WorldWideScience

Sample records for therapeutic glucocorticoid mimetics

  1. Nicotinic Acid-Mediated Activation of Both Membrane and Nuclear Receptors towards Therapeutic Glucocorticoid Mimetics for Treating Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    W. Todd Penberthy

    2009-01-01

    Full Text Available Acute attacks of multiple sclerosis (MS are most commonly treated with glucocorticoids, which can provide life-saving albeit only temporary symptomatic relief. The mechanism of action (MOA is now known to involve induction of indoleamine 2,3-dioxygenase (IDO and interleukin-10 (IL-10, where IL-10 requires subsequent heme oxygenase-1 (HMOX-1 induction. Ectopic expression studies reveal that even small changes in expression of IDO, HMOX-1, or mitochondrial superoxide dismutase (SOD2 can prevent demyelination in experimental autoimmune encephalomyelitis (EAE animal models of MS. An alternative to glucocorticoids is needed for a long-term treatment of MS. A distinctly short list of endogenous activators of both membrane G-protein-coupled receptors and nuclear peroxisome proliferating antigen receptors (PPARs demonstrably ameliorate EAE pathogenesis by MOAs resembling that of glucocorticoids. These dual activators and potential MS therapeutics include endocannabinoids and the prostaglandin 15-deoxy-Δ12,14-PGJ2. Nicotinamide profoundly ameliorates and prevents autoimmune-mediated demyelination in EAE via maintaining levels of nicotinamide adenine dinucleotide (NAD, without activating PPAR nor any G-protein-coupled receptor. By comparison, nicotinic acid provides even greater levels of NAD than nicotinamide in many tissues, while additionally activating the PPAR-dependent pathway already shown to provide relief in animal models of MS after activation of GPR109a/HM74a. Thus nicotinic acid is uniquely suited for providing therapeutic relief in MS. However nicotinic acid is unexamined in MS research. Nicotinic acid penetrates the blood brain barrier, cures pellagric dementia, has been used for over 50 years clinically without toxicity, and raises HDL concentrations to a greater degree than any pharmaceutical, thus providing unparalleled benefits against lipodystrophy. Summary analysis reveals that the expected therapeutic benefits of high-dose nicotinic

  2. [Incretin mimetic drugs: therapeutic positioning].

    Science.gov (United States)

    López Simarro, F

    2014-07-01

    Type 2 diabetes is a chronic and complex disease, due to the differences among affected individuals, which affect choice of treatment. The number of drug families has increased in the last few years, and these families have widely differing mechanisms of action, which contributes greatly to the individualization of treatment according to the patient's characteristics and comorbidities. The present article discusses incretin mimetic drugs. Their development has been based on knowledge of the effects of natural incretin hormones: GLP-1 (glucagon-like peptide 1), GIP (glucose-dependent insulinotropic peptide) and dipeptidyl peptidase enzyme 4 (DPP4), which rapidly degrade them in the systemic circulation. This group is composed of 2 different types of molecules: GLP-1 analogs and DPP4 enzyme inhibitors. The benefits of these molecules include a reduction in plasma glucose without the risk of hypoglycemias or weight gain. There are a series of questions that require new studies to establish a possible association between the use of these drugs and notification of cases of pancreatitis, as well as their relationship with pancreatic and thyroid cancer. Also awaited is the publication of several studies that will provide information on the relationship between these drugs and cardiovascular risk in people with diabetes. All these questions will probably be progressively elucidated with greater experience in the use of these drugs. Copyright © 2014 Elsevier España, S.L.U. y Sociedad Española de Medicina Rural y Generalista (SEMERGEN). All rights reserved.

  3. Overcoming EMT-driven therapeutic resistance by BH3 mimetics.

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    Keitel, Ulrike; Scheel, Christina; Dobbelstein, Matthias

    2014-01-01

    Epithelial-mesenchymal transition (EMT) contributes to the progression of cancer through enhanced invasion and stem-like properties of cancer cells. Additionally, EMT confers resistance towards many chemotherapeutics. We recently described a mechanism that mediates EMT-driven chemoresistance through augmented levels of Bcl-xL, an anti-apoptotic member of the Bcl-2 family (Keitel et al., Oncotarget, in press). Here, we elaborate on how these findings pertain to cancer cells dispersed in the tumor-adjacent stroma of breast cancer tissues, and how BH3-mimetics may provide a therapeutic strategy to eliminate cancer cell populations that have passed through an EMT.

  4. Mimetics of Suppressor of cytokine signalling 3: novel potential therapeutics in triple breast cancer.

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    La Manna, Sara; Lee, Eunmi; Ouzounova, Maria; Di Natale, Concetta; Novellino, Ettore; Merlino, Antonello; Korkaya, Hasan; Marasco, Daniela

    2018-05-11

    Suppressor of cytokine signaling (SOCS) family of proteins plays critical role in the regulation of immune responses controlling JAK/STAT mediated inflammatory cytokines. Among the members, SOCS1 and SOCS3 contain a kinase inhibitory region (KIR) and SOCS3 binds to JAK/STAT/gp130 complex by inhibiting the downstream signaling and suppressing inflammatory cytokines. Loss or reduced levels of SOCS3 have been linked to cancer-associated inflammation and suppressive immunity leading to enhanced tumour growth and metastasis. In line with these reports, we previously demonstrated that proteolytic degradation of SOCS3 in triple negative breast cancer (TNBC) subtype drives the expression of inflammatory cytokines. Therefore, we postulated that SOCS3 mimetics might suppress the inflammatory cytokine production in TNBC subtype and inhibit tumor growth and metastasis. Here we designed and characterized five linear peptides derived from the N-terminal region of SOCS3 encompassing regions that interface with the JAK2/gp130 complex by using the Circular Dichroism and Surface Plasmon Resonance spectroscopies. The KIRESS peptide resulted the sequence containing the most part of the hot-spots required for binding to JAK2 and was further investigated in vivo in mouse xenografts of MDA-MB-231-luci tumours as models of human TNBC subtype. Expectedly, this peptide showed a significant inhibition of primary tumour growth and pulmonary metastasis. Our studies suggest that SOCS3 peptidomimetics may possess a therapeutic potential in aggressive cancers, such as TNBC subtype, with activated inflammatory cytokines. This article is protected by copyright. All rights reserved. © 2018 UICC.

