposure of cells to dexamethasone. In the presence of exogenous IL-2, dexamethasone failed to exert a significant effect on the production of IL-2R protein. These data indicate that dexamethasone has a greater effect on the expression of the IL-2 gene than on the IL-2R gene. Dexamethasone both inhibits transcription of the IL-2 gene and decreases the stability of IL-2 mRNA. The effect of dexamethasone on the IL-2R gene is post-transcriptional and may result indirectly from decreased IL-2 production. Images PMID:2022743

  18. Effect of dexamethasone on testicular enzymes of the Embden-Meyerhof and pentose-phosphate pathways.

    PubMed

    Valivullah, H M; Aruldhas, M M; Govindarajulu, P

    1983-04-01

    The influence of dexamethasone on the specific activities of testicular enzymes involved in the Embden-Meyerhof and pentose-phosphate pathways was studied in pre-pubertal, pubertal and adult rats. All of the enzymes showed a decrease in specific activity after dexamethasone treatment, an effect which was most drastic in pre-pubertal animals. After cessation of treatment, the specific activity of all the enzymes reverted to normal levels, except for glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase in the pre-pubertal group.

  19. Hematologic, biochemical, and endocrine effects of dexamethasone on bottlenose dolphins (Tursiops truncatus).

    PubMed

    Reidarson, T H; McBain, J F

    1999-06-01

    Two Atlantic bottlenose dolphins (Tursiops truncatus) were given 0.11 mg/kg dexamethasone p.o., and complete blood count and serum chemistry analyses, including insulin, thyroxine (T4) adrenocorticotrophic hormone (ACTH), and cortisol level determinations, were performed at 0 hr, 24 hr, 36 hr, 48 hr, 7 days, and 17 days. Significant changes included neutrophilia, eosinopenia, lymphopenia, elevated insulin, and depressed ACTH and cortisol levels within 24 hr of dexamethasone administration. These effects were rapid, and values returned to normal within 48 hr.

  20. The anti-inflammatory effects of dexamethasone and therapeutic ultrasound in oral surgery.

    PubMed

    ElHag, M; Coghlan, K; Christmas, P; Harvey, W; Harris, M

    1985-02-01

    A single blind, controlled trial was carried out to assess the anti-inflammatory effects of 10 mg dexamethasone given pre- and post-operatively and also ultrasound therapy in patients following the removal of impacted lower third molars. Facial swelling and trismus were significantly reduced in both the dexamethasone- and the ultrasound-treated groups compared with an untreated control group. This first report of the anti-inflammatory properties of ultrasound in a controlled clinical trial indicates its potential clinical use in reducing post-operative morbidity in oral surgery.

  1. Anti-CD163-dexamethasone conjugate inhibits the acute phase response to lipopolysaccharide in rats

    PubMed Central

    Thomsen, Karen Louise; Møller, Holger Jon; Graversen, Jonas Heilskov; Magnusson, Nils E; Moestrup, Søren K; Vilstrup, Hendrik; Grønbæk, Henning

    2016-01-01

    AIM: To study the effect of a new anti-CD163-dexamethasone conjugate targeting activated macrophages on the hepatic acute phase response in rats. METHODS: Wistar rats were injected intravenous with either the CD163 targeted dexamethasone-conjugate (0.02 mg/kg) or free dexamethasone (0.02 or 1 mg/kg) 24 h prior to lipopolysaccharide (LPS) (2.5 mg/kg intraperitoneal). We measured plasma concentrations of tumour necrosis factor-α (TNF-α) and interleukin 6 (IL-6) 2 h post-LPS and liver mRNAs and serum concentrations of the rat acute phase protein α-2-macroglobulin (α-2-M) 24 h after LPS. Also, plasma concentrations of alanine aminotransferase and bilirubin were measured at termination of the study. Spleen weight served as an indicator of systemic steroid effects. RESULTS: The conjugate halved the α-2-M liver mRNA (3.3 ± 0.6 vs 6.8 ± 1.1, P < 0.01) and serum protein (201 ± 48 μg/mL vs 389 ± 67 μg/mL, P = 0.04) after LPS compared to low dose dexamethasone treated animals, while none of the free dexamethasone doses had an effect on liver mRNA or serum levels of α-2-M. Also, the conjugate reduced TNF-α (7208 ± 1977 pg/mL vs 21583 ± 7117 pg/mL, P = 0.03) and IL-6 (15685 ± 3779 pg/mL vs 25715 ± 4036 pg/mL, P = 0.03) compared to the low dose dexamethasone. The high dose dexamethasone dose decreased the spleen weight (421 ± 11 mg vs 465 ± 12 mg, P < 0.05) compared to controls, an effect not seen in any other group. CONCLUSION: Low-dose anti-CD163-dexamethasone conjugate effectively decreased the hepatic acute phase response to LPS. This indicates an anti-inflammatory potential of the conjugate in vivo. PMID:27330681

  2. Catecholaminergic responses to stressful motion stimuli, scopolamine plus amphetamine, and dexamethasone

    NASA Technical Reports Server (NTRS)

    Kohl, R. L.; Chelen, W. E.

    1992-01-01

    Peripheral levels of epinephrine (EPI) and neoepinephrine (NE) generally rise following stressful motion stimuli. Effective anti-motion sickness drugs, scopolamine plus, d-amphetamine (S/D) and dexamthasone (DEX) modulate release of EPI and NE. This modulation may be of etiological relevance. Methods: Severe nausea was induced by exposure to coriolis simulation using a rotating chair. Chronic administration of S/D (0.4 and 5 mg/da) DEX (3 mg/day) and placebo preceded coriolis simulation. EPI and NE were measured immediately before and after simulation. A double-blind crossover design was used. Results: Nausea-induced elevations of EPI (2.5 fold, p less than .01) and NE were not diminished upon repeated exposure and adaptation to the stressor. Subjects with more pronounced elevations of EPI following simulation displayed higher resistance to stressful motion (p less .05). Alteration of peripheral catechlomaine levels following drug suggested that motion sickness was not mediated by peripheral catechlolamine receptor simulation. EPI and NE levels were 2.8 and 3.6-fold higher (p less than .03 and .01) after nausea without DEX treatment. DEX loading halved pre-stress levels of EPI and NE (p less than .05). Conclusions: Marked differences were noted in individual responses to drug and systematic responses of EPI and NE. It is possible that the responses of EPI to motion sickness may predict resistance to stressful motion and represent a peripheral manifestation of some as yet unknown central event of etiologic relevance.

  3. Recent advances in the discovery of alpha1-adrenoceptor agonists.

    PubMed

    Bishop, Michael J

    2007-01-01

    The alpha(1) adrenoceptors are three of nine well-characterized receptors that are activated by epinephrine and norepinephrine. Agonists acting at the alpha(1) adrenoceptors produce numerous physiological effects, and are used therapeutically for several indications. Many known alpha(1) adrenoceptor agonists are alpha(1A) selective, but the discovery of highly selective alpha(1B) and alpha(1D) adrenoceptor agonists has proven to be an extremely difficult goal to achieve. This review will focus on recent advances in the discovery, development and clinical utility of subtype-specific alpha(1) agonists as well as contributions to our understanding of agonist-receptor interactions.

  4. Increased agonist affinity at the mu-opioid receptor induced by prolonged agonist exposure

    PubMed Central

    Birdsong, William T.; Arttamangkul, Seksiri; Clark, Mary J.; Cheng, Kejun; Rice, Kenner C.; Traynor, John R.; Williams, John T.

    2013-01-01

    Prolonged exposure to high-efficacy agonists results in desensitization of the mu opioid receptor (MOR). Desensitized receptors are thought to be unable to couple to G-proteins, preventing downstream signaling, however the changes to the receptor itself are not well characterized. In the current study, confocal imaging was used to determine whether desensitizing conditions cause a change in agonist-receptor interactions. Using rapid solution exchange, the binding kinetics of fluorescently labeled opioid agonist, dermorphin Alexa594 (derm A594), to MORs was measured in live cells. The affinity of derm A594 binding increased following prolonged treatment of cells with multiple agonists that are known to cause receptor desensitization. In contrast, binding of a fluorescent antagonist, naltrexamine Alexa 594, was unaffected by similar agonist pre-treatment. The increased affinity of derm A594 for the receptor was long-lived and partially reversed after a 45 min wash. Treatment of the cells with pertussis toxin did not alter the increase in affinity of the derm A594 for MOR. Likewise the affinity of derm A594 for MORs expressed in mouse embryonic fibroblasts derived from arrestin 1 and 2 knockout animals increased following treatment of the cells with the desensitization protocol. Thus, opioid receptors were “imprinted” with a memory of prior agonist exposure that was independent of G-protein activation or arrestin binding that altered subsequent agonist-receptor interactions. The increased affinity suggests that acute desensitization results in a long lasting but reversible conformational change in the receptor. PMID:23447620

  5. Agonistic and reproductive interactions in Betta splendens.

    PubMed

    Bronstein, P M

    1984-12-01

    Reproductive and agonistic behaviors in Siamese fighting fish were investigated in eight experiments, and some consequences and determinants of these sequences were isolated. First, fights and the formation of dominance-subordinancy relations were studied. Second, it was determined that large body size as well as males' prior residency in a tank produced an agonistic advantage; the magnitude of this advantage was positively related to the duration of residency. Third, the prior-residency effect in Bettas was determined by males' familiarity with visual and/or tactile cues in their home tanks. Fourth, dominant males had greater access to living space and were more likely to display at a mirror, build nests, and approach females than were subordinates. Finally, it was discovered that chemical cues associated with presumedly inert plastic tank dividers influence Bettas' social behavior.

  6. Signal Use by Octopuses in Agonistic Interactions.

    PubMed

    Scheel, David; Godfrey-Smith, Peter; Lawrence, Matthew

    2016-02-01

    Cephalopods show behavioral parallels to birds and mammals despite considerable evolutionary distance [1, 2]. Many cephalopods produce complex body patterns and visual signals, documented especially in cuttlefish and squid, where they are used both in camouflage and a range of interspecific interactions [1, 3-5]. Octopuses, in contrast, are usually seen as solitary and asocial [6, 7]; their body patterns and color changes have primarily been interpreted as camouflage and anti-predator tactics [8-12], though the familiar view of the solitary octopus faces a growing list of exceptions. Here, we show by field observation that in a shallow-water octopus, Octopus tetricus, a range of visible displays are produced during agonistic interactions, and these displays correlate with the outcome of those interactions. Interactions in which dark body color by an approaching octopus was matched by similar color in the reacting octopus were more likely to escalate to grappling. Darkness in an approaching octopus met by paler color in the reacting octopus accompanied retreat of the paler octopus. Octopuses also displayed on high ground and stood with spread web and elevated mantle, often producing these behaviors in combinations. This study is the first to document the systematic use of signals during agonistic interactions among octopuses. We show prima facie conformity of our results to an influential model of agonistic signaling [13]. These results suggest that interactions have a greater influence on octopus evolution than has been recognized and show the importance of convergent evolution in behavioral traits. PMID:26832440

  7. Signal Use by Octopuses in Agonistic Interactions.

    PubMed

    Scheel, David; Godfrey-Smith, Peter; Lawrence, Matthew

    2016-02-01

    Cephalopods show behavioral parallels to birds and mammals despite considerable evolutionary distance [1, 2]. Many cephalopods produce complex body patterns and visual signals, documented especially in cuttlefish and squid, where they are used both in camouflage and a range of interspecific interactions [1, 3-5]. Octopuses, in contrast, are usually seen as solitary and asocial [6, 7]; their body patterns and color changes have primarily been interpreted as camouflage and anti-predator tactics [8-12], though the familiar view of the solitary octopus faces a growing list of exceptions. Here, we show by field observation that in a shallow-water octopus, Octopus tetricus, a range of visible displays are produced during agonistic interactions, and these displays correlate with the outcome of those interactions. Interactions in which dark body color by an approaching octopus was matched by similar color in the reacting octopus were more likely to escalate to grappling. Darkness in an approaching octopus met by paler color in the reacting octopus accompanied retreat of the paler octopus. Octopuses also displayed on high ground and stood with spread web and elevated mantle, often producing these behaviors in combinations. This study is the first to document the systematic use of signals during agonistic interactions among octopuses. We show prima facie conformity of our results to an influential model of agonistic signaling [13]. These results suggest that interactions have a greater influence on octopus evolution than has been recognized and show the importance of convergent evolution in behavioral traits.