  5. Glucocorticoids for the treatment of post-traumatic stress disorder and phobias: a novel therapeutic approach.

    Science.gov (United States)

    de Quervain, Dominique J-F; Margraf, Jürgen

    2008-04-07

    Post-traumatic stress disorder (PTSD) and phobias belong to the most common anxiety disorders and to the most common psychiatric illnesses in general. In both disorders, aversive memories are thought to play an important role in the pathogenesis and symptomatology. Previously, we have reported that elevated glucocorticoid levels inhibit memory retrieval in animals and healthy humans. We therefore hypothesized that the administration of glucocorticoids might also inhibit the retrieval of aversive memory, thereby reducing symptoms in patients with PTSD and phobias. In recent clinical studies, we found first evidence to support this hypothesis. In patients with PTSD, low-dose cortisol treatment for one month reduced symptoms of traumatic memories without causing adverse side effects. Furthermore, we found evidence for a prolonged effect of the cortisol treatment. Persistent retrieval and reconsolidation of traumatic memories is a process that keeps these memories vivid and thereby the disorder alive. By inhibiting memory retrieval, cortisol may weaken the traumatic memory trace, and thus reduce symptoms even beyond the treatment period. In patients with social phobia, we found that a single oral administration of cortisone 1 h before a socio-evaluative stressor significantly reduced self-reported fear during the anticipation-, exposure-, and recovery phase of the stressor. In subjects with spider phobia, repeated oral administration of cortisol 1 h before exposure to a spider photograph induced a progressive reduction of stimulus-induced fear. This effect was maintained when subjects were exposed to the stimulus again two days after the last cortisol administration, indicating that cortisol facilitated the extinction of phobic fear. In conclusion, by a common mechanism of reducing the retrieval of aversive memories, glucocorticoids may be suited for the treatment of PTSD as well as phobias. More studies are needed to further evaluate the therapeutic efficacy of

  6. Mimetic Learning

    Directory of Open Access Journals (Sweden)

    Christoph Wulf

    2008-03-01

    Full Text Available Mimetic learning, learning by imitation, constitutes one of the most important forms of learning. Mimetic learning does not, however, just denote mere imitation or copying: Rather, it is a process by which the act of relating to other persons and worlds in a mimetic way leads to an en-hancement of one’s own world view, action, and behaviour. Mimetic learning is productive; it is related to the body, and it establishes a connection between the individual and the world as well as other persons; it creates practical knowledge, which is what makes it constitutive of social, artistic, and practical action. Mimetic learning is cultural learning, and as such it is crucial to teaching and education (Wulf, 2004; 2005.

  7. Antibody mimetics: promising complementary agents to animal-sourced antibodies.

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    Baloch, Abdul Rasheed; Baloch, Abdul Wahid; Sutton, Brian J; Zhang, Xiaoying

    2016-01-01

    Despite their wide use as therapeutic, diagnostic and detection agents, the limitations of polyclonal and monoclonal antibodies have inspired scientists to design the next generation biomedical agents, so-called antibody mimetics that offer many advantages over conventional antibodies. Antibody mimetics can be constructed by protein-directed evolution or fusion of complementarity-determining regions through intervening framework regions. Substantial progress in exploiting human, butterfly (Pieris brassicae) and bacterial systems to design and select mimetics using display technologies has been made in the past 10 years, and one of these mimetics [Kalbitor® (Dyax)] has made its way to market. Many challenges lie ahead to develop mimetics for various biomedical applications, especially those for which conventional antibodies are ineffective, and this review describes the current characteristics, construction and applications of antibody mimetics compared to animal-sourced antibodies. The possible limitations of mimetics and future perspectives are also discussed.

  8. Novel Manganese-Porphyrin Superoxide Dismutase-Mimetic Widens the Therapeutic Margin in a Preclinical Head and Neck Cancer Model

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    Ashcraft, Kathleen A. [Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina (United States); Boss, Mary-Keara [Department of Molecular Biomedical Sciences, North Carolina State College of Veterinary Medicine, Raleigh, North Carolina (United States); Tovmasyan, Artak [Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina (United States); Roy Choudhury, Kingshuk [Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina (United States); Fontanella, Andrew N. [Department of Biomedical Engineering, Duke University, Durham, North Carolina (United States); Young, Kenneth H.; Palmer, Gregory M.; Birer, Samuel R.; Landon, Chelsea D.; Park, Won [Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina (United States); Das, Shiva K. [Physics and Computing Division, Department of Radiation Oncology, University of North Carolina School of Medicine, Chapel Hill, North Carolina (United States); Weitner, Tin [Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina (United States); Sheng, Huaxin; Warner, David S. [Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina (United States); Brizel, David M. [Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina (United States); Department of Surgery, Duke University Medical Center, Durham, North Carolina (United States); Spasojevic, Ivan [Department of Medicine, Duke University Medical Center, Durham, North Carolina (United States); Batinic-Haberle, Ines [Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina (United States); Dewhirst, Mark W., E-mail: mark.dewhirst@duke.edu [Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina (United States); Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina (United States)

    2015-11-15

    Purpose: To test the effects of a novel Mn porphyrin oxidative stress modifier, Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin (MnBuOE), for its radioprotective and radiosensitizing properties in normal tissue versus tumor, respectively. Methods and Materials: Murine oral mucosa and salivary glands were treated with a range of radiation doses with or without MnBuOE to establish the dose–effect curves for mucositis and xerostomia. Radiation injury was quantified by intravital near-infrared imaging of cathepsin activity, assessment of salivation, and histologic analysis. To evaluate effects of MnBuOE on the tumor radiation response, we administered the drug as an adjuvant to fractionated radiation of FaDu xenografts. Again, a range of radiation therapy (RT) doses was administered to establish the radiation dose–effect curve. The 50% tumor control dose values with or without MnBuOE and dose-modifying factor were determined. Results: MnBuOE protected normal tissue by reducing RT-mediated mucositis, xerostomia, and fibrosis. The dose-modifying factor for protection against xerostomia was 0.77. In contrast, MnBuOE increased tumor local control rates compared with controls. The dose-modifying factor, based on the ratio of 50% tumor control dose values, was 1.3. Immunohistochemistry showed that MnBuOE-treated tumors exhibited a significant influx of M1 tumor-associated macrophages, which provides mechanistic insight into its radiosensitizing effects in tumors. Conclusions: MnBuOE widens the therapeutic margin by decreasing the dose of radiation required to control tumor, while increasing normal tissue resistance to RT-mediated injury. This is the first study to quantitatively demonstrate the magnitude of a single drug's ability to radioprotect normal tissue while radiosensitizing tumor.

  9. Org 214007-0: a novel non-steroidal selective glucocorticoid receptor modulator with full anti-inflammatory properties and improved therapeutic index.

    Science.gov (United States)

    van Lierop, Marie-José C; Alkema, Wynand; Laskewitz, Anke J; Dijkema, Rein; van der Maaden, Hans M; Smit, Martin J; Plate, Ralf; Conti, Paolo G M; Jans, Christan G J M; Timmers, C Marco; van Boeckel, Constant A A; Lusher, Scott J; McGuire, Ross; van Schaik, Rene C; de Vlieg, Jacob; Smeets, Ruben L; Hofstra, Claudia L; Boots, Annemieke M H; van Duin, Marcel; Ingelse, Benno A; Schoonen, Willem G E J; Grefhorst, Aldo; van Dijk, Theo H; Kuipers, Folkert; Dokter, Wim H A

    2012-01-01

    Glucocorticoids (GCs) such as prednisolone are potent immunosuppressive drugs but suffer from severe adverse effects, including the induction of insulin resistance. Therefore, development of so-called Selective Glucocorticoid Receptor Modulators (SGRM) is highly desirable. Here we describe a non-steroidal Glucocorticoid Receptor (GR)-selective compound (Org 214007-0) with a binding affinity to GR similar to that of prednisolone. Structural modelling of the GR-Org 214007-0 binding site shows disturbance of the loop between helix 11 and helix 12 of GR, confirmed by partial recruitment of the TIF2-3 peptide. Using various cell lines and primary human cells, we show here that Org 214007-0 acts as a partial GC agonist, since it repressed inflammatory genes and was less effective in induction of metabolic genes. More importantly, in vivo studies in mice indicated that Org 214007-0 retained full efficacy in acute inflammation models as well as in a chronic collagen-induced arthritis (CIA) model. Gene expression profiling of muscle tissue derived from arthritic mice showed a partial activity of Org 214007-0 at an equi-efficacious dosage of prednisolone, with an increased ratio in repression versus induction of genes. Finally, in mice Org 214007-0 did not induce elevated fasting glucose nor the shift in glucose/glycogen balance in the liver seen with an equi-efficacious dose of prednisolone. All together, our data demonstrate that Org 214007-0 is a novel SGRMs with an improved therapeutic index compared to prednisolone. This class of SGRMs can contribute to effective anti-inflammatory therapy with a lower risk for metabolic side effects.