  8. PROSPECTING IN LATE-TYPE DWARFS: A CALIBRATION OF INFRARED AND VISIBLE SPECTROSCOPIC METALLICITIES OF LATE K AND M DWARFS SPANNING 1.5 dex

    SciTech Connect

    Mann, Andrew W.; Hilton, Eric J.; Brewer, John M.; Gaidos, Eric; Lepine, Sebastien

    2013-02-01

    Knowledge of late K and M dwarf metallicities can be used to guide planet searches and constrain planet formation models. However, the determination of metallicities of late-type stars is difficult because visible wavelength spectra of their cool atmospheres contain many overlapping absorption lines, preventing the measurement of equivalent widths. We present new methods, and improved calibrations of existing methods, to determine metallicities of late K and M dwarfs from moderate resolution (1300 < R < 2000) visible and infrared spectra. We select a sample of 112 wide binary systems that contain a late-type companion to a solar-type primary star. Our sample includes 62 primary stars with previously published metallicities, as well as 50 stars with metallicities determined from our own observations. We use our sample to empirically determine which features in the spectrum of the companion are best correlated with the metallicity of the primary. We find {approx_equal}120 features in K and M dwarf spectra that are useful for predicting metallicity. We derive metallicity calibrations for different wavelength ranges, and show that it is possible to get metallicities reliable to <0.10 dex using either visible, J-, H-, or K-band spectra. We find that the most accurate metallicities derived from visible spectra requires the use of different calibrations for early-type (K5.5-M2) and late-type (M2-M6) dwarfs. Our calibrations are applicable to dwarfs with metallicities of -1.04 < [Fe/H] <+0.56 and spectral types from K7 to M5. Lastly, we use our sample of wide binaries to test and refine existing calibrations to determine M dwarf metallicities. We find that the {zeta} parameter, which measures the ratio of TiO can CaH bands, is correlated with [Fe/H] for super-solar metallicities, and {zeta} does not always correctly identify metal-poor M dwarfs. We also find that existing calibrations in the K and H bands are quite reliable for stars with [Fe/H] >-0.5, but are less useful

  9. Low dose dexamethasone reverses depressive-like parameters and memory impairment in rats submitted to sepsis.

    PubMed

    Cassol-Jr, Omar J; Comim, Clarissa M; Petronilho, Fabricia; Constantino, Larissa S; Streck, Emilio L; Quevedo, João; Dal-Pizzol, Felipe

    2010-04-01

    Sepsis is characterized by a systemic inflammatory response of the immune system against an infection, presenting with hypothalamic-pituitary-adrenal (HPA) axis dysfunction, behavior alterations, and high mortality. In this study, we aimed to evaluate the effects of dexamethasone on mortality, anhedonia, circulating corticosterone and adrenocorticotropin hormone (ACTH) levels, body and adrenal gland weight, and aversive memory in sepsis survivor rats. Male Wistar rats underwent sham operation or cecal ligation and perforation (CLP) procedure. Rats subjected to CLP were treated with "basic support" and dexamethasone (at 0.2 and 2mg/kg daily for 7 days after CLP, intraperitonially) or saline. After 10 days of sepsis procedure, it was evaluated aversive memory, sweet food consumption, and body and adrenal gland weight. Serum and plasma were also obtained. It was observed that low dose dexamethasone reverted anhedonia, normalized adrenal gland and body weight, corticosterone and ACTH levels, and decreased mortality and avoidance memory impairment, demonstrating that low doses of dexamethasone for moderate periods may be beneficial for sepsis treatment and its sequelae-depressive-like parameters and memory impairment. PMID:20184944

  10. Dexamethasone action on caudal fin regeneration of carp Cyprinus carpio (Linnaeus, 1758).

    PubMed

    Ochandio, B S; Bechara, I J; Parise-Maltempi, P P

    2015-05-01

    Studies have demonstrated that the prolonged use of corticoids can delay the healing process, affecting re-epithelialization, neovascularization and collagen synthesis. As the fins of teleost fish contain a large amount of collagen, the aim of the present study was to investigate the effect of dexamethasone (anti-inflammatory and glucocorticoid steroid widely used in the treatment of rheumatic diseases) during the regeneration process in the caudal fin of specimens of carp (Cyprinus carpio). For such, two glass aquaria were used - one for a group of fish treated with dexamethasone (Henrifarma) in a 20 mg/L concentration and the other for the control group. The caudal fins were amputated transversally and fish remained in their respective aquaria until regeneration occurred. Samples of regenerating fins were collected on days 1, 2, 4, 6, 8 and 10 after amputation. The fins in the control group regenerated normally and grew within the expected in time course. The fins in the group treated with dexamethasone were significantly smaller in comparison to the control group at every evaluation time. Thus, it was possible to verify that, at this concentration of dexamethasone, the regeneration of the caudal fins was delayed, but not completely inhibited. The results show that the caudal fin is a good model for histological studies on regeneration and the action of drug toxicity, but it's also of great importance the interaction with further studies for a better knowledge and understanding of all the changes in all the phases.

  11. Low dose dexamethasone reverses depressive-like parameters and memory impairment in rats submitted to sepsis.

    PubMed

    Cassol-Jr, Omar J; Comim, Clarissa M; Petronilho, Fabricia; Constantino, Larissa S; Streck, Emilio L; Quevedo, João; Dal-Pizzol, Felipe

    2010-04-01

    Sepsis is characterized by a systemic inflammatory response of the immune system against an infection, presenting with hypothalamic-pituitary-adrenal (HPA) axis dysfunction, behavior alterations, and high mortality. In this study, we aimed to evaluate the effects of dexamethasone on mortality, anhedonia, circulating corticosterone and adrenocorticotropin hormone (ACTH) levels, body and adrenal gland weight, and aversive memory in sepsis survivor rats. Male Wistar rats underwent sham operation or cecal ligation and perforation (CLP) procedure. Rats subjected to CLP were treated with "basic support" and dexamethasone (at 0.2 and 2mg/kg daily for 7 days after CLP, intraperitonially) or saline. After 10 days of sepsis procedure, it was evaluated aversive memory, sweet food consumption, and body and adrenal gland weight. Serum and plasma were also obtained. It was observed that low dose dexamethasone reverted anhedonia, normalized adrenal gland and body weight, corticosterone and ACTH levels, and decreased mortality and avoidance memory impairment, demonstrating that low doses of dexamethasone for moderate periods may be beneficial for sepsis treatment and its sequelae-depressive-like parameters and memory impairment.

  12. Effectiveness of Submucosal Dexamethasone to Control Postoperative Pain & Swelling in Apicectomy of Maxillary Anterior Teeth

    PubMed Central

    Shah, Shahzad Ali; Khan, Irfanullah; Shah, Humera Shahzad

    2011-01-01

    Purpose The purpose of this study was to evaluate the effect of submucosal dexamethasone injection to control postoperative pain and swelling in apicectomy of maxillary anterior teeth. Methods A randomized, controlled trial comprising 60 adult patients (68.3% male, 31.7% female) with no local or systemic problems was conducted. Patients were randomly divided into two groups: Group A was given 4mg dexamethasone injection perioperatively. Group B (control group) was treated conventionally without any steroid injection. Postoperative pain and swelling was evaluated using a visual analog scale (VAS). Objective measurements of facial pain and swelling were performed daily up to six days postoperatively. Results Dexamethasone group showed significant reduction in pain and swelling postoperatively compared with the control. Conclusion Submucosal dexamethasone 4mg injection is an effective therapeutic strategy for swift and comfortable improvement after surgical procedure and has a significant effect on reducing postoperative pain and swelling. The treatment offers a simple, safe, painless, noninvasive and cost effective therapeutic option for moderate and severe cases. PMID:23267293

  13. Isolated extraocular muscle infiltration with plasmacytoma treated with localized injection of dexamethasone.

    PubMed

    Painter, Sally L; Dickens, Emmy; Elston, John S

    2015-06-01

    Plasmacytoma of the orbit secondary to multiple myeloma is rare and has not previously been reported limited to an extraocular muscle. Conventional treatment is either localized radiotherapy or systemic chemotherapy. We report a case of plasmacytoma within the medial rectus muscle, which regressed completely with localized infiltration of dexamethasone.

  14. Dexamethasone diffusion across contact lenses is inhibited by Staphylococcus epidermidis biofilms in vitro

    PubMed Central

    Brothers, Kimberly M.; Nau, Amy C.; Romanowski, Eric G.; Shanks, Robert M. Q.

    2014-01-01

    Purpose This study was designed to measure the impact of bacterial biofilms on diffusion of an ocular therapeutic through silicone hydrogel bandage lenses in vitro. Methods An assay was designed to study the passage of a commonly used steroid dexamethasone through the silicone hydrogel soft contact lenses. Diffused dexamethasone was measured using a spectrophotometer over a period of 18 hours and quantified using a standard curve. This assay was performed with control and Staphylococcus epidermidis biofilm-coated contact lenses composed of lotrafilcon A and methafilcon. Biofilms were formed in brain heart infusion broth supplemented with D-glucose. Results The presented data validate a simple in vitro model that can be used to measure penetration of a topical therapeutic through silicone hydrogel soft contact lenses. Using this model we measured a reduction of dexamethasone diffusion by up to 88% through S. epidermidis biofilm-coated silicon hydrogel lenses compared to control lenses. Conclusions The results of this in vitro study demonstrate that bacterial biofilms impede dexamethasone diffusion through silicon hydrogel contact lenses, and warrant future studies regarding the clinical benefit of using ocular therapeutics in the setting of bandage contact lens use for corneal epithelial defects. PMID:25090165

  15. Dexamethasone suppresses the locomotor response of neonatal rats to novel environment.

    PubMed

    Menshanov, Petr N; Bannova, Anita V; Dygalo, Nikolay N

    2014-09-01

    Locomotion of animals in the novel environment is determined by two main factors-the intrinsic motor activity and the specific locomotor response to novelty. Glucocorticoids alter neurobehavioral development of mammals and its locomotor manifestations. However, it remains unclear whether the intrinsic and/or the novelty-induced activity are affected by glucocorticoids during early life. Here, the principal component analysis was used to determine the main factors that underlie alterations in locomotion of rat pups treated with dexamethasone. It was shown that neonatal rats exhibited an enhanced locomotion in the novel environment beginning from postnatal day (PD) 5. We found for the first time that this reaction was significantly suppressed by dexamethasone. The effect was specific to the novelty-induced component of behavior, while the intrinsic locomotor activity was not affected by glucocorticoid treatment. The suppression of the behavioral response to novelty was maximal at PD7 and vanquished at PD10-11. In parallel with the hormonal effect on the behavior, dexamethasone upregulated the main cell death executor-active caspase-3 in the prefrontal cortex of 7-day old rats. Thus, dexamethasone-induced alterations in the novelty-related behavior may be the earliest visible signs of the brain damage that could lead to forthcoming depressive state or schizophrenia, emerging as a result of neonatal stress or glucocorticoid treatment.

  16. Improved Cryptosporidium parvum oocysts propagation using dexamethasone suppressed CF-1 mice

    EPA Science Inventory

    This study evaluates Cryptosporidium parvum oocyst production in dexamethasone suppressed CF-1 and C57BL/6 mice. Both models can yield 1 x 109 total oocysts over a 20 day production period; however, only 20 CF-1 mice are required to reliably achieve this goal compared...

  17. Analgesic Effect of Dexamethasone after Arthroscopic Knee Surgery: A Randomized Controlled Trial

    PubMed Central

    García, Maria; Caicedo, Maria

    2016-01-01

    Background. Dexamethasone is sometimes used as a coanalgesic because of its anti-inflammatory properties. Objective. To evaluate opioid use, postoperative pain intensity, and side effects after a single dose of dexamethasone in patients undergoing arthroscopic knee surgery. Methods. In this randomized controlled study patients were randomized to receive either 10 mg of intravenous dexamethasone (DM group) or 0.9% normal saline (NS group) during the intraoperative period. Primary outcomes were pain intensity and total morphine and codeine use after surgery. Results. Seventy-eight patients were included in the study. The DM group showed statistically significant higher pain intensity at the fourth postoperative hour (DM: 3.96/10, standard deviation [SD] 0.54; NS: 2.46/10, SD 0.45; p = 0.036). No statistically significant difference in total opioid use (morphine plus codeine) was identified with 15.9 (SD 1.97) codeine tablets used in DM group and 20 (SD 2.14) in NS group (p = 0.25). Discussion. Pain intensity tended to decrease in both groups suggesting morphine as the main source of analgesia. Conclusions. Intravenous dexamethasone during the intraoperative period has no clinical impact on postoperative pain intensity during the first 48 h after arthroscopic knee surgery. This trial is registered with R000020892. PMID:27795670

  18. Endotoxin-induced prostaglandin (PGF2 alpha) biosynthesis, fever and miosis in dexamethasone-treated goats.

    PubMed

    Jónasson, H; Augustinsson, O; Kindahl, H

    1987-10-01

    Prostaglandin-releasing, adrenocortical, febrile and miotic responses to endotoxin (ET) (E. coli lipopolysaccharide; 0.25 microgram kg-1) were studied in goats with and without prolonged dexamethasone influence. The i.v. injection of ET induced a three-fold peak elevation in plasma 15-ketodihydro-PGF2 alpha at 1.5 h post-injection, that is, between the first and second phase of the temperature elevation. During the latter phase, the plasma concentration of this primary PGF 2 alpha metabolite gradually returned to basal level, which implies that the second phase of ET fever is not PG dependent. The PG response exhibited a similar pattern, but was less pronounced in the dexamethasone-ET experiments, where the duration of maximum temperature elevation and of the miosis became shortened by about 20 min, and the typical biphasic pattern of ET fever was no longer seen. The ET-induced rise in plasma aldosterone concentration was completely blocked by dexamethasone. The corresponding rise in plasma cortisol concentration was prevented for 2 h, but was later only partially inhibited in spite of the repeated dexamethasone treatment. PMID:3314353

  19. Concurrent delivery of dexamethasone and VEGF for localized inflammation control and angiogenesis.

    PubMed

    Patil, Siddhesh D; Papadmitrakopoulos, Fotios; Burgess, Diane J

    2007-01-22

    Localized elution of corticosteroids has been used in suppressing inflammation and fibrosis associated with implantation and continuous in vivo residence of bio-medical devices. However, these agents also inhibit endogenous growth factors preventing angiogenesis at the local tissue, interface thereby delaying the healing process and negatively impacting device performance. In this work, a combination of dexamethasone and vascular endothelial growth factor (VEGF) was investigated for concurrent localized delivery using PLGA microsphere/PVA hydrogel composites. Pharmacodynamic effects were evaluated by histopathological examination of subcutaneous tissue surrounding implanted composites using a rat model. The hydrogel composites were capable of simultaneously releasing VEGF and dexamethasone with approximately zero order kinetics. Composites were successful in controlling the implant/tissue interface by suppressing inflammation and fibrosis as well as facilitating neo-angiogenesis at a fraction of their typical oral or i.v. bolus doses. Implants containing VEGF showed a significantly higher number of mature blood vessels at the end of the 4 week study irrespective of the presence of dexamethasone. Thus, localized concurrent elution of VEGF and dexamethasone can overcome the anti-angiogenic effects of the corticosteroid and can be used to engineer inflammation-free and well-vascularized tissue in the vicinity of the implant. These PLGA microsphere/PVA hydrogel composites show promise as coatings for implantable bio-medical devices to improve biocompatibility and ensure in vivo performance.

  20. Comparative Study of Proton Pump Inhibitors on Dexamethasone Plus Pylorus Ligation Induced Ulcer Model in Rats

    PubMed Central

    Thippeswamy, A. H. M.; Sajjan, M.; Palkar, M. B.; Koti, B. C.; Viswanathaswamy, A. H. M.

    2010-01-01

    The present study was designed to compare ulcer protective effect of proton pump inhibitors viz. omeprazole, rabeprazole and lansoprazole against dexamethasone plus pylorus ligation induced ulcer model. Dexamethasone (5 mg/kg) was used as an ulcerogen. Dexamethasone suspended in 1% CMC in water was given orally to all the rats 15 min after the pylorus ligation. Omeprazole (20 mg/kg), rabeprazole (20 mg/kg), and lansoprazole (20 mg/kg) were administered by oral route 30 min prior to ligation was used for ulcer protective studies, gastric secretion and mucosal studies. Effects of proton pump inhibitors were determined by the evaluation of various biochemical parameters such as ulcer index, free and total acidity, gastric pH, mucin, pepsin and total proteins. Oral administration of proton pump inhibitors showed significant reduction in gastric acid secretion and ulcer protective activity against dexamethasone plus pylorus ligation induced ulcer model. The % protection of omeprazole, rabeprazole and lansoprazole was 84.04, 89.36 and 79.78, respectively. Rabeprazole significantly inhibited the acid-pepsin secretion and increased the gastric mucin secretion. The observations made in the present study suggest that rabeprazole is the most effective gastric antisecretory and ulcer healing agent as compared to omeprazole and lansoprazole. PMID:21188049

  1. Dexamethasone effects on ritodrine-induced changes in myometrial contractility and beta-adrenergic receptor function.

    PubMed

    Ward, S M; Caritis, S N; Chiao, J P; Moore, J J

    1988-12-01

    We have previously demonstrated in pregnant sheep that ritodrine infusion for 24 hours reduces myometrial beta-adrenergic receptor density and isoproterenol-stimulated adenylate cyclase activity. These receptor-associated changes were accompanied by an increasing inability of ritodrine to inhibit uterine contractility induced by a bolus of oxytocin. In the present study, we evaluated whether these ritodrine-induced effects could be altered by dexamethasone. Ten pregnant sheep at gestational ages of 92 to 130 days received ritodrine 2 micrograms/kg/min for 24 hours. Five animals also received dexamethasone 10 mg intravascularly twice during the ritodrine infusion. Before and at 4 and 24 hours of ritodrine infusion, the animals were given an identical dose of oxytocin as a bolus, and the area under the uterine pressure-time curve was quantified. Myometrial biopsy specimens were obtained before and after ritodrine infusion. Dexamethasone treatment prevented ritodrine-induced reductions in beta-adrenergic receptor density and isoproterenol-stimulated adenylate cyclase activity. Despite these receptor-associated effects, dexamethasone did not prevent the loss of tocolytic efficacy associated with prolonged ritodrine infusion.

  2. [Extraction, Purification and Identification of a Dexamethasone-degrading Enzymes Generated by Pseudomonas Alcaligenes].

    PubMed

    Zhu, Lili; Yang, Zhibang; Yang, Qian; Shi, Zhongquan; Deng, Xichuan

    2015-10-01

    In this research a strain of isolated Pseudomonas alcaligenes which causes degradation of dexamethasone was acclimated further and its proteins of every position in the bacterium were separated by the osmotic shock method. The separated intracellular proteins which had the highest enzyme activity were extracted by the salting out with ammonium sulfate and were purified with the cation exchange chromatography and gel chromatography. The purified proteins which was active to cause degradation of dexamethasone had been detected were cut with enzyme and were analyzed with mass spectrometry. The results showed that the degradation rate to dexamethasone by acclimated Pseudomonas alcaligenes were increased from 23.63% to 52.84%. The degrading enzymes were located mainly in the intracellular of the bacteria and its molecular weight was about 41 kD. The specific activity of the purified degrading enzymes were achieved to 1.02 U x mg(-1). Its 5-peptide amino acid sequences were consistent with some sequences of the isovaleryl-CoA dehydrogenase. The protein enzyme may be a new kind degrading enzyme of steroidal compounds. Our experimental results provided new strategies for cleanup of dexamethasone in water environment with microbial bioremediation technique.

  3. Silibinin, dexamethasone, and doxycycline as potential therapeutic agents for treating vesicant-inflicted ocular injuries

    SciTech Connect

    Tewari-Singh, Neera; Jain, Anil K.; Inturi, Swetha; Ammar, David A.; Agarwal, Chapla; Tyagi, Puneet; Kompella, Uday B.; Enzenauer, Robert W.; Petrash, J. Mark; Agarwal, Rajesh

    2012-10-01

    There are no effective and approved therapies against devastating ocular injuries caused by vesicating chemical agents sulfur mustard (SM) and nitrogen mustard (NM). Herein, studies were carried out in rabbit corneal cultures to establish relevant ocular injury biomarkers with NM for screening potential efficacious agents in laboratory settings. NM (100 nmol) exposure of the corneas for 2 h (cultured for 24 h), showed increases in epithelial thickness, ulceration, apoptotic cell death, epithelial detachment microbullae formation, and the levels of VEGF, cyclooxygenase-2 (COX-2) and matrix metalloproteinase-9 (MMP-9). Employing these biomarkers, efficacy studies were performed with agent treatments 2 h and every 4 h thereafter, for 24 h following NM exposure. Three agents were evaluated, including prescription drugs dexamethasone (0.1%; anti-inflammatory steroid) and doxycycline (100 nmol; antibiotic and MMP inhibitor) that have been studied earlier for treating vesicant-induced eye injuries. We also examined silibinin (100 μg), a non-toxic natural flavanone found to be effective in treating SM analog-induced skin injuries in our earlier studies. Treatments of doxycycline + dexamethasone, and silibinin were more effective than doxycycline or dexamethasone alone in reversing NM-induced epithelial thickening, microbullae formation, apoptotic cell death, and MMP-9 elevation. However, dexamethasone and silibinin alone were more effective in reversing NM-induced VEGF levels. Doxycycline, dexamethasone and silibinin were all effective in reversing NM-induced COX-2 levels. Apart from therapeutic efficacy of doxycycline and dexamethasone, these results show strong multifunctional efficacy of silibinin in reversing NM-induced ocular injuries, which could help develop effective and safe therapeutics against ocular injuries by vesicants. -- Highlights: ► Established injury biomarkers in rabbit corneal culture with nitrogen mustard (NM) ► This NM model is a cost effective

  4. β-Hydroxy-β-Methylbutyrate (HMB) Normalizes Dexamethasone-Induced Autophagy-Lysosomal Pathway in Skeletal Muscle

    PubMed Central

    Girón, María D.; Vílchez, Jose D.; Shreeram, Sathyavageeswaran; Salto, Rafael; Manzano, Manuel; Cabrera, Elena; Campos, Nefertiti; Edens, Neile K.; Rueda, Ricardo; López-Pedrosa, Jose M.

    2015-01-01

    Dexamethasone-induced muscle atrophy is due to an increase in protein breakdown and a decrease in protein synthesis, associated with an over-stimulation of the autophagy-lysosomal pathway. These effects are mediated by alterations in IGF-1 and PI3K/Akt signaling. In this study, we have investigated the effects of β-Hydroxy-β-methylbutyrate (HMB) on the regulation of autophagy and proteosomal systems. Rats were treated during 21 days with dexamethasone as a model of muscle atrophy. Co-administration of HMB attenuated the effects promoted by dexamethasone. HMB ameliorated the loss in body weight, lean mass and the reduction of the muscle fiber cross-sectional area (shrinkage) in gastrocnemius muscle. Consequently, HMB produced an improvement in muscle strength in the dexamethasone-treated rats. To elucidate the molecular mechanisms responsible for these effects, rat L6 myotubes were used. In these cells, HMB significantly attenuated lysosomal proteolysis induced by dexamethasone by normalizing the changes observed in autophagosome formation, LC3 II, p62 and Bnip3 expression after dexamethasone treatment. HMB effects were mediated by an increase in FoxO3a phosphorylation and concomitant decrease in FoxO transcriptional activity. The HMB effect was due to the restoration of Akt signaling diminished by dexamethasone treatment. Moreover, HMB was also involved in the regulation of the activity of ubiquitin and expression of MurF1 and Atrogin-1, components of the proteasome system that are activated or up-regulated by dexamethasone. In conclusion, in vivo and in vitro studies suggest that HMB exerts protective effects against dexamethasone-induced muscle atrophy by normalizing the Akt/FoxO axis that controls autophagy and ubiquitin proteolysis. PMID:25658432

  5. Association between Postnatal Dexamethasone for Treatment of Bronchopulmonary Dysplasia and Brain Volumes at Adolescence in Infants Born Very Preterm

    PubMed Central

    Cheong, Jeanie L.Y.; Burnett, Alice C.; Lee, Katherine J.; Roberts, Gehan; Thompson, Deanne K.; Wood, Stephen J.; Connelly, Alan; Anderson, Peter J.; Doyle, Lex W.

    2014-01-01

    Objectives To compare brain volumes in adolescents who were born extremely preterm (<28 weeks gestation) who had received postnatal dexamethasone, and to determine if there was a postnatal dexamethasone dose–response effect on brain volumes. Study design Geographical cohort study of extremely preterm adolescents born in 1991-1992 in Victoria, Australia. T1-weighted magnetic resonance imaging was performed at 18 years of age. Segmented and parcellated brain volumes were calculated using an automated segmentation method (FreeSurfer) and compared between groups, with and without adjustment for potential confounders. The relationships between total postnatal dexamethasone dose and brain volumes were explored using linear regression. Results Of the 148 extremely preterm participants, 55 (37%) had received postnatal dexamethasone, with a cumulative mean dose of 7.7 mg/kg. Compared with participants who did not receive postnatal dexamethasone, those who did had smaller total brain tissue volumes (mean difference −3.6%, 95% CI [−7.0%, −0.3%], P value = .04) and smaller white matter, thalami, and basal ganglia volumes (all P < .05). There was a trend of smaller total brain and white matter volumes with increasing dose of postnatal dexamethasone (regression coefficient −7.7 [95% CI −16.2, 0.8] and −3.2 [−6.6, 0.2], respectively). Conclusions Extremely preterm adolescents who received postnatal dexamethasone in the newborn period had smaller total brain tissue volumes than those who did not receive postnatal dexamethasone, particularly white matter, thalami, and basal ganglia. Vulnerability of brain tissues or structures associated with postnatal dexamethasone varies by structure and persists into adolescence. PMID:24332820

  6. β-Hydroxy-β-methylbutyrate (HMB) normalizes dexamethasone-induced autophagy-lysosomal pathway in skeletal muscle.