  10. Kidney tissue targeted metabolic profiling of glucocorticoid-induced osteoporosis and the proposed therapeutic effects of Rhizoma Drynariae studied using UHPLC/MS/MS.

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    Huang, Yue; Liu, Xinyu; Zhao, Longshan; Li, Famei; Xiong, Zhili

    2014-06-01

    Traditional Chinese medicine and modern science have indicated that there is a close relationship between bone and kidney. In light of this, this project was designed to study the metabolic profiling by UHPLC/MS/MS of glucocorticoid-induced osteoporosis in kidney tissue and the possible therapeutic effects of Rhizoma Drynariae (RD), a classic traditional Chinese medicine, in improving the kidney function and strengthening bone. Twenty-one Wistar rats were divided into three groups: control group (rats before prednisolone inducing), a model group (prednisolone-induced group) and a treatment group (prednisolone-induced rats that were then administered RD ethanol extracts). By using pattern recognition analysis, a significant change in the metabolic profile of kidney tissue samples was observed in the model group and restoration of the profile was observed after the administration of RD ethanol extracts. Some significantly changed biomarkers related to osteoporosis such as sphingolipids (C16 dihydrosphingosine, C18 dihydrosphingosine, C18 phytosphingosine, C20 phytosphingosine), lysophosphatidycholines (C16:0 LPC, C18:0 LPC) and phenylalanine were identified. As a complement to the metabolic profiling of RD in plasma, these biomarkers suggest that kidney damage, cell cytotoxicity and apoptosis exist in osteoporosis rats, which is helpful in further understanding the underlying process of glucocorticoid-induced osetoporosis and the suggested therapeutic effects of RD. The method shows that tissue target metabonomics might provide a powerful tool to further understand the process of disease and the mechanism of therapeutic effect of Chinese medicines. Copyright © 2014 John Wiley & Sons, Ltd.

  11. Mimetic discretization methods

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    Castillo, Jose E

    2013-01-01

    To help solve physical and engineering problems, mimetic or compatible algebraic discretization methods employ discrete constructs to mimic the continuous identities and theorems found in vector calculus. Mimetic Discretization Methods focuses on the recent mimetic discretization method co-developed by the first author. Based on the Castillo-Grone operators, this simple mimetic discretization method is invariably valid for spatial dimensions no greater than three. The book also presents a numerical method for obtaining corresponding discrete operators that mimic the continuum differential and

  12. Glucocorticoid Signaling and Bone Biology.

    Science.gov (United States)

    Komori, T

    2016-11-01

    Since glucocorticoids remain an effective therapeutic option for the treatment of many inflammatory and autoimmune diseases, glucocorticoid-induced osteoporosis is the most common form of secondary osteoporosis. Fractures may occur in as many as 30-50% of patients receiving chronic glucocorticoid therapy. Under physiological conditions, glucocorticoids are required for normal bone development due to their regulation of osteoblast differentiation, possibly via the Wnt/β-catenin pathway and TSC22D3. However, serum levels of endogenous corticosterone are elevated in aged mice and glucocorticoids exert negative effects on the survival of osteoblasts and osteocytes as well as angiogenesis. Glucocorticoid treatments impair bone formation and enhance bone resorption. Excess glucocorticoids induce osteoblast and osteocyte apoptosis by increasing pro-apoptotic molecules, reactive oxygen species, and endoplasmic reticulum stress and suppressing the Wnt/β-catenin pathway. Autophagy protects osteocytes from glucocorticoid-induced apoptosis, but passed some threshold, the process of autophagy leads the cells to apoptosis. Excess glucocorticoids impair osteoblastogenesis by inducing Wnt antagonists, including Dkk1, Sost, and sFRP-1. However, the findings are controversial and the involvement of Wnt antagonists requires further study. Excess glucocorticoids reduce the phosphorylation of Akt and GSK3β, which enhances the degradation of β-catenin. Excess glucocorticoids have been shown to modulate the expression of miRNAs, including miR-29a, miR-34a-5p, and miR-199a-5p, which regulate the proliferation and differentiation of osteoblast lineage cells. Excess glucocorticoids also enhance bone resorption by reducing OPG expression, increasing Rankl expression and reactive oxygen species, and prolonging the life span of osteoclasts; however, they also suppress the bone-degrading capacity of osteoclasts by disturbing the organization of the cytoskeleton. © Georg Thieme Verlag KG

  13. Unimodular-mimetic cosmology

    International Nuclear Information System (INIS)

    Nojiri, S; Odintsov, S D; Oikonomou, V K

    2016-01-01

    We combine the unimodular gravity and mimetic gravity theories into a unified theoretical framework, which is proposed to provide a suggestive proposal for a framework that may assist in the discussion and search for a solution to the cosmological constant problem and the dark matter issue. After providing the formulation of the unimodular mimetic gravity and investigating all the new features that the vacuum unimodular gravity implies, by using the underlying reconstruction method, we realize some well known cosmological evolutions, with some of these being exotic for the ordinary Einstein–Hilbert gravity. Specifically we provide the vacuum unimodular mimetic gravity description of the de Sitter cosmology and of the perfect fluid with constant equation of state cosmology. As we demonstrate, these cosmologies can be realized by vacuum mimetic unimodular gravity, without the existence of any matter fluid source. Moreover, we investigate how cosmologically viable cosmologies, which are compatible with the recent observational data, can be realized by the vacuum unimodular mimetic gravity. Since in some cases, a graceful exit from inflation problem might exist, we provide a qualitative description of the mechanism that can potentially generate the graceful exit from inflation in these theories, by searching for the unstable de Sitter solutions in the context of unimodular mimetic theories of gravity. (paper)

  14. Mimetic finite difference method

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    Lipnikov, Konstantin; Manzini, Gianmarco; Shashkov, Mikhail

    2014-01-01

    The mimetic finite difference (MFD) method mimics fundamental properties of mathematical and physical systems including conservation laws, symmetry and positivity of solutions, duality and self-adjointness of differential operators, and exact mathematical identities of the vector and tensor calculus. This article is the first comprehensive review of the 50-year long history of the mimetic methodology and describes in a systematic way the major mimetic ideas and their relevance to academic and real-life problems. The supporting applications include diffusion, electromagnetics, fluid flow, and Lagrangian hydrodynamics problems. The article provides enough details to build various discrete operators on unstructured polygonal and polyhedral meshes and summarizes the major convergence results for the mimetic approximations. Most of these theoretical results, which are presented here as lemmas, propositions and theorems, are either original or an extension of existing results to a more general formulation using polyhedral meshes. Finally, flexibility and extensibility of the mimetic methodology are shown by deriving higher-order approximations, enforcing discrete maximum principles for diffusion problems, and ensuring the numerical stability for saddle-point systems.

  15. Glucocorticoid receptor signaling in health and disease

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    Kadmiel, Mahita; Cidlowski, John A.

    2013-01-01

    Glucocorticoids are steroid hormones regulated in a circadian and stres-associated manner to maintain various metabolic and homeostatic functions that are necessary for life. Synthetic glucocorticoids are widely prescribed drugs for many conditions including asthma, chronic obstructive pulmonary disease (COPD), and inflammatory disorders of the eye. Research in the last few years has begun to unravel the profound complexity of glucocorticoid signaling and has contributed remarkably to improved therapeutic strategies. Glucocorticoids signal through the glucocorticoid receptor, a member of the superfamily of nuclear receptors, in both genomic and non-genomic ways in almost every tissue in the human body. In this review, we will provide an update on glucocorticoid receptor signaling and highlight the role of GR signaling in physiological and pathophysiological conditions in the major organ systems in the human body. PMID:23953592

  16. Glucocorticoid programming of neuroimmune function.

    Science.gov (United States)

    Walker, David J; Spencer, Karen A

    2018-01-15

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

  17. Are BDNF and glucocorticoid activities calibrated?

    Science.gov (United States)

    Jeanneteau, Freddy; Chao, Moses V.

    2012-01-01

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

  18. Glucocorticoid-induced hyperglycaemia

    NARCIS (Netherlands)

    Gerards, M.C.

    2018-01-01

    This thesis contains studies on current practice, clinical implications and treatment of excess glucocorticoid receptor (GCR) stimulation, with a focus on glucocorticoid-induced hyperglycaemia (GCIH). Chapter 1 is a general introduction to the glucocorticoid hormone. In chapter 2 , we have

  19. Instabilities in mimetic matter perturbations

    Energy Technology Data Exchange (ETDEWEB)

    Firouzjahi, Hassan; Gorji, Mohammad Ali [School of Astronomy, Institute for Research in Fundamental Sciences (IPM), P.O. Box 19395-5531, Tehran (Iran, Islamic Republic of); Mansoori, Seyed Ali Hosseini, E-mail: firouz@ipm.ir, E-mail: gorji@ipm.ir, E-mail: shosseini@shahroodut.ac.ir, E-mail: shossein@ipm.ir [Physics Department, Shahrood University of Technology, P.O. Box 3619995161 Shahrood (Iran, Islamic Republic of)

    2017-07-01

    We study cosmological perturbations in mimetic matter scenario with a general higher derivative function. We calculate the quadratic action and show that both the kinetic term and the gradient term have the wrong sings. We perform the analysis in both comoving and Newtonian gauges and confirm that the Hamiltonians and the associated instabilities are consistent with each other in both gauges. The existence of instabilities is independent of the specific form of higher derivative function which generates gradients for mimetic field perturbations. It is verified that the ghost instability in mimetic perturbations is not associated with the higher derivative instabilities such as the Ostrogradsky ghost.

  20. Cardioprotection by Conditioning Mimetic Drugs.

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    Santillo, Elpidio; Migale, Monica; Postacchini, Demetrio; Balestrini, Fabrizio; Incalzi, Raffaele Antonelli

    2016-01-01

    At present, ischemic heart disease (IHD) is one of the main causes of morbidity and mortality world-wide. An important insight into both IHD pathophysiology and cardioprotection was achieved in 1986 when Murry et al. described for the first time the ischemic preconditioning (IP). IP can be defined as an innate phenomenon by which brief episodes of ischemia confer protection to a tissue from a subsequent more protracted ischemic insult. Suggested mechanisms explaining IP comprise the action of circulating substances (e.g. adenosine, bradykinin, nitric oxide). These mediators are released after a prolonged ischemic stress, causing activation of molecular pathways that induce favorable posttranslational changes of proteins and adaptive modifications in genetic expression. Briefly review evidences from clinical studies on drugs that exert their effects by mimicking IP, discussing their therapeutic properties and the potential clinical employment in order to obtain cardioprotection. Literature regarding IP mimicking pharmacological agents was searched in Medline and Google Scholar. Authors reviewed relevant researches in English language including both clinical studies and reviews of clinical studies published from 1986 to 2016. Several pharmacological agents reproducing IP protective actions have been evaluated in many clinical trials. Examined molecules include adenosine, nicorandil and atrial natriuretic peptide. Interestingly IP mimicking effects of drugs have been also analyzed perioperatively in the context of ischaemia-reperfusion heart injury. Moreover evidences suggest that also some anaesthetic drugs (especially volatile agents) are able to provide myocardial protection by inducing IP. Drugs capable of mimicking IP exhibit a high therapeutic potential because of their properties of eliciting an effective cardioprotective signaling. Future studies should clarify the optimal doses and timing of administration of IP mimetic agents in order to favor the advent of

  1. Glucocorticoids and hemopoietic stem cells

    International Nuclear Information System (INIS)

    Romashko, O.O.; Berin, G.I.

    1978-01-01

    Analyzing the data of home and foreign investigators the problems of the glucocorticoid effect on blood and bone marrow of experimental (including irradiated ones) animals are discussed. Considered are a character and mechanism of the adrenal cortex hormones effect on blood formation, as well as the effect of pharmacological doses of corticosteroids on CFU, their erythropoietic effect in physiological doses on a morphological picture of bone marrow after irradiation and subsequent introduction of hormones and the hormone effect on intensity of erythropoiesis recovery in irradiated mice. Presented are the experimental data on studying the effect of endogenic hypercorticoidism and a reduced level of endogenic corticosteroids on blood-forming stem cells in the irradiated mice and the data on the ACTH injection effect on CFU migration after irradiation. Evaluated are already available data and further investigations to ground advisability and conditions of using corticosteroids as well as determining rational therapeutic effects on secretion of endogenic glucocorticoids when treating blood system diseases

  2. [Glucocorticoid induced osteoporosis].

    Science.gov (United States)

    Anić, Branimir; Mayer, Miroslav

    2014-01-01

    Secondary osteoporosis most often develops due to glucocorticoid therapy. Glucocorticoids affect all stages of the bone remodeling cycle, its formation and resorption. Osteoblasts are primarily affected, decreasing their activity and enhancing apoptosis. Patients treated with glucocorticoids have lower bone mineral density and increased fracture risk. Glucocorticoid-induced osteoporosis can be prevented by administering the minimal effective dose of glucocorticoids, calcium and vitamin D supplementation or, if possible, by hormone replace- ment therapy. Moreover, appropriate physical activity should be encouraged. Patients who are at higher risk for low-energy fractures (for example post-menopausal women) have to be actively treated, usually with antiresorptive drugs among which bisphosphonates are currently the first line therapy.