    PubMed

    Girón, María D; Vílchez, Jose D; Shreeram, Sathyavageeswaran; Salto, Rafael; Manzano, Manuel; Cabrera, Elena; Campos, Nefertiti; Edens, Neile K; Rueda, Ricardo; López-Pedrosa, Jose M

    2015-01-01

    Dexamethasone-induced muscle atrophy is due to an increase in protein breakdown and a decrease in protein synthesis, associated with an over-stimulation of the autophagy-lysosomal pathway. These effects are mediated by alterations in IGF-1 and PI3K/Akt signaling. In this study, we have investigated the effects of β-Hydroxy-β-methylbutyrate (HMB) on the regulation of autophagy and proteosomal systems. Rats were treated during 21 days with dexamethasone as a model of muscle atrophy. Co-administration of HMB attenuated the effects promoted by dexamethasone. HMB ameliorated the loss in body weight, lean mass and the reduction of the muscle fiber cross-sectional area (shrinkage) in gastrocnemius muscle. Consequently, HMB produced an improvement in muscle strength in the dexamethasone-treated rats. To elucidate the molecular mechanisms responsible for these effects, rat L6 myotubes were used. In these cells, HMB significantly attenuated lysosomal proteolysis induced by dexamethasone by normalizing the changes observed in autophagosome formation, LC3 II, p62 and Bnip3 expression after dexamethasone treatment. HMB effects were mediated by an increase in FoxO3a phosphorylation and concomitant decrease in FoxO transcriptional activity. The HMB effect was due to the restoration of Akt signaling diminished by dexamethasone treatment. Moreover, HMB was also involved in the regulation of the activity of ubiquitin and expression of MurF1 and Atrogin-1, components of the proteasome system that are activated or up-regulated by dexamethasone. In conclusion, in vivo and in vitro studies suggest that HMB exerts protective effects against dexamethasone-induced muscle atrophy by normalizing the Akt/FoxO axis that controls autophagy and ubiquitin proteolysis.

  7. Topical application of the adenosine A2A receptor agonist CGS-21680 prevents phorbol-induced epidermal hyperplasia and inflammation in mice.

    PubMed

    Arasa, Jorge; Martos, Patricio; Terencio, María Carmen; Valcuende-Cavero, Francisca; Montesinos, María Carmen

    2014-08-01

    The nucleoside adenosine is a known regulator of immunity and inflammation that mediates, at least in part, the anti-inflammatory effect of methotrexate, an immunosuppressive agent widely used to treat autoimmune inflammatory diseases. Adenosine A2A receptors play a key role in the inhibition of the inflammatory process besides promoting wound healing. Therefore, we aimed to determine the topical effect of a selective agonist, CGS-21680, on a murine model of skin hyperplasia with a marked inflammatory component. Pretreatment with either CGS-21680 (5 μg per site) or the reference agent dexamethasone (200 μg/site) prevented the epidermal hyperplasia and inflammatory response induced by topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA, 2 nmol/site) for three consecutive days. The histological analysis showed that both CGS-21680 and dexamethasone produced a marked reduction of inflammatory cell infiltrate, which correlated with diminished myeloperoxidase (MPO) activity in skin homogenates. Both treatments reduced the levels of the chemotactic mediators LTB4 and CXCL-1, and the inflammatory cytokine TNF-α, through the suppression of NFκB phosphorylation. The immunohistochemical analysis of the hyperproliferative markers cytokeratin 6 (CK6) and Ki67 revealed that while both agents inhibit the number of proliferating cells in the epidermis, CGS-21680 treatment promoted dermal fibroblasts proliferation. Consistently, increased collagen deposition in dermis was observed in tissue sections from agonist-treated mice. Our results showed that CGS 21680 efficiently prevents phorbol-induced epidermal hyperplasia and inflammation in mice without the deleterious atrophic effect of topical corticosteroids. PMID:24889129

  8. Fat feeding potentiates the diabetogenic effect of dexamethasone in Wistar rats

    PubMed Central

    Sivabalan, Shanmugam; Renuka, Shanmugam; Menon, Venugopal P

    2008-01-01

    Background The role of cortisol and its increased action/availability is implicated in the pathogenesis of insulin resistance associated with obesity and metabolic syndrome but the mechanism of increased action/availability is not known. Availability of several other lipophilic hormones, drugs and pollutants are also reported to be increased in obesity. Increased lipids in the circulation are reported to alter the fluidity and permeability of membranes. Hyperlipidemia is also reported to alter the pharmacokinetics and pharmacodynamics of lipophilic molecules and also membrane fluidity and permeability. In this context we assumed that the hyperlipidemia associated with human obesity might play a role in the altered action/availability of cortisol and this in turn might have initiated the metabolic complications. To evaluate our assumption we have administered dexamethasone [low [50 μg/kg/day] or high [250 μg/kg/day] dose] to high-fat [coconut oil & vanaspati] fed rats and the results were compared with rats administered with either dexamethasone or high-fat. Results and Discussion Within two weeks, the rats co-administered with high-fat and dexamethasone developed severe hyperglycemia, hyperlipidemia and insulin resistance compared to rats treated either of them alone. High-fat fed rats treated with higher dose of dexamethasone were presented with severe hyperglycemia, insulin resistance and also severe glycosuria. The hyperlipidemia caused by high-fat feeding might have altered the transport and distribution of dexamethasone, probably by altering the physical state of membranes and transport proteins. Conclusion From the results obtained, it can be speculated that the altered lipid and cortisol metabolism could affect one another, forming a vicious cycle. PMID:18500989

  9. Proteomics of endometrial fluid after dexamethasone treatment in mares susceptible to endometritis.

    PubMed

    Arlas, T R; Wolf, C A; Petrucci, B P L; Estanislau, J F; Gregory, R M; Jobim, M I M; Mattos, R C

    2015-09-01

    Corticotherapy is a common treatment in mares susceptible to endometritis. Isoflupredone improves pregnancy rates and affects the protein profile of endometrial fluid in comparison to untreated mares. Dexamethasone decreases postbreeding fluid accumulation and uterine edema; however, its effects on the protein profile of the endometrial fluid have not yet been studied. The aim of the present study was to verify the effect of dexamethasone on the protein profile of endometrial fluid, in the presence or absence of infection, from mares susceptible to persistent postbreeding endometritis. Nine susceptible mares aged between 7 and 18 years were used. After checking for signs of estrus, mares were subjected to four treatments: C: mares received no treatment and served as control; D: mares received 40-mg dexamethasone at breeding, with collection of samples after 6 hours; I-6 and I-24: intrauterine infusion of 1 × 10(9)Streptococcus zooepidemicus/mL and samples collected after 6 and 24 hours; I/D-6 and I/D-24: intrauterine infusion of 1 × 10(9)S zooepidemicus/mL and 40-mg dexamethasone, collecting the sample after 6 and 24 hours. All mares were subjected to all treatments. Samples were collected and subjected to two-dimensional electrophoresis and mass spectrometry for the identification of relevant protein spots. Corticotherapy altered the protein profile of the endometrial fluid of susceptible mares, characterized by an increase and/or decrease in the optical density of inflammatory acute-phase proteins. We conclude that the use of dexamethasone in mares with and without infection alters the protein profile of endometrial fluid of susceptible mares. PMID:25998273

  10. Protective effects of dexamethasone on early acute lung injury induced by oleic acid in rats

    PubMed Central

    Huang, Bin; Wang, Dao-Xin; Deng, Wang

    2014-01-01

    Objective: Whether alveolar edema could be cleared by alveolar epithelial is a key to the treatment and prognosis of ALI (acute lung injury). In this study, oleic acid(OA)-induced ALI model was established, the expression of α1 Na+/K+-ATPase (NKA) and β1 Na+/K+-ATPase were performed in vivo to investigate the mechanism of alveolar fluid clearance (AFC) in ALI and the effect of early low doses of dexamethasone on alveolar fluid clearance. Methods: In this study, Male rats were challenged by OA with or without dexamethasone (1 mg/kg, iv) post-treatment. Lung histopathology, blood gas, pulmonary vascular permeability, BALF IL-6, MPO and NKA activity of lung were examined. α1NKA and β1NKA mRNA and protein expression were detected. Results: The results indicated that compared with sham operated group, NKA activity, mRNA and protein expression of α1NKA and β1NKA were decreased in OA treated group, while wet/dry ratio, lung index, IL-6, and MPO activity were increased significantly. Pulmonary edema was obviously seen under light microscope. Those indexes were improved in dexamethasone treated group compared to OA treated group. Conclusion: The expression of NKA to decline for the lung injury is one important mechanism of pulmonary edema. Early low dose of dexamethasone treatment could suppress the expression of inflammatory mediators, improved lung epithelial-endothelial barrier permeability, increased the expressions of α1 NKA and β1 NKA mRNA, α1 NKA and β1 NKA protein level, stimulated NKA activity and decreased pulmonary edema. In conclusion, these observations suggest that early low dose of dexamethasone treatment has a protective effect on OA induced ALI. PMID:25663967

  11. Addition of Dexamethasone and Buprenorphine to Bupivacaine Sciatic Nerve Block: A Randomized, Controlled Trial

    PubMed Central

    YaDeau, Jacques T.; Paroli, Leonardo; Fields, Kara G.; Kahn, Richard L.; LaSala, Vincent R.; Jules-Elysee, Kethy M.; Kim, David H.; Haskins, Stephen C.; Hedden, Jacob; Goon, Amanda; Roberts, Matthew M.; Levine, David S.

    2015-01-01

    Background and Objectives Sciatic nerve block provides analgesia after foot and ankle surgery, but block duration may be insufficient. We hypothesized that perineural dexamethasone and buprenorphine would reduce pain scores at 24 hours. Methods Ninety patients received ultrasound-guided sciatic (25 mL 0.25% bupivacaine) and adductor canal (10 mL 0.25% bupivacaine) blockade, with random assignment into 3 groups (30 patients per group): control blocks + intravenous dexamethasone (4 mg) (control); control blocks + intravenous buprenorphine (150 mcg) + intravenous dexamethasone (intravenous buprenorphine); nerve blocks containing buprenorphine + dexamethasone (perineural). Patients received mepivacaine neuraxial anesthesia and postoperative oxycodone / acetaminophen, meloxicam, pregabalin, and ondansetron. Patients and assessors were blinded to group assignment. The primary outcome was pain with movement at 24 hours. Results There was no difference in pain with movement at 24 hours (median score 0). However, the perineural group had longer block duration vs control (45.6 vs 30.0 hr). Perineural patients had lower scores for “worst pain” vs control (median 0 vs 2). Both intravenous buprenorphine and perineural groups were less likely to use opioids on the day after surgery, vs control (28.6%, 28.6%, 60.7%, respectively). Nausea after intravenous buprenorphine (but not perineural buprenorphine) was severe, frequent, and bothersome. Conclusions Pain scores were very low at 24 hours after surgery in the context of multimodal analgesia and were not improved by additives. However, perineural buprenorphine and dexamethasone prolonged block duration, reduced the worst pain experienced, and reduced opioid use. Intravenous buprenorphine caused troubling nausea and vomiting. Future research is needed to confirm and extend these observations. PMID:25974277

  12. The prophylactic effect of dexamethasone on postoperative sore throat in prone position surgery

    PubMed Central

    Lee, Sang Ho; Lee, Yoon Chan; Choi, So Ron; Lee, Seung-Cheol; Lee, Jong Hwan; Chung, Chan Jong

    2016-01-01

    Background Sore throat and hoarseness are common complications after general anesthesia with tracheal intubation. The position for patients can affect the incidence of postoperative sore throat (POST) by causing displacement of the endotracheal tube. This study investigated the prophylactic effect of dexamethasone in prone position surgeries. Methods One hundred-fifty patients undergoing lumbar spine surgery (18-75 yr) were randomly allocated into the normal saline group (group P, n = 50), dexamethasone 0.1 mg/kg group (group D1, n = 50) or dexamethasone 0.2 mg/kg group (group D2, n = 50). The incidence and severity of POST, hoarseness, and cough were measured using direct interview at 1, 6, and 24 h after tracheal extubation. The severity of POST, hoarseness, and cough were graded using a 4-point scale. Results At 1, 6, and 24 h after extubation, the incidence of sore throat was significantly lower in group D1 (1 h; P = 0.015, 6 h; P < 0.001, 24 h; P = 0.038) and group D2 (1 h; P < 0.001, 6 h; P < 0.001, 24 h; P = 0.017) compared to group P. There were less number of patients in the groups D1 and D2 than group P suffering from moderate grade of POST at 1, 24 h after extubation. The incidence of hoarseness at 1, 6, and 24 h after extubation was significantly lower in groups D2 than group P (P < 0.001). There were no significant differences in the incidence of cough among the three groups. Conclusions The prophylactic use of dexamethasone 0.1 mg/kg and 0.2 mg/kg in prone surgery reduces the incidence of postoperative sore throat and dexamethasone 0.2 mg/kg decreases the incidence of hoarseness. PMID:27274371