  3. Glucocorticoid receptor modulators.

    Science.gov (United States)

    Meijer, Onno C; Koorneef, Lisa L; Kroon, Jan

    2018-06-01

    The glucocorticoid hormone cortisol acts throughout the body to support circadian processes and adaptation to stress. The glucocorticoid receptor is the target of cortisol and of synthetic glucocorticoids, which are used widely in the clinic. Both agonism and antagonism of the glucocorticoid receptor may be beneficial in disease, but given the wide expression of the receptor and involvement in various processes, beneficial effects are often accompanied by unwanted side effects. Selective glucocorticoid receptor modulators are ligands that induce a receptor conformation that allows activation of only a subset of downstream signaling pathways. Such molecules thereby combine agonistic and antagonistic properties. Here we discuss the mechanisms underlying selective receptor modulation and their promise in treating diseases in several organ systems where cortisol signaling plays a role. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  4. Cosmological dynamics of mimetic gravity

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    Dutta, Jibitesh; Khyllep, Wompherdeiki; Saridakis, Emmanuel N.; Tamanini, Nicola; Vagnozzi, Sunny

    2018-02-01

    We present a detailed investigation of the dynamical behavior of mimetic gravity with a general potential for the mimetic scalar field. Performing a phase-space and stability analysis, we show that the scenario at hand can successfully describe the thermal history of the universe, namely the successive sequence of radiation, matter, and dark-energy eras. Additionally, at late times the universe can either approach a de Sitter solution, or a scaling accelerated attractor where the dark-matter and dark-energy density parameters are of the same order, thus offering an alleviation of the cosmic coincidence problem. Applying our general analysis to various specific potential choices, including the power-law and the exponential ones, we show that mimetic gravity can be brought into good agreement with the observed behavior of the universe. Moreover, with an inverse square potential we find that mimetic gravity offers an appealing unified cosmological scenario where both dark energy and dark matter are characterized by a single scalar field, and where the cosmic coincidence problem is alleviated.

  5. Bio-mimetic Flow Control

    Science.gov (United States)

    Choi, Haecheon

    2009-11-01

    Bio-mimetic engineering or bio-mimetics is the application of biological methods and systems found in nature to the study and design of engineering systems and modern technology (from Wikipedia). The concept itself is old, but successful developments have been made recently, especially in the research field of flow control. The objective of flow control based on the bio-mimetic approach is to develop novel concepts for reducing drag, increasing lift and enhancing aerodynamic performance. For skin friction reduction, a few ideas have been suggested such as the riblet from shark, compliant surface from dolphin, microbubble injection and multiple front-body curvature from penguin, and V-shaped protrusion from sailfish. For form drag reduction, several new attempts have been also made recently. Examples include the V-shaped spanwise grooves from saguaro cactus, overall shape of box fish, longitudinal grooves on scallop shell, bill of swordfish, hooked comb on owl wing, trailing-edge protrusion on dragonfly wing, and fillet. For the enhancement of aerodynamic performance, focuses have been made on the birds, fish and insects: e.g., double layered feather of landing bird, leading-edge serration of humpback-whale flipper, pectoral fin of flying fish, long tail on swallowtail-butterfly wing, wing flapping motion of dragonfly, and alula in birds. Living animals adapt their bodies to better performance in multi purposes, but engineering requires single purpose in most cases. Therefore, bio-mimetic approaches often produce excellent results more than expected. However, they are sometimes based on people's wrong understanding of nature and produce unwanted results. Successes and failures from bio-mimetic approaches in flow control will be discussed in the presentation.

  6. A novel peptide thrombopoietin mimetic designing and optimization using computational approach

    Directory of Open Access Journals (Sweden)

    Vimal kishor Singh

    2016-08-01

    Full Text Available Thrombopoietin receptor (TPOR is a cytokine receptor protein; activation of cell surface TPOR by thrombopoietin (TPO triggers an intracellular cascade of megakaryocytopoiesis for the formation of platelets. TPO is a glycoprotein hormone which stimulates megakaryocytes formation and maturation to platelets in bone marrow. Ex vivo megakaryocytopoiesis is in highlight for its vast role in therapeutics and field of regenerative medicine. For therapeutic uses, various TPO alternatives have been used however they are associated with issues like recombinant TPO administration is associated with the generation of auto antibodies and its production is an expensive process. Moreover, reported thrombopoietin mimetic peptide (TMP has no sequence homology with TPO and low specificity to TPOR. Hence, in this study, a novel peptidic TPO mimetic is designed through computational studies by studying the binding sites of TPO and TMP to TPOR and analogs of known mimetics. Screening of combinatorial library was done through molecular docking using ClusPro and mimetic-9 was found to have better binding score of -938.8 kcal/mol with seven hydrogen bonds and a high number of hydrophobic interactions, than known mimetic TMP with docking score of -798.4 kcal/mol and TMP dimer with docking score of -811.9 kcal/mol for TPOR. Mimetic-9 interaction with TPOR was further assessed by the molecular dynamics simulation and their complex was found to be stable with an RMSD value of 0.091 Aº. Resulting mimetic-9 was found to have overall good physiochemical properties with positive grand average hydropathy (GRAVY score and high instability index score and it was found to be localized in the extracellular region. The designed mimetic-9 might prove to be a useful lead molecule for mimicking the role of TPO and to help for platelet production in vitro with higher efficiency.

  7. Glucocorticoid-Induced Osteoporosis

    Science.gov (United States)

    ... nervosa Cigarette smoking Alcohol abuse Low calcium and vitamin D, by low dietary intake or poor absorption in your gut Sedentary (inactive) lifestyle or immobility Certain medications besides glucocorticoids, including the following: excess thyroid hormone replacement the blood thinner heparin some ...

  8. Research progress of nanoparticles as enzyme mimetics

    Science.gov (United States)

    Hu, XiaoNa; Liu, JianBo; Hou, Shuai; Wen, Tao; Liu, WenQi; Zhang, Ke; He, WeiWei; Ji, YingLu; Ren, HongXuan; Wang, Qi; Wu, XiaoChun

    2011-10-01

    Natural enzymes as biological catalysts possess remarkable advantages, especially their highly efficient and selective catalysis under mild conditions. However, most natural enzymes are proteins, thus exhibiting an inherent low durability to harsh reaction conditions. Artificial enzyme mimetics have been pursued extensively to avoid this drawback. Quite recently, some inorganic nanoparticles (NPs) have been found to exhibit unique enzyme mimetics. In addition, their much higher stability overcomes the inherent disadvantage of natural enzymes. Furthermore, easy mass-production and low cost endow them more benefits. As a new member of artificial enzyme mimetics, they have received intense attention. In this review article, major progress in this field is summarized and future perspectives are highlighted.

  9. Glucocorticoid-related bone changes from endogenous or exogenous glucocorticoids.

    Science.gov (United States)

    Warriner, Amy H; Saag, Kenneth G

    2013-12-01

    Glucocorticoids have a negative impact on bone through direct effects on bone cells and indirect effects on calcium absorption. Here, recent findings regarding glucocorticoid-induced osteoporosis, bone changes in patients with endogenous glucocorticoid derangements, and treatment of steroid-induced bone disease are reviewed. Although the majority of our understanding arises from the outcomes of patients treated with exogenous steroids, endogenous overproduction appears to be similarly destructive to bone, but these effects are reversible with cure of the underlying disease process. Additionally, there are bone changes that occur in diseases that interrupt adrenal glucocorticoid production, both in response to our inability to perfectly match glucocorticoid replacement and also related to the underlying disease process. More investigation is required to understand which patients with endogenous overproduction or underproduction of glucocorticoid would benefit from osteoporosis treatment. Better understood is the benefit that can be achieved with currently approved treatments for glucocorticoid-induced osteoporosis from exogenous steroids. With growing concern of long-term use of bisphosphonates, however, further investigation into the duration of use and use in certain populations, such as children and premenopausal women, is essential. Glucocorticoid-induced osteoporosis is a complex disease that is becoming better understood through advances in the study of exogenous and endogenous glucocorticoid exposure. Further advancement of proper treatment and prevention is on the horizon.

  10. Pathophysiology of Glucocorticoid Signaling.

    Science.gov (United States)

    Vitellius, Géraldine; Trabado, Séverine; Bouligand, Jérôme; Delemer, Brigitte; Lombès, Marc

    2018-06-01

    Glucocorticoids (GC), such as cortisol or dexamethasone, control various physiological functions, notably those involved in development, metabolism, inflammatory processes and stress, and exert most of their effects upon binding to the glucocorticoid receptor (GR, encoded by NR3C1 gene). GC signaling follows several consecutive steps leading to target gene transactivation, including ligand binding, nuclear translocation of ligand-activated GR complexes, DNA binding, coactivator interaction and recruitment of functional transcriptional machinery. Any step may be impaired and may account for altered GC signaling. Partial or generalized glucocorticoid resistance syndrome may result in a reduced level of functional GR, a decreased hormone affinity and binding, a defect in nuclear GR translocation, a decrease or lack of DNA binding and/or post-transcriptional GR modifications. To date, 26 loss-of-function NR3C1 mutations have been reported in the context of hypertension, hirsutism, adrenal hyperplasia or metabolic disorders. These clinical signs are generally associated with biological features including hypercortisolism without negative regulatory feedback loop on the hypothalamic-pituitary-adrenal axis. Patients had often low plasma aldosterone and renin levels despite hypertension. Only one GR gain-of-function mutation has been described associating Cushing's syndrome phenotype with normal urinary-free cortisol. Some GR polymorphisms (ER22/23EK, GR-9β) have been linked to glucocorticoid resistance and a healthier metabolic profile whereas some others seemed to be associated with GC hypersensitivity (N363S, BclI), increasing cardiovascular risk (diabetes type 2, visceral obesity). This review focuses on the earlier findings on the pathophysiology of GR signaling and presents criteria facilitating identification of novel NR3C1 mutations in selected patients. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  11. Risk of catecholaminergic crisis following glucocorticoid administration in patients with an adrenal mass: a literature review

    NARCIS (Netherlands)

    Barrett, C.; Uum, S.H. van; Lenders, J.W.M.

    2015-01-01

    BACKGROUND: Glucocorticoids as diagnostic or therapeutic agents have been reported to carry an increased risk of catecholaminergic crisis (CC) in patients with pheochromocytoma or paraganglioma (PPGL). METHODS: We searched literature databases using the following terms: pheochromocytoma,

  12. Glucocorticoids, chronic stress, and obesity

    NARCIS (Netherlands)

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

    2006-01-01

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

  13. Glucocorticoid receptor beta increases migration of human bladder cancer cells.

    Science.gov (United States)

    McBeth, Lucien; Nwaneri, Assumpta C; Grabnar, Maria; Demeter, Jonathan; Nestor-Kalinoski, Andrea; Hinds, Terry D

    2016-05-10

    Bladder cancer is observed worldwide having been associated with a host of environmental and lifestyle risk factors. Recent investigations on anti-inflammatory glucocorticoid signaling point to a pathway that may impact bladder cancer. Here we show an inverse effect on the glucocorticoid receptor (GR) isoform signaling that may lead to bladder cancer. We found similar GRα expression levels in the transitional uroepithelial cancer cell lines T24 and UMUC-3. However, the T24 cells showed a significant (p bladder cancer cells. Therefore, GRβ may have a significant role in bladder cancer, and possibly serve as a therapeutic target for the disease.

  14. Modular protein switches derived from antibody mimetic proteins.

    Science.gov (United States)

    Nicholes, N; Date, A; Beaujean, P; Hauk, P; Kanwar, M; Ostermeier, M

    2016-02-01

    Protein switches have potential applications as biosensors and selective protein therapeutics. Protein switches built by fusion of proteins with the prerequisite input and output functions are currently developed using an ad hoc process. A modular switch platform in which existing switches could be readily adapted to respond to any ligand would be advantageous. We investigated the feasibility of a modular protein switch platform based on fusions of the enzyme TEM-1 β-lactamase (BLA) with two different antibody mimetic proteins: designed ankyrin repeat proteins (DARPins) and monobodies. We created libraries of random insertions of the gene encoding BLA into genes encoding a DARPin or a monobody designed to bind maltose-binding protein (MBP). From these libraries, we used a genetic selection system for β-lactamase activity to identify genes that conferred MBP-dependent ampicillin resistance to Escherichia coli. Some of these selected genes encoded switch proteins whose enzymatic activity increased up to 14-fold in the presence of MBP. We next introduced mutations into the antibody mimetic domain of these switches that were known to cause binding to different ligands. To different degrees, introduction of the mutations resulted in switches with the desired specificity, illustrating the potential modularity of these platforms. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  15. Xenobiotics and the Glucocorticoid Receptor

    International Nuclear Information System (INIS)

    Gulliver, Linda S M

    2017-01-01

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

  16. Xenobiotics and the Glucocorticoid Receptor

    Energy Technology Data Exchange (ETDEWEB)

    Gulliver, Linda S M, E-mail: linda.gulliver@otago.ac.nz

    2017-03-15

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

  17. Instructions for producing a mouse model of glucocorticoid-induced osteoporosis

    DEFF Research Database (Denmark)

    Thiele, S.; Baschant, U.; Rauch, A.

    2014-01-01

    Glucocorticoids are effective drugs used for the treatment of inflammatory diseases such as rheumatoid arthritis or asthma. Furthermore, they regulate various physiological processes, including bone remodeling. However, long-term high- and even low-dose glucocorticoid use is associated...... with a compromised bone quality and an increased fracture risk. At the cellular level, glucocorticoids suppress bone formation and stimulate bone resorption, which leads to loss of bone mass. To investigate the underlying mechanisms and new therapeutic strategies, the in vivo model for glucocorticoid-induced bone...... loss is widely used. This protocol outlines the common procedure that is currently used for the induction of bone loss in mice using glucocorticoids. It further provides useful hints and highlights possible pitfalls to take into account before starting an experiment....

  18. Impact of glucocorticoid on neurogenesis

    Directory of Open Access Journals (Sweden)

    Haruki Odaka

    2017-01-01

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

  19. Diabetes-impaired wound healing is improved by matrix therapy with heparan sulfate glycosaminoglycan mimetic OTR4120 in rats

    NARCIS (Netherlands)

    M. Tong (Miao); B. Tuk (Bastiaan); P. Shang (Peng); J.M. Hekking-Weijma (Ineke); E.M.G. Fijneman (Esther ); M. Guijt (Marnix); S.E.R. Hovius (Steven); J.W. van Neck (Han)

    2012-01-01

    textabstractWound healing in diabetes is frequently impaired, and its treatment remains a challenge. We tested a therapeutic strategy of potentiating intrinsic tissue regeneration by restoring the wound cellular environment using a heparan sulfate glycosaminoglycan mimetic, OTR4120. The effect of

  20. Optimal glucocorticoid therapy.

    Science.gov (United States)

    Debono, Miguel; Ross, Richard J

    2011-01-01

    The rhythmic regulation of human physiology and behaviour is controlled by a central endogenous clock located in the suprachiasmatic nucleus. Most tissues have peripheral clocks that oscillate in time with this central clock. How the central time keeper controls peripheral clocks is not established, however there is evidence to suggest that the cortisol rhythm is one important secondary messenger. Loss of the endogenous cortisol rhythm is associated with sleep disturbance, depression, and metabolic abnormalities. In adrenal insufficiency, current glucocorticoid replacement regimens cannot replace the normal circadian rhythm of cortisol, and patients have an increased mortality and impaired quality of life. We propose that reproducing circadian cortisol levels may improve quality of life in patients with adrenal insufficiency and we have been investigating the impact of circadian hydrocortisone replacement. Using Chronocort, a modified release preparation of hydrocortisone, we have demonstrated that it is possible to simulate the overnight rise in cortisol release and, in preliminary studies in patients with congenital adrenal hyperplasia, control morning androgen levels. Future studies are now required to determine whether Chronocort can improve quality of life in patients with adrenal insufficiency. Copyright © 2011 S. Karger AG, Basel.