  13. Montelukast versus Dexamethasone Treatment in a Guinea Pig Model of Chronic Pulmonary Neutrophilic Inflammation.

    PubMed

    Abdel Kawy, Hala S

    2016-08-01

    Airway inflammation in chronic obstructive pulmonary disease (COPD) is refractory to corticosteroids and hence COPD treatment is hindered and insufficient. This study assessed the effects of oral treatment with Montelukast (10 and 30 mg/kg) or dexamethasone (20 mg/kg) for 20 days on COPD model induced by chronic exposure to lipopolysaccharide (LPS). Six groups of male guinea pigs were studied. Group 1: naïve group, group 2: exposed to saline nebulization. Groups 3, 4, 5, and 6: exposed to 9 nebulizations of LPS (30 μg/ml) for 1 hour, 48 hours apart with or without treatment with Montelukast or dexamethasone. Airway hyperreactivity (AHR) to methacholine (MCh), histopathological study and bronchoalveolar lavage fluid (BALF) as well as lung tissue analyses were performed 48 hours after the final exposure to LPS (day 20). LPS-induced pulmonary dysfunction was associated with increased neutrophil count, leukotriene (LT) B4, and tumor necrosis factor (TNF)-α in BALF. Moreover, there was an increase in malondialdehyde (MDA) level and a decrease in histone deacetylases(HDAC) activity in the lung tissue. Both Montelukast (10 or 30 mg /kg) and dexamethasone significantly reduced neutrophil count in BALF and inflammatory cells in lung parenchyma as well as TNF-α, and MDA levels. However, dexamethasone was more effective (p < 0.05). Montelukast, at a dose of 30 mg /kg, significantly reduced specific airway resistance after the 9th LPS exposure, attenuated AHR to MCh, decreased LTB4 and increased HDAC activity in comparison to dexamethasone. These results suggest that treatment with Montelukast can be useful in chronic airway inflammatory diseases including COPD poorly responsive to glucocorticoids. PMID:26751767

  14. Adrenal enlargement and failure of suppression of circulating cortisol by dexamethasone in patients with malignancy.

    PubMed

    Jenkins, P J; Sohaib, S A; Trainer, P J; Lister, T A; Besser, G M; Reznek, R

    1999-08-01

    The aim of this study was to further elucidate the activity of the hypothalamo-pituitary-adrenal (HPA) axis in patients with malignancy and to correlate this with the size of the adrenal glands. Fourteen patients with a variety of malignancies were studied prior to receiving cytotoxic chemotherapy. During routine staging computerized tomographic (CT) scans, the size of the body, medial and lateral limbs of the adrenal glands were measured and compared with those of a normal group of patients studied previously. Measurements of 09:00 h serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels were made before and after the administration of dexamethasone (0.5 mg 6-hourly for 48 h) in addition to the peak cortisol response to i.v corticotropin releasing hormone (CRH). Overall, patients with malignancy had significantly larger adrenal glands than patients without malignancy; those with non-haematological malignancies had larger glands than patients with haematological malignancies. Following dexamethasone to suppress circulating cortisol levels, nine patients (64%) demonstrated abnormal resistance with cortisol levels > 50 nmol l(-1): mean value 294 nmol l(-1) (range 67-1147). Those patients who failed to suppress after dexamethasone had significantly larger adrenal glands than those that did suppress and tended to have non-haematological malignancies. ACTH levels were undetectable or low in three patients in whom it was measured and who did not suppress with dexamethasone. Following CRH, the cortisol levels were highest (823 and 853 nmol l(-1)) in two of these patients. Malignancy is associated with diffuse enlargement of the adrenal glands and resistance to dexamethasone-induced suppression of the HPA axis, which is not due to ectopic ACTH secretion. This disturbance of the normal control of the HPA axis is unexplained and its functional significance remains uncertain.

  15. Lipocortin 1 mediates dexamethasone-induced growth arrest of the A549 lung adenocarcinoma cell line.

    PubMed Central

    Croxtall, J D; Flower, R J

    1992-01-01

    The synthetic glucocorticoid dexamethasone (1 microM to 1 pM) strongly (maximum greater than 80%) inhibits proliferation of the A549 human lung adenocarcinoma line (EC50 greater than 1 nM) and leads to the appearance, or a further increase (approximately 3-fold) in the expression on the cell surface, of the calcium and phospholipid binding protein lipocortin (annexin) 1. Both these effects, which are shared by hydrocortisone (1 microM) but not by progesterone or aldosterone (1 microM), are inhibited by the antiglucocorticoids RU38486 and RU43044 (1 microM). The nonsteroidal antiinflammatory drugs indomethacin (1 microM) and naproxen (10 microM) and human recombinant lipocortin 1 (0.05-5.0 micrograms/ml) also produce growth arrest in this cell line. During proliferation A549 cells spontaneously release prostaglandin E2 [10-20 ng (28-57 pmol) per ml per 5-day period] into the growth medium. In concentrations that cause growth-arrest, dexamethasone, indomethacin, and lipocortin 1 abolish the generation of this eicosanoid by A549 cells. Prostaglandin E2 itself (0.01-1 pM) stimulates cell growth and partially reverses (approximately 50%) the inhibition of growth caused by dexamethasone and indomethacin. Addition of the neutralizing anti-lipocortin 1 monoclonal antibody 1A (5 micrograms/ml), but not the nonneutralizing anti-lipocortin monoclonal antibody 1B, substantially reversed (greater than 80%) the inhibitory activity of dexamethasone on both growth and prostaglandin E2 synthesis. The generation of prostaglandin E2 by A549 cells seems to be an important regulator of cell proliferation in vitro and the dexamethasone-induced suppression of proliferation in this model is attributable to eicosanoid inhibition caused by lipocortin 1. Images PMID:1533045

  16. Effects of trophic exposure to dexamethasone and diclofenac in freshwater fish.

    PubMed

    Guiloski, Izonete Cristina; Ribas, João Luiz Coelho; Pereira, Letícia da Silva; Neves, Ana Paula Perbiche; Silva de Assis, Helena Cristina

    2015-04-01

    Steroidal and non-steroidalanti-inflammatories are pharmaceutical prescribed in human medicine and have the potential to contaminate water and sediments via inputs from sewage treatment plants. Their impacts on humans and ecosystems are emerging issues in environmental health. The aim of the present work was to evaluate the effects of diclofenac and dexamethasone in male fish Hoplias malabaricus after trophic exposure. Fish were fed twice every week with Astyanax sp. submitted to intraperitoneal inoculation with diclofenac (0; 0.2; 2.0 or 20.0 μg/kg) or dexamethasone (0; 0.03; 0.3 or 3.0 μg/kg). After 12 doses, blood was collected for testosterone dosage. The gonad and liver were collected to calculate gonadosomatic (GSI) and hepatosomatic index (HSI). Antioxidants enzymes activity and biotransformation were also evaluated in liver and gonads. In liver, diclofenac caused oxidative stress with increased superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities and lipoperoxidation (LPO). The GST activity was reduced by diclofenac in liver. Trophic exposure of H. malabaricus to dexamethasone caused an increase in antioxidant system (GPx, CAT, GST, and GSH) and LPO in liver. However, it reduced antioxidant system (GPX and GST activities and GSH) in gonads. Both diclofenac and dexamethasone reduced the levels of testosterone, causing impairment to reproduction. Diclofenac reduced HSI at the 0.2 μg/kg, but not GSI. Our results suggest that the anti-inflammatory drugs diclofenac and dexamethasone caused oxidative stress and reduced testosterone levels that can have a negative impact in aquatic organisms.

  17. [Thyroxine caused modulation of dexamethasone effects on the skeletal muscle of white rats].

    PubMed

    Trush, V V; Soboliev, V I

    2014-01-01

    Experiments in situ on mature white female rats performed with the use of electrophysiological methods allowed to investigate the modulatory influence of thyroxin at the dose which does not cause the signs of hyperthyroidism (10 mkg/ kg), upon the manifestation of the dexamethasone effects on the functional state of the anterior tibial muscle. It has been established that the chronic isolated application of dexamethasone was accompanied by reduction of the amplitude ofmuscle contraction (by 29.7-59.3 per cent after 10-50 days of the drug injection) and the weight of anterior tibial muscle (by 22.4-12.7 per cent after 10-60 days of the drug injection). Combination of thyroxin with dexamethasone smoothed the negative effects of the synthetic glucocorticoid upon the muscle contraction amplitude and even caused its increase (by 41.2-62.1 per cent after 20-60 days of injection of the pair of preparations), as well as prevented the reduction of the muscle weight. The isolated application ofdexamethasone after the first 20 days of injections caused the decrease of the muscle speed that was confirmed through a lengthened control of the muscle active state duration (by 20.5 per cent) and the reduction of its single contraction development speed (by 45.3 per cent), as well as the decrease of frequency of muscle tetanization (to 12-20 imp/s against 26-28 imp/s in control). The application of thyroxine with dexamethasone shortened the active state of the muscle (by 19.3 per cent) and increased the speed of single contraction development (by 72.4), which remained throughout whole further period the preparations were injected. These observations favor for improvement of high-speed characteristics of the muscle under the influence of thyroxine. At the same time, during chronic injection of dexamethasone either alone or in combination with thyroxin, an increased muscle fatigue during the first 10-20 days has been observed.

  18. Differential effects of rapamycin and dexamethasone in mouse models of established allergic asthma.

    PubMed

    Mushaben, Elizabeth M; Brandt, Eric B; Hershey, Gurjit K Khurana; Le Cras, Timothy D

    2013-01-01

    The mammalian target of rapamycin (mTOR) plays an important role in cell growth/differentiation, integrating environmental cues, and regulating immune responses. Our lab previously demonstrated that inhibition of mTOR with rapamycin prevented house dust mite (HDM)-induced allergic asthma in mice. Here, we utilized two treatment protocols to investigate whether rapamycin, compared to the steroid, dexamethasone, could inhibit allergic responses during the later stages of the disease process, namely allergen re-exposure and/or during progression of chronic allergic disease. In protocol 1, BALB/c mice were sensitized to HDM (three i.p. injections) and administered two intranasal HDM exposures. After 6 weeks of rest/recovery, mice were re-exposed to HDM while being treated with rapamycin or dexamethasone. In protocol 2, mice were exposed to HDM for 3 or 6 weeks and treated with rapamycin or dexamethasone during weeks 4-6. Characteristic features of allergic asthma, including IgE, goblet cells, airway hyperreactivity (AHR), inflammatory cells, cytokines/chemokines, and T cell responses were assessed. In protocol 1, both rapamycin and dexamethasone suppressed goblet cells and total CD4(+) T cells including activated, effector, and regulatory T cells in the lung tissue, with no effect on AHR or total inflammatory cell numbers in the bronchoalveolar lavage fluid. Rapamycin also suppressed IgE, although IL-4 and eotaxin 1 levels were augmented. In protocol 2, both drugs suppressed total CD4(+) T cells, including activated, effector, and regulatory T cells and IgE levels. IL-4, eotaxin, and inflammatory cell numbers were increased after rapamycin and no effect on AHR was observed. Dexamethasone suppressed inflammatory cell numbers, especially eosinophils, but had limited effects on AHR. We conclude that while mTOR signaling is critical during the early phases of allergic asthma, its role is much more limited once disease is established.