  1. Self-assembly of fibronectin mimetic peptide-amphiphile nanofibers

    Science.gov (United States)

    Rexeisen, Emilie Lynn

    Many therapeutic strategies incorporate peptides into their designs to mimic the natural protein ligands found in vivo. A few examples are the short peptide sequences RGD and PHSRN that mimic the primary and synergy-binding domains of the extracellular matrix protein, fibronectin, which is recognized by the cell surface receptor, alpha5beta 1 integrin. Even though scaffold modification with biomimetic peptides remains one of the most promising approaches for tissue engineering, the use of these peptides in therapeutic tissue-engineered products and drug delivery systems available on the commercial market is limited because the peptides are not easily able to mimic the natural protein. The design of a peptide that can effectively target the alpha5beta1 integrin would greatly increase biomimetic scaffold therapeutic potential. A novel peptide containing both the RGD primary binding domain and PHSRN synergy-binding domain for fibronectin joined with the appropriate linker should bind alpha 5beta1 integrin more efficiently and lead to greater cell adhesion over RGD alone. Several fibronectin mimetic peptides were designed and coupled to dialkyl hydrocarbon tails to make peptide-amphiphiles. The peptides contained different linkers connecting the two binding domains and different spacers separating the hydrophobic tails from the hydrophilic headgroups. The peptide-amphiphiles were deposited on mica substrates using the Langmuir-Blodgett technique. Langmuir isotherms indicated that the peptide-amphiphiles that contained higher numbers of serine residues formed a more tightly packed monolayer, but the increased number of serines also made transferring the amphiphiles to the mica substrate more difficult. Atomic force microscopy (AFM) images of the bilayers showed that the headgroups might be bent, forming small divots in the surface. These divots may help expose the PHSRN synergy-binding domain. Parallel studies undertaken by fellow group members showed that human

  2. Apolipoprotein E Mimetic Promotes Functional and Histological Recovery in Lysolecithin-Induced Spinal Cord Demyelination in Mice

    OpenAIRE

    Gu, Zhen; Li, Fengqiao; Zhang, Yi Ping; Shields, Lisa B.E.; Hu, Xiaoling; Zheng, Yiyan; Yu, Panpan; Zhang, Yongjie; Cai, Jun; Vitek, Michael P.; Shields, Christopher B.

    2014-01-01

    Objective Considering demyelination is the pathological hallmark of multiple sclerosis (MS), reducing demyelination and/or promoting remyelination is a practical therapeutic strategy to improve functional recovery for MS. An apolipoprotein E (apoE)-mimetic peptide COG112 has previously demonstrated therapeutic efficacy on functional and histological recovery in a mouse experimental autoimmune encephalomyelitis (EAE) model of human MS. In the current study, we further investigated whether COG1...

  3. Oestrogene mimetic isoflavones’ pharmacokinetics and pharmacodynamics

    Directory of Open Access Journals (Sweden)

    Anca Dragomirescu,

    2008-12-01

    Full Text Available Genisteine is the most abundant and the most studied estrogen-mimetic izoflavone. It's chemical formula is 4',5,7 – trihidroxyisoflavone. It has also estrogen-modulated properties by its binding ability to the beta type estrogen receptor. Genisteine presents the following farmacodinamic effects: antiaterogen effect, prevention of estrogen-dependent cancers, especially breast cancer, prevention of skin aging body, osteoprogen effect, prevention of osteoporosis at the menopauses women. Despite all these real benefits, there are also many adverse effects, registered both in humans and animals. Thus, the sheep feeding with some Fabaceae species, containing estrogen-mimetic isoflavones were stopped their reproductive function(isoflavones acted as an oral contraceptive. In humans, phytoestroges influence is still under evaluation, being suspected effects such as cerebral involution - via abusive apoptosis - or disturbance in hormonal status, in male children. All these are added to already known allergies, caused by soy proteins.

  4. NEC violation in mimetic cosmology revisited

    Directory of Open Access Journals (Sweden)

    Anna Ijjas

    2016-09-01

    Full Text Available In the context of Einstein gravity, if the null energy condition (NEC is satisfied, the energy density in expanding space–times always decreases while in contracting space–times the energy density grows and the universe eventually collapses into a singularity. In particular, no non-singular bounce is possible. It is, though, an open question if this energy condition can be violated in a controlled way, i.e., without introducing pathologies, such as unstable negative-energy states or an imaginary speed of sound. In this letter, we will re-examine the claim that the recently proposed mimetic scenario can violate the NEC without pathologies. We show that mimetic cosmology is prone to gradient instabilities even in cases when the NEC is satisfied (except for trivial examples. Most interestingly, the source of the instability is always the Einstein–Hilbert term in the action. The matter stress-energy component does not contribute spatial gradient terms but instead makes the problematic curvature modes dynamical. We also show that mimetic cosmology can be understood as a singular limit of known, well-behaved theories involving higher-derivative kinetic terms and discuss ways of removing the instability.

  5. Progress of Mimetic Enzymes and Their Applications in Chemical Sensors.

    Science.gov (United States)

    Yang, Bin; Li, Jianping; Deng, Huan; Zhang, Lianming

    2016-11-01

    The need to develop innovative and reformative approaches to synthesize chemical sensors has increased in recent years because of demands for selectivity, stability, and reproducibility. Mimetic enzymes provide an efficient and convenient method for chemical sensors. This review summarizes the application of mimetic enzymes in chemical sensors. Mimetic enzymes can be classified into five categories: hydrolases, oxidoreductases, transferases, isomerases, and induced enzymes. Potential and recent applications of mimetic enzymes in chemical sensors are reviewed in detail, and the outlook of profound development has been illustrated.

  6. Apolipoprotein Mimetic Peptides: A New Approach for the Treatment of Asthma

    Directory of Open Access Journals (Sweden)

    Xianglan eYao

    2012-03-01

    Full Text Available New treatments are needed for severe asthmatics to improve disease control and avoid severe toxicities associated with oral corticosteroids. We have used a murine model of house dust mite (HDM-induced asthma to identify steroid-unresponsive genes that might represent targets for new therapeutic approaches for severe asthma. This strategy identified apolipoprotein E as a steroid-unresponsive gene with increased mRNA expression in the lungs of HDM-challenged mice. Furthermore, apolipoprotein E functioned as an endogenous negative regulator of airway hyperreactivity and goblet cell hyperplasia in experimental HDM-induced asthma. The ability of apolipoprotein E, which is expressed by lung macrophages, to attenuate AHR and goblet cell hyperplasia is mediated by low density lipoprotein (LDL receptors expressed by airway epithelial cells. Consistent with this, administration of an apolipoprotein E mimetic peptide, corresponding to amino acids 130 to 149 of the LDL receptor-binding domain of the holo-apoE protein, significantly reduced AHR and goblet cell hyperplasia in HDM-challenged apoE-/- mice. These findings identified the apolipoprotein E - LDL receptor pathway as a new druggable target for asthma that can be activated by administration of apoE mimetic peptides. Similarly, apolipoprotein A-I may have therapeutic potential in asthma based upon its anti-inflammatory, anti-oxidative and anti-fibrotic properties. Furthermore, administration of apolipoprotein A-I mimetic peptides has attenuated airway inflammation, airway remodeling and airway hyperreactivity in murine models of experimental asthma. Thus, site-directed delivery of inhaled apolipoprotein E or apolipoprotein A-I mimetic peptides may represent novel treatment approaches that can be developed for asthma, including severe disease.