  19. Protection against dexamethasone-induced muscle atrophy is related to modulation by testosterone of FOXO1 and PGC-1{alpha}

    SciTech Connect

    Qin, Weiping; Pan, Jiangping; Wu, Yong; Bauman, William A.; Cardozo, Christopher

    2010-12-17

    Research highlights: {yields} In rat gastrocnemius muscle, dexamethasone reduced PGC-1{alpha} cellular and nuclear levels without altering mRNA levels for this factor. {yields} Dexamethasone reduced phosphorylating of p38 MAPK, which stabilizes PGC-1{alpha} and promotes its nuclear entry. {yields} Co-administration of testosterone with dexamethasone increased cellular and nuclear levels of PGC-1{alpha} protein without changing its mRNA levels. {yields} Co-administration of testosterone restored p38 MAPK levels to those of controls. -- Abstract: Glucocorticoid-induced muscle atrophy results from muscle protein catabolism and reduced protein synthesis, associated with increased expression of two muscle-specific ubiquitin ligases (MAFbx and MuRF1), and of two inhibitors of protein synthesis, REDD1 and 4EBP1. MAFbx, MuRF1, REDD1 and 4EBP1 are up-regulated by the transcription factors FOXO1 and FOXO3A. The transcriptional co-activator PGC-1{alpha} has been shown to attenuate many forms of muscle atrophy and to repress FOXO3A-mediated transcription of atrophy-specific genes. Dexamethasone-induced muscle atrophy can be prevented by testosterone, which blocks up-regulation by dexamethasone of FOXO1. Here, an animal model of dexamethasone-induced muscle atrophy was used to further characterize effects of testosterone to abrogate adverse actions of dexamethasone on FOXO1 levels and nuclear localization, and to determine how these agents affect PGC-1{alpha}, and its upstream activators, p38 MAPK and AMPK. In rat gastrocnemius muscle, testosterone blunted the dexamethasone-mediated increase in levels of FOXO1 mRNA, and FOXO1 total and nuclear protein. Dexamethasone reduced total and nuclear PGC-1{alpha} protein levels in the gastrocnemius; co-administration of testosterone with dexamethasone increased total and nuclear PGC-1{alpha} levels above those present in untreated controls. Testosterone blocked dexamethasone-induced decreases in activity of p38 MAPK in the gastrocnemius

  20. Agonist-Directed Desensitization of the β2-Adrenergic Receptor

    PubMed Central

    Goral, Vasiliy; Jin, Yan; Sun, Haiyan; Ferrie, Ann M.; Wu, Qi; Fang, Ye

    2011-01-01

    The β2-adrenergic receptor (β2AR) agonists with reduced tachyphylaxis may offer new therapeutic agents with improved tolerance profile. However, receptor desensitization assays are often inferred at the single signaling molecule level, thus ligand-directed desensitization is poorly understood. Here we report a label-free biosensor whole cell assay with microfluidics to determine ligand-directed desensitization of the β2AR. Together with mechanistic deconvolution using small molecule inhibitors, the receptor desensitization and resensitization patterns under the short-term agonist exposure manifested the long-acting agonism of salmeterol, and differentiated the mechanisms of agonist-directed desensitization between a full agonist epinephrine and a partial agonist pindolol. This study reveals the cellular mechanisms of agonist-selective β2AR desensitization at the whole cell level. PMID:21541288

  1. Sports doping: emerging designer and therapeutic β2-agonists.

    PubMed

    Fragkaki, A G; Georgakopoulos, C; Sterk, S; Nielen, M W F

    2013-10-21

    Beta2-adrenergic agonists, or β2-agonists, are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptom-relievers and, in combination with inhaled corticosteroids, as disease-controllers. The use of β2-agonists is prohibited in sports by the World Anti-Doping Agency (WADA) due to claimed anabolic effects, and also, is prohibited as growth promoters in cattle fattening in the European Union. This paper reviews the last seven-year (2006-2012) literature concerning the development of novel β2-agonists molecules either by modifying the molecule of known β2-agonists or by introducing moieties producing indole-, adamantyl- or phenyl urea derivatives. New emerging β2-agonists molecules for future therapeutic use are also presented, intending to emphasize their potential use for doping purposes or as growth promoters in the near future.

  2. Modulation of Innate Immune Responses via Covalently Linked TLR Agonists

    PubMed Central

    2015-01-01

    We present the synthesis of novel adjuvants for vaccine development using multivalent scaffolds and bioconjugation chemistry to spatially manipulate Toll-like receptor (TLR) agonists. TLRs are primary receptors for activation of the innate immune system during vaccination. Vaccines that contain a combination of small and macromolecule TLR agonists elicit more directed immune responses and prolong responses against foreign pathogens. In addition, immune activation is enhanced upon stimulation of two distinct TLRs. Here, we synthesized combinations of TLR agonists as spatially defined tri- and di-agonists to understand how specific TLR agonist combinations contribute to the overall immune response. We covalently conjugated three TLR agonists (TLR4, 7, and 9) to a small molecule core to probe the spatial arrangement of the agonists. Treating immune cells with the linked agonists increased activation of the transcription factor NF-κB and enhanced and directed immune related cytokine production and gene expression beyond cells treated with an unconjugated mixture of the same three agonists. The use of TLR signaling inhibitors and knockout studies confirmed that the tri-agonist molecule activated multiple signaling pathways leading to the observed higher activity. To validate that the TLR4, 7, and 9 agonist combination would activate the immune response to a greater extent, we performed in vivo studies using a vaccinia vaccination model. Mice vaccinated with the linked TLR agonists showed an increase in antibody depth and breadth compared to mice vaccinated with the unconjugated mixture. These studies demonstrate how activation of multiple TLRs through chemically and spatially defined organization assists in guiding immune responses, providing the potential to use chemical tools to design and develop more effective vaccines. PMID:26640818

  3. Effect of a single dose of dexamethasone on glucose homeostasis in healthy horses by using the combined intravenous glucose and insulin test.

    PubMed

    Haffner, J C; Eiler, H; Hoffman, R M; Fecteau, K A; Oliver, J W

    2009-01-01

    Sustained dexamethasone administration to horses results in insulin resistance, which may predispose them to laminitis. A single dose of dexamethasone is commonly used as a diagnostic aid, yet the effect of a single dose of dexamethasone on glucose homeostasis in horses is not well defined. The objective of this study was to characterize the change in glucose dynamics over time in response to a single dose of dexamethasone. A combined glucose-insulin tolerance test (CGIT) was performed on 6 adult geldings before and at 2, 24, and 72 h postdexamethasone (40 microg/kg of BW, i.v.); a minimum of 1 wk of rest was allowed between treatments. Before any treatment, the CGIT resulted in a hyperglycemic phase followed by a hypoglycemic phase. Dexamethasone affected glucose dynamics in 3 ways: 1) at 2 h, dexamethasone shortened the ascending branch of the negative phase (P < 0.001) of the test, indicating moderate insulin resistance; 2) at 24 h, dexamethasone impaired glucose clearance by extending the positive phase and eliminating the negative phase while insulin was elevated before the CGIT, indicating a decreased response to insulin; and 3) at 72 h, dexamethasone caused a deeper nadir value (P < 0.001) compared with predexamethasone, indicating an increased response to insulin. It was concluded that dexamethasone decreased the response to insulin as early as 2 h and maximally at 24 h. At 72 h, dexamethasone caused an increased response to insulin, which was unexpected.

  4. [Dexamethasone affect on the expression of bcl-2 and mTOR genes in T-lymphocytes from healthy donors].

    PubMed

    Fatkhullina, A R; Abramov, S N; Skibo, Iu V; Abramova, Z I

    2014-01-01

    Synthetic glucocorticoids are able to activate apoptosis in the cells by regulating the transcription of the respective genes. Effect of dexamethasone on apoptosis is an established fact. However, its influence on another program of cell death autophagy, is currently unproven. Therefore, in this paper we have analyzed the influence of dexamethasone on the expression of bcl-2 and mTOR genes in T-lymphocytes from healthy donors. The results showed that dexamethasone reduced the expression of bcl-2 and mTOR genes. However, the nature of the effect of dexamethasone on mTOR and bcl-2 expression was different: the expression of bcl-2 gene in the long-term cultivation was maintained at the same reduced level, while the expression of mTOR was first reduced and then increased.

  5. A New Technique for Quantitative Determination of Dexamethasone in Pharmaceutical and Biological Samples Using Kinetic Spectrophotometric Method

    PubMed Central

    Akhoundi-Khalafi, Ali Mohammad; Shishehbore, Masoud Reza

    2015-01-01

    Dexamethasone is a type of steroidal medications that is prescribed in many cases. In this study, a new reaction system using kinetic spectrophotometric method for quantitative determination of dexamethasone is proposed. The method is based on the catalytic effect of dexamethasone on the oxidation of Orange G by bromate in acidic media. The change in absorbance as a criterion of the oxidation reaction progress was followed spectrophotometrically. To obtain the maximum sensitivity, the effective reaction variables were optimized. Under optimized experimental conditions, calibration graph was linear over the range 0.2–54.0 mg L−1. The calculated detection limit (3sb/m) was 0.14 mg L−1 for six replicate determinations of blank signal. The interfering effect of various species was also investigated. The present method was successfully applied for the determination of dexamethasone in pharmaceutical and biological samples satisfactorily. PMID:25737724

  6. Dexamethasone effects on creatine kinase activity and insulin-like growth factor receptors in cultured muscle cells

    NASA Technical Reports Server (NTRS)

    Whitson, Peggy A.; Stuart, Charles A.; Huls, M. H.; Sams, Clarence F.; Cintron, Nitza M.

    1989-01-01

    The effect of dexamethasone on the activity of creatine kinase (CK) and the insulin-like growth factor I (IGF-I) binding were investigated using skeletal- and cardiac-muscle-derived cultured cell lines (mouse, C2C12; rat, L6 and H9c2). It was found that, in skeletal muscle cells, dexamethasone treatment during differentiation of skeletal-muscle cells caused dose-dependent increases in CK activity and increases in the degree of myotube formation, whereas cardiac cells (H9c2) exhibited very low CK activity during culture or dexamethasone treatment. Results for IGF-I binding were similar in all three cell lines. The IGF-I binding to dexamethasone-treated cells (50 nM for 24 hr on the day prior to confluence) resulted in an increased number of available binding sites, with no effect on the binding affinities.

  7. Dexamethasone vs prednisone in induction treatment of pediatric ALL: results of the randomized trial AIEOP-BFM ALL 2000.

    PubMed

    Möricke, Anja; Zimmermann, Martin; Valsecchi, Maria Grazia; Stanulla, Martin; Biondi, Andrea; Mann, Georg; Locatelli, Franco; Cazzaniga, Giovanni; Niggli, Felix; Aricò, Maurizio; Bartram, Claus R; Attarbaschi, Andishe; Silvestri, Daniela; Beier, Rita; Basso, Giuseppe; Ratei, Richard; Kulozik, Andreas E; Lo Nigro, Luca; Kremens, Bernhard; Greiner, Jeanette; Parasole, Rosanna; Harbott, Jochen; Caruso, Roberta; von Stackelberg, Arend; Barisone, Elena; Rössig, Claudia; Conter, Valentino; Schrappe, Martin

    2016-04-28

    Induction therapy for childhood acute lymphoblastic leukemia (ALL) traditionally includes prednisone; yet, dexamethasone may have higher antileukemic potency, leading to fewer relapses and improved survival. After a 7-day prednisone prephase, 3720 patients enrolled on trial Associazione Italiana di Ematologia e Oncologia Pediatrica and Berlin-Frankfurt-Münster (AIEOP-BFM) ALL 2000 were randomly selected to receive either dexamethasone (10 mg/m(2) per day) or prednisone (60 mg/m(2) per day) for 3 weeks plus tapering in induction. The 5-year cumulative incidence of relapse (± standard error) was 10.8 ± 0.7% in the dexamethasone and 15.6 ± 0.8% in the prednisone group (P < .0001), showing the largest effect on extramedullary relapses. The benefit of dexamethasone was partially counterbalanced by a significantly higher induction-related death rate (2.5% vs 0.9%, P = .00013), resulting in 5-year event-free survival rates of 83.9 ± 0.9% for dexamethasone and 80.8 ± 0.9% for prednisone (P = .024). No difference was seen in 5-year overall survival (OS) in the total cohort (dexamethasone, 90.3 ± 0.7%; prednisone, 90.5 ± 0.7%). Retrospective analyses of predefined subgroups revealed a significant survival benefit from dexamethasone only for patients with T-cell ALL and good response to the prednisone prephase (prednisone good-response [PGR]) (dexamethasone, 91.4 ± 2.4%; prednisone, 82.6 ± 3.2%; P = .036). In patients with precursor B-cell ALL and PGR, survival after relapse was found to be significantly worse if patients were previously assigned to the dexamethasone arm. We conclude that, for patients with PGR in the large subgroup of precursor B-cell ALL, dexamethasone especially reduced the incidence of better salvageable relapses, resulting in inferior survival after relapse. This explains the lack of benefit from dexamethasone in overall survival that we observed in the total cohort except in the subset of T-cell ALL patients with PGR. This trial was registered

  8. Small Molecule Bax Agonists for Cancer Therapy

    PubMed Central

    Xin, Meiguo; Li, Rui; Xie, Maohua; Park, Dongkyoo; Owonikoko, Taofeek K.; Sica, Gabriel L.; Corsino, Patrick E.; Zhou, Jia; Ding, Chunyong; White, Mark A.; Magis, Andrew T.; Ramalingam, Suresh S.; Curran, Walter J.; Khuri, Fadlo R.; Deng, Xingming

    2014-01-01

    Bax, a central death regulator, is required at the decisional stage of apoptosis. We recently identified serine 184 (S184) of Bax as a critical functional switch controlling its proapoptotic activity. Here, we employed the structural pocket around S184 as a docking site to screen the NCI library of small molecules using the UCSF-DOCK program suite. Three compounds, small molecule Bax agonists SMBA1, SMBA2 and SMBA3, induce conformational changes in Bax by blocking S184 phosphorylation, facilitating Bax insertion into mitochondrial membranes and forming Bax oligomers. The latter leads to cytochrome c release and apoptosis in human lung cancer cells, which occurs in a Bax- but not Bak-dependent fashion. SMBA1 potently suppresses lung tumor growth via apoptosis by selectively activating Bax in vivo without significant normal tissue toxicity. Development of Bax agonists as a new class of anti-cancer drugs offers a strategy for the treatment of lung cancer and other Bax-expressing malignancies. PMID:25230299

  9. Efficacy of dexamethasone on postoperative analgesia in children undergoing hypospadias repair

    PubMed Central

    Shirazi, Mehdi; Mahmoudi, Hilda; Nasihatkon, Behnam; Ghaffaripour, Sina; Eslahi, Ali

    2016-01-01

    Background and Objective: Management of post operative pain in children undergoing hypospadiasis repair, accounts for optimized surgery outcomes and improved patients’ satisfaction. Thus, various studies have widely investigated the best approaches for the pain management. In this study our aim was to determine the effect of dexamethasone in combination with penile nerve block on the postoperative pain and complications in the children undergoing hypospadias surgery. Methods: In this randomized double-blind placebo controlled trial, after obtaining informed consent from parents or legal guardians, 42 children undergoing surgical treatment of hypospadias were randomized in two groups to receive either IV dexamethasone 0.5 mg/kg (n=23) or placebo (normal saline) (n=19) during the operation. Penile block was performed in both groups using Bupivacaine 0.5% (1mg/kg) at the end of the procedure. By the end of the operation, FLACC (Face, Leg, Activity, Cry, Consolability) pain score was assessed as the primary outcome of the study. Secondary outcomes includes timing and episodes of rescue medication consumption, post operative nausea \\vomiting and bleeding. All the outcomes were assessed in the recovery room and after 2, 6, 12, and 24 hours. Results: The median of FLACC pain scores at the recovery room and 2, 6, 12, and 24 hours post operation was 2, 1, 1, 1, and 2 for the dexamethasone group and 8, 8, 7, 7, and 8 for the placebo group respectively. This were significantly different (P<0.000). The median time of first rescue medication consumption was 8 hours post operation for the dexamethasone group and three hours for the placebo group which was significantly different (z= 4.57, p<0.000). The maximum episode of post operative rescue medication consumption in dexamethasone group was 4 episodes in only one patient and the minimum was one episode in 11 patients. In comparison numbers in placebo group were five episodes in seven patients and three episodes in four

  10. Aerosolized clindamycin is superior to aerosolized dexamethasone or clindamycin-dexamethasone combination in the treatment of severe Porphyromonas gingivalis aspiration pneumonia in an experimental murine model.

    PubMed

    Nemec, Ana; Pavlica, Zlatko; Nemec-Svete, Alenka; Eržen, Damijan; Milutinović, Aleksandra; Petelin, Milan

    2012-02-01

    Adjunctive corticosteroid treatment to reduce excessive local inflammatory response in pneumonia is controversial. To study the effects of an early local adjunct dexamethasone treatment on the course of pneumonia and inflammatory/cytokine response, mice were intratracheally inoculated with live Porphyromonas gingivalis and treated with either clindamycin (C), dexamethasone (D), C+D combination, or were not treated (Pg). Six mice from each group were euthanized at 6, 24, 72, and 168 hours after inoculation. Levels of tumor necrosis factor (TNF)-α, soluble TNF-α receptors (sTNFR1 and sTNFR2), interleukin (IL)-1β, and IL-6 in the serum and lung-homogenate supernatant were determined. Lung samples were histopathologically assessed and all findings compared to those found in 24 sham-inoculated mice (phosphate-buffered saline [PBS]). Severe P. gingivalis-induced bronchopneumonia progressed from 24 hours, peaked at 72 hours, and resolved after 168 hours with changes in local and systemic cytokine levels. Clindamycin-treated mice developed only mild bronchopneumonia that resolved fast (72 hours) with an early (6-24 hours) normalization of local and systemic cytokine levels. Similar course of pneumonia and cytokine level changes were observed in mice treated with C+D, but later. Early (6-24 hours) local elevation of sTNFRs was observed in C and C+D groups of mice, whereas nontreated (Pg) mice had increased systemic sTNFRs. Severe bronchopneumonia with delayed resolution was observed in D-group mice, with an early local and systemic decrease in sTNFR1 and persistent elevation of local TNF-α. Clindamycin or a clindamycin-dexamethasone combination treatment significantly improves the course of P. gingivalis-aspiration pneumonia, but more so if clindamycin alone is used. A favorable course of pneumonia seems to be associated with an early elevation of sTNFRs and normalization of TNF-α.

  11. Ghrelin Protects against Dexamethasone-Induced INS-1 Cell Apoptosis via ERK and p38MAPK Signaling

    PubMed Central

    2016-01-01

    Glucocorticoid excess induces apoptosis of islet cells, which may result in diabetes. In this study, we investigated the protective effect of ghrelin on dexamethasone-induced INS-1 cell apoptosis. Our data showed that ghrelin (0.1 μM) inhibited dexamethasone-induced (0.1 μM) apoptosis of INS-1 cells and facilitated cell proliferation. Moreover, ghrelin upregulated Bcl-2 expression, downregulated Bax expression, and decreased caspase-3 activity. The protective effect of ghrelin against dexamethasone-induced INS-1 cell apoptosis was mediated via growth hormone secretagogue receptor 1a. Further studies revealed that ghrelin increased ERK activation and decreased p38MAPK expression after dexamethasone treatment. Ghrelin-mediated protection of dexamethasone-induced apoptosis of INS-1 cells was attenuated using the ERK inhibitor U0126 (10 μM), and cell viability increased using the p38MAPK inhibitor SB203580 (10 μM). In conclusion, ghrelin could protect against dexamethasone-induced INS-1 cell apoptosis, at least partially via GHS-R1a and the signaling pathway of ERK and p38MAPK. PMID:27190513

  12. Dexamethasone-(C21-phosphoramide)-[anti-EGFR]: molecular design, synthetic organic chemistry reactions, and antineoplastic cytotoxic potency against pulmonary adenocarcinoma (A549)

    PubMed Central

    Coyne, Cody P; Narayanan, Lakshmi

    2016-01-01

    Purpose Corticosteroids are effective in the management of a variety of disease states, such as several forms of neoplasia (leukemia and lymphoma), autoimmune conditions, and severe inflammatory responses. Molecular strategies that selectively “target” delivery of corticosteroids minimize or prevents large amounts of the pharmaceutical moiety from passively diffusing into normal healthy cell populations residing within tissues and organ systems. Materials and methods The covalent immunopharmaceutical, dexamethasone-(C21-phosphoramide)-[anti-EGFR] was synthesized by reacting dexamethasone-21-monophosphate with a carbodiimide reagent to form a dexamethasone phosphate carbodiimide ester that was subsequently reacted with imidazole to create an amine-reactive dexamethasone-(C21-phosphorylimidazolide) intermediate. Monoclonal anti-EGFR immunoglobulin was combined with the amine-reactive dexamethasone-(C21-phosphorylimidazolide) intermediate, resulting in the synthesis of the covalent immunopharmaceutical, dexamethasone-(C21-phosphoramide)-[anti-EGFR]. Following spectrophotometric analysis and validation of retained epidermal growth factor receptor type 1 (EGFR)-binding avidity by cell-ELISA, the selective anti-neoplasic cytotoxic potency of dexamethasone-(C21-phosphoramide)-[anti-EGFR] was established by MTT-based vitality stain methodology using adherent monolayer populations of human pulmonary adenocarcinoma (A549) known to overexpress the tropic membrane receptors EGFR and insulin-like growth factor receptor type 1. Results The dexamethasone:IgG molar-incorporation-index for dexamethasone-(C21-phosphoramide)-[anti-EGFR] was 6.95:1 following exhaustive serial microfiltration. Cytotoxicity analysis: covalent bonding of dexamethasone to monoclonal anti-EGFR immunoglobulin did not significantly modify the ex vivo antineoplastic cytotoxicity of dexamethasone against pulmonary adenocarcinoma at and between the standardized dexamethasone equivalent concentrations of 10

  13. The alpha-foetoprotein proximal enhancer: localization, cell specificity and modulation by dexamethasone.

    PubMed Central

    Houart, C; Szpirer, J; Szpirer, C

    1990-01-01

    The enhancer element present in the 5' proximal region flanking the mouse alpha-foetoprotein (AFP) gene, active in AFP-producing hepatoma cells and inactive in non-producing hepatoma cells, was localized between positions -203 and -79. This enhancer segment contains a sequence resembling the steroid hormone response element. We demonstrated that this sequence is dispensable for the enhancer activity but mediates dose-dependent effects of dexamethasone on the enhancer activity: dexamethasone decreases the proximal enhancer activity at low concentrations but this inhibitory effect vanishes at high concentrations. Our results indicate that several transcriptional factors, one of which is absent in AFP-non-producing hepatoma cells, control the AFP proximal enhancer activity. Images PMID:1700853

  14. Linezolid and dexamethasone experience in a serious case of listeria rhombencephalitis.

    PubMed

    Yılmaz, Pakize Ö; Mutlu, Nevzat M; Sertçelik, Ahmet; Baştuğ, Aliye; Doğu, Cihangir; Kışlak, Sümeyye

    2016-01-01

    Listeria rhombencephalitis is a rare cause of brain stem encephalitis. We report a case with a history of immunosupressive therapy due to Takayasu's arteritis that was treated with corticosteroids and linezolid for Listeria rhombencephalitis. A 63-year-old woman was admitted to the hospital with fever, headache, nausea, and vomiting. The patient's body temperature was 38°C, and she had a stiff neck. Listeria monocytogenes was isolated from the cerebrospinal fluid (CSF), and penicillin G and gentamicin treatment was initiated. Linezolid and dexamethasone were added. Due to hematuria and thrombocytopenia, the linezolid was discontinued. In immunocompromised patients with CNS infections, Listeria rhombencephalitis should be suspected. Linezolid can be used in combination with dexamethasone. PMID:26860968

  15. Peptic ulcer disease and other complications in patients receiving dexamethasone palliation for brain metastasis

    SciTech Connect

    Penzner, R.D.; Lipsett, J.A.

    1982-11-01

    A retrospective analysis was done of 106 patients who received radiation therapy for brain metastasis. Dexamethasone therapy was instituted in 97 patients. Peptic ulcer disease developed in 5 of 89 patients (5.6 percent) who received a dosage of at least 12 mg a day, but did not occur in patients who received a lower dose or in those who did not receive steroids. The interval between institution of dexamethasone therapy and the development of peptic ulcer disease ranged from three to nine weeks. Two patients had perforated ulcers, one of whom required surgical resection. Peptic ulcer disease contributed to the general deterioration and death of three of the five patients. Overall, in 14 of the 89 patients (15.7 percent) a complication of steroid therapy developed in the form of peptic ulcer disease, steroid myopathy or diabetes mellitus (or a combination of these).

  16. Morphometric study of cartilage dynamics in the chick embryo tibia. II. Dexamethasone-treated embryos.

    PubMed Central

    Ranz, F B; Aceitero, J; Gaytan, F

    1987-01-01

    The cartilage dynamics in the tibia of dexamethasone-treated chick embryos has been studied by means of morphometric methods. Treated embryos showed a delay in the longitudinal growth of the tibia, as well as in the growth of all structures enclosed by the perichondrium-periosteum. The cartilage formation rate remained nearly unchanged (above 1 mm3/day) from Day 12 to Day 14, whereas the cartilage resorption rate was zero up to Day 13, and showed a non-significant increase from Day 13 onwards. This might be related to the scarcity of resorptive cells found in the cartilage-marrow interface. By Day 14 a certain recovery of the growth rhythm was observed. These results indicate that the greatest effect of dexamethasone occurs at the level of cartilage resorption. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:3446667

  17. Development and characterization of nanoparticulate formulation of a water soluble prodrug of dexamethasone by HIP complexation

    PubMed Central

    Gaudana, Ripal; Parenky, Ashwin; Vaishya, Ravi; Samanta, Swapan K.; Mitra, Ashim K.

    2015-01-01

    The objective of this study was to develop and characterize a nanoparticulate-based sustained release formulation of a water soluble dipeptide prodrug of dexamethasone, valine–valine-dexamethasone (VVD). Being hydrophilic in nature, it readily leaches out in the external aqueous medium and hence partitions poorly into the polymeric matrix resulting in minimal entrapment in nanoparticles. Hence, hydrophobic ion pairing (HIP) complexation of the prodrug was employed with dextran sulphate as a complexing polymer. A novel, solid in oil in water emulsion method was employed to encapsulate the prodrug in HIP complex form in poly(lactic-co-glycolic acid) matrix. Nanoparticles were characterized with respect to size, zeta potential, crystallinity of entrapped drug and surface morphology. A significant enhancement in the entrapment of the prodrug in nanoparticles was achieved. Finally, a simple yet novel method was developed which can also be applicable to encapsulate other charged hydrophilic molecules, such as peptides and proteins. PMID:20939702

  18. Fabrication of graphene oxide-modified chitosan for controlled release of dexamethasone phosphate

    NASA Astrophysics Data System (ADS)

    Sun, Huanghui; Zhang, Lingfan; Xia, Wei; Chen, Linxiao; Xu, Zhizhen; Zhang, Wenqing

    2016-07-01

    Functionalized graphene oxide with its unique physical and chemical properties is widely applied in biomaterials, especially in drug carrier materials. In the past few years, a number of different drugs have been loaded on functionalized graphene oxide via π-π stacking and hydrophobic interactions. The present report described a new approach, dexamethasone phosphate successfully loaded onto graphene oxide-chitosan nanocomposites as drug carrier materials by covalent bonding of phosphate ester linkage. Compared with the graphene oxide-chitosan nanocomposites that dexamethasone phosphate was loaded on via simple physical attachment, covalently linked composites as drug carrier materials were more biocompatible which effectively reduced the burst release of drug, and controlled the release of drug in different pH conditions.

  19. Upregulation of AQP3 and AQP5 induced by dexamethasone and ambroxol in A549 cells.

    PubMed

    Ben, Yong; Chen, Jie; Zhu, Rong; Gao, Lei; Bai, Chunxue

    2008-04-30

    Aquaporins (AQPs) are membrane channel proteins that play roles in the regulation of water permeability in many tissues. AQP1 and AQP5 expressed in lung provide the principal route for osmotically driven water transport. In the airways, AQP3 and AQP4 facilitate water transport. Dexamethasone and ambroxol are often used to treat patients with pulmonary diseases accompanied by airway hypersecretion. The role of AQPs in these effective treatments has not been addressed. In this study, we analyzed the expression of AQPs in a human airway epithelial cell line (A549 cells) and showed that AQP3 and 5, but not AQP1 and 4, were expressed in A549 cells. Both dexamethasone and ambroxol stimulated the expression of AQP3 and 5 at the mRNA and protein levels. The data suggest potential roles of AQP3 and 5 in the regulation of airway hypersecretion, perhaps ultimately providing a target for treating such diseases.

  20. Beta-adrenergic receptor agonists and antagonists counteract LPS-induced neuronal death in retinal cultures by different mechanisms.

    PubMed

    Arai, Kunizo; Wood, John P M; Osborne, Neville N

    2003-09-26

    Treatment with lipopolysaccharide (LPS) for 72 h was shown to dose-dependently increase nitric oxide production from 6-day-old retinal cultures. Cell death, as determined by lactate dehydrogenase (LDH) release and an increase in neuronal labelling for TUNEL, was elevated concurrently. During treatment there was an increase of both inducible nitric oxide synthase and glial fibrillary acidic protein labelling in glial cells and a reduction in the number of gamma-aminobutyric acid-positive neurones. The NOS inhibitors, N-nitro-L-arginine methyl ester, dexamethasone and indomethacin potently inhibited both nitric oxide stimulation and cell death caused by LPS. In this study, the beta(2)- (ICI-18551), beta(1)- (betaxolol) and mixed beta(1)/beta(2)- (timolol, metipranolol) adrenergic receptor antagonists were all shown to attenuate LPS-induced LDH release from these cultures, but to have no effect on LPS-stimulated nitric oxide production. This effect was mimicked by the calcium channel blocker, nifedipine. Interestingly, the beta-adrenergic receptor agonists, salbutamol, arterenol and isoproterenol were also able to attenuate cell death caused by LPS. Moreover, these compounds also inhibited LPS-stimulated nitric oxide release. These studies suggest that LPS stimulates nitric oxide release from cultured retinal glial cells and that this process leads to neurone death. beta-adrenergic receptor agonists prevent the effects of LPS by inhibiting the stimulation of nitric oxide production. The data also suggest that beta-adrenergic receptor antagonists can attenuate LPS-induced death of neurones, but that these compounds act in a manner that is neurone-dependent, is mimicked by blockade of calcium channels and is independent of the stimulation of nitric oxide release.

  1. Physical Chemistry to the Rescue: Differentiating Nicotinic and Cholinergic Agonists

    ERIC Educational Resources Information Center

    King, Angela G.

    2005-01-01

    Researches suggest that two agonists can bind to the same binding site of an important transmembrane protein and elicit a biological response through strikingly different binding interactions. Evidence is provided which suggests two possible types of nicotinic acetylcholine receptor agonist binding like acetlycholine (cholinergic) or like nicotine…

  2. GLP-1 agonist treatment: implications for diabetic retinopathy screening.

    PubMed

    Varadhan, Lakshminarayanan; Humphreys, Tracy; Hariman, Christian; Walker, Adrian B; Varughese, George I

    2011-12-01

    Rapid improvement in glycaemic control induced by GLP-1 agonist therapy could be yet another illustration of transient or permanent progression of diabetic retinopathy, similar to documented examples such as pregnancy and continuous subcutaneous insulin infusion. Specific guidelines would be needed to monitor this paradoxical phenomenon during treatment with GLP-1 agonists. PMID:21906831

  3. TOXICITY OF AHR AGONISTS TO FISH EARLY LIFE STAGES

    EPA Science Inventory

    Fish early life stages are exceptionally sensitive to the lethal toxicity of chemicals that act as arylhydrocarbon receptor (AhR) agonists. Toxicity characterizations based on 2,3,7,8-tetrachlorodibenzo-p-dioxin, generally the most potent AhR agonist, support the toxicity equiva...

  4. Long-lasting corneal endothelial graft rejection successfully reversed after dexamethasone intravitreal implant.

    PubMed

    Giannaccare, Giuseppe; Fresina, Michela; Pazzaglia, Alberto; Versura, Piera

    2016-01-01

    Graft rejection is the most significant complication corneal transplantation and the leading indication for overall corneal transplantation. Corticosteroid therapy represents the mainstay of graft rejection treatment; however, the optimal route of administration of corticosteroid remains uncertain. We report herein for the first time the multimodal imaging of a case of long-lasting corneal endothelial graft rejection successfully reversed 3 months after dexamethasone intravitreal implant. A 29-year-old Asian female presented with a long-lasting corneal endothelial graft rejection in her left phakic eye. She underwent penetrating keratoplasty for advanced keratoconus 24 months before presentation. Hourly dexamethasone eyedrops, daily intravenous methylprednisolone, and one parabulbar injection of methylprednisolone acetate were administered during the 5 days of hospitalization. However, the clinical picture remained approximately unchanged despite therapy. By mutual agreement, we opted for the off-label injection of dexamethasone 0.7 mg intravitreal implant in order to provide therapeutic concentrations of steroid for a period of ~6 months. No other concomitant therapies were prescribed to the patient. Visual acuity measurement, slit lamp biomicroscopy, anterior segment photography, confocal microscopy, anterior segment optical coherence tomography, laser cell flare meter, intraocular pressure measurement, and ophthalmoscopy were performed monthly for the first postoperative 6 months. Three months after injection, both clinical and subclinical signs of rejection disappeared with a full recovery of visual acuity to 20/30 as before the episode. Currently, at the 12-month follow-up visit, the clinical picture remains stable without any sign of rejection, recurrence, or graft failure. Dexamethasone intravitreal implant seems to be a new potential effective treatment for corneal graft rejection, particularly in case of poor compliance or lack of response to conventional

  5. Long-lasting corneal endothelial graft rejection successfully reversed after dexamethasone intravitreal implant

    PubMed Central

    Giannaccare, Giuseppe; Fresina, Michela; Pazzaglia, Alberto; Versura, Piera

    2016-01-01

    Graft rejection is the most significant complication corneal transplantation and the leading indication for overall corneal transplantation. Corticosteroid therapy represents the mainstay of graft rejection treatment; however, the optimal route of administration of corticosteroid remains uncertain. We report herein for the first time the multimodal imaging of a case of long-lasting corneal endothelial graft rejection successfully reversed 3 months after dexamethasone intravitreal implant. A 29-year-old Asian female presented with a long-lasting corneal endothelial graft rejection in her left phakic eye. She underwent penetrating keratoplasty for advanced keratoconus 24 months before presentation. Hourly dexamethasone eyedrops, daily intravenous methylprednisolone, and one parabulbar injection of methylprednisolone acetate were administered during the 5 days of hospitalization. However, the clinical picture remained approximately unchanged despite therapy. By mutual agreement, we opted for the off-label injection of dexamethasone 0.7 mg intravitreal implant in order to provide therapeutic concentrations of steroid for a period of ~6 months. No other concomitant therapies were prescribed to the patient. Visual acuity measurement, slit lamp biomicroscopy, anterior segment photography, confocal microscopy, anterior segment optical coherence tomography, laser cell flare meter, intraocular pressure measurement, and ophthalmoscopy were performed monthly for the first postoperative 6 months. Three months after injection, both clinical and subclinical signs of rejection disappeared with a full recovery of visual acuity to 20/30 as before the episode. Currently, at the 12-month follow-up visit, the clinical picture remains stable without any sign of rejection, recurrence, or graft failure. Dexamethasone intravitreal implant seems to be a new potential effective treatment for corneal graft rejection, particularly in case of poor compliance or lack of response to conventional

  6. A comparison of dexamethasone and clonidine as an adjuvant for caudal blocks in pediatric urogenital surgeries

    PubMed Central

    Sinha, Chandni; Kumar, Bindey; Bhadani, Umesh Kumar; Kumar, Ajeet; Kumar, Amarjeet; Ranjan, Alok

    2016-01-01

    Background: Caudal block is a reliable regional analgesic technique for pediatric urogenital surgeries. Various adjuvants have been tried to enhance the duration of action of bupivicaine. Though clonidine is extensively used as an adjuvant in caudal anaesthesia, it can have troublesome adverse effects like bradycardia, hypotension and sedation. Lately dexamethasone has become popular as an adjuvant in paediatric caudals due to its safety profile. Aim: The aim of this study was to compare dexamethasone and clonidine coadministered with bupivicaine caudally in paediatric patients undergoing urogenital surgeries in terms of analgesia and adverse effects. Settings and Design: Prospective, double blinded randomised study. Subjects and Method: Sixty American Society of Anesthesiologists physical status I and II children, aged 1-6 years undergoing urogenital surgeries were allocated in 2 groups: Group I: 0.5 mL.kg−1 of 0.25% bupivicaine with dexamethasone 0.1 mg.kg−1 in 1 ml normal saline (NS) Group II: 0.5 mL.kg−1 of 0.25% bupivicaine with clonidine 1 μg.kg−1 diluted in 1 ml normal saline. The parameters studied included duration of analgesia, intraoperative and postoperative hemodynamics, sedation scores and incidence of adverse effects like wound dehiscence, bleeding, vomiting and respiratory depression. Statistical Analysis Used: Statistical analysis was carried out using Stata Version 10. After checking for the normality assumption, t-test for comparing means of two independent samples was used for comparing baseline continuous variables. P values <0.05 were considered significant. Results: Patients in Group II had longer duration of analgesia postoperatively. Patients in this group also had lower heart rate and more sedation scores. Conclusion: Our study shows that caudal dexamethasone is a good alternative to clonidine with more stable hemodynamics and lesser sedation scores in the immediate postoperative period. Both the drugs offer good analgesia

  7. Streptococcal infection of endocardial and other intravascular vegetations in rabbits: natural history and effect of dexamethasone.

    PubMed Central

    Francioli, P B; Freedman, L R

    1979-01-01

    Experiments were designed to study the natural history of infection in different parts of the vascular system. Sterile vegetations were produced in rabbits by placing catheters in the inferior vena cava, tricuspid or aortic valves, and thoracic or abdominal aorta and then were infected by the intravenous inoculation of Streptococcus sanguis. At 1 day after bacterial challenge, all VEGS were infected, mean bacterial densities being highest in the VEGS of the aortic and tricuspid valves. By 14 days, there was a significant decrease in the mean bacterial density in all VEGS except for the aortic valve: the VEGS of the inferior vena cava and abdominal aorta were sterile, as were half of those of the thoracic aorta. There were no deaths except for animals with aortic valve infection. Dexamethasone inhibited the sterilization of the thoracic aorta VEGS, but was without effect on aortic valve VEGS, 5 mm distant. Sterilization of tricuspid valve VEGS after catheter removal was also inhibited by dexamethasone. Thus, there are host defense mechanisms which lead to the sterilization of infections everywhere in the vascular system except in the left side of the heart, and these mechanisms, as yet undefined, are inhibited by dexamethasone. Images PMID:457283

  8. Mechanism of Fibronectin Binding to Human Trabecular Meshwork Exosomes and Its Modulation by Dexamethasone

    PubMed Central

    Klingeborn, Mikael; Stamer, W. Daniel