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

    Directory of Open Access Journals (Sweden)

    Sabrina Paolino

    2017-08-01

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

  8. Glucocorticoids in early rheumatoid arthritis

    NARCIS (Netherlands)

    Everdingen, Amalia A. van

    2002-01-01

    For 50 years, glucocorticoids (GC) are used for symptomatic treatment of rheumatoid arthritis (RA). In the last decade, results from clinical studies of treatment with GC as additional therapy to long-acting antirheumatic drugs in patients with early RA suggested also disease-modifying properties of

  9. Glucocorticoid programming of intrauterine development.

    Science.gov (United States)

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

    2016-07-01

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

  10. Smac Mimetic Bypasses Apoptosis Resistance in FADD- or Caspase-8-Deficient Cells by Priming for Tumor Necrosis Factor α-Induced Necroptosis

    Directory of Open Access Journals (Sweden)

    Bram Laukens

    2011-10-01

    Full Text Available Searching for new strategies to bypass apoptosis resistance, we investigated the potential of the Smac mimetic BV6 in Jurkat leukemia cells deficient in key molecules of the death receptor pathway. Here, we demonstrate for the first time that Smac mimetic primes apoptosis-resistant, FADD- or caspase-8-deficient leukemia cells for TNFα-induced necroptosis in a synergistic manner. In contrast to TNFα, Smac mimetic significantly enhances CD95-induced apoptosis in wild-type but not in FADD-deficient cells. Interestingly, Smac mimetic- and TNFα-mediated cell death occurs without characteristic features of apoptosis (i.e., caspase activation, DNA fragmentation in FADD-deficient cells. By comparison, Smac mimetic and TNFα trigger activation of caspase-8, -9, and -3 and DNA fragmentation in wild-type cells. Consistently, the caspase inhibitor zVAD.fmk fails to block Smac mimetic- and TNFα-triggered cell death in FADD- or caspase-8-deficient cells, while it confers protection in wild-type cells. By comparison, necrostatin-1, an RIP1 kinase inhibitor, abolishes Smac mimetic- and TNFα-induced cell death in FADD- or caspase-8-deficient. Thus, Smac mimetic enhances TNFα-induced cell death in leukemia cells via two distinct pathways in a context-dependent manner: it primes apoptosis-resistant cells lacking FADD or caspase-8 to TNFα-induced, RIP1-dependent and caspase-independent necroptosis, whereas it sensitizes apoptosis-proficient cells to TNFα-mediated, caspase-dependent apoptosis. These findings have important implications for the therapeutic exploitation of necroptosis as an alternative cell death program to overcome apoptosis resistance.

  11. Testosterone supplementation, glucocorticoid milieu and bone homeostasis in the ageing male.

    Science.gov (United States)

    Ajdžanović, Vladimir Z; Filipović, Branko R; Šošić Jurjević, Branka T; Milošević, Verica Lj

    2017-08-01

    Male ageing is entwined with a continuous fall in free testosterone levels, which contributes to the pathogenesis of bone loss. Glucocorticoid excess, either dependent on the ageing process or iatrogenically induced, was found to additionally impair the bone structure and metabolism. Cautious testosterone supplementation in this respect may positively affect the glucocorticoid milieu and bone homeostasis, while testosterone-induced changes in the glucocorticoid output could serve as a determinant of bone-related therapeutic outcome. Namely, bone mineral content/density, the parameters of trabecular bone structure as well as bone strength are enhanced, serum calcitonin levels tend to increase, while serum osteocalcin, serum parathyroid hormone and urinary calcium decrease, all upon testosterone administration to the ageing male. In parallel, testosterone application decreases glucocorticoid secretion in the animal models of male ageing, while clinical data in this field are still inconsistent. Importantly, a physiological link exists between testosterone-induced changes in glucocorticoid levels and the tendency of bone status improvement in the ageing male. We believe that the assessment of circulating adrenocorticotropic hormone concentrations together with glucocorticoid levels, reflecting the hypothalamic-pituitary-adrenal axis feedback loop operativeness during testosterone supplementation, represents a well-balanced bone-related therapeutic update. © 2017 Société Française de Pharmacologie et de Thérapeutique.

  12. Black hole solutions in mimetic Born-Infeld gravity

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Che-Yu [National Taiwan University, Department of Physics and Center for Theoretical Sciences, Taipei (China); LeCosPA, National Taiwan University, Taipei (China); Bouhmadi-Lopez, Mariam [University of the Basque Country UPV/EHU, Department of Theoretical Physics, Bilbao (Spain); IKERBASQUE, Basque Foundation for Science, Bilbao (Spain); Chen, Pisin [National Taiwan University, Department of Physics and Center for Theoretical Sciences, Taipei (China); LeCosPA, National Taiwan University, Taipei (China); Stanford University, Kavli Institute for Particle Astrophysics and Cosmology, SLAC National Accelerator Laboratory, Stanford, CA (United States)

    2018-01-15

    The vacuum, static, and spherically symmetric solutions in the mimetic Born-Infeld gravity are studied. The mimetic Born-Infeld gravity is a reformulation of the Eddington-inspired-Born-Infeld (EiBI) model under the mimetic approach. Due to the mimetic field, the theory contains non-trivial vacuum solutions different from those in Einstein gravity. We find that with the existence of the mimetic field, the spacelike singularity inside a Schwarzschild black hole could be altered to a lightlike singularity, even though the curvature invariants still diverge at the singularity. Furthermore, in this case, the maximal proper time for a timelike radially-infalling observer to reach the singularity is found to be infinite. (orig.)

  13. Black hole solutions in mimetic Born-Infeld gravity.

    Science.gov (United States)

    Chen, Che-Yu; Bouhmadi-López, Mariam; Chen, Pisin

    2018-01-01

    The vacuum, static, and spherically symmetric solutions in the mimetic Born-Infeld gravity are studied. The mimetic Born-Infeld gravity is a reformulation of the Eddington-inspired-Born-Infeld (EiBI) model under the mimetic approach. Due to the mimetic field, the theory contains non-trivial vacuum solutions different from those in Einstein gravity. We find that with the existence of the mimetic field, the spacelike singularity inside a Schwarzschild black hole could be altered to a lightlike singularity, even though the curvature invariants still diverge at the singularity. Furthermore, in this case, the maximal proper time for a timelike radially-infalling observer to reach the singularity is found to be infinite.

  14. [Glucocorticoid therapy: what is the information sought by patients? Traffic analysis of the website cortisone-info.fr].

    Science.gov (United States)

    Poisson, J; Six, M; Morin, C; Fardet, L

    2013-05-01

    About 1% of the general population are receiving systemic glucocorticoids. The information about this treatment sought by patients is unknown. The website www.cortisone-info.fr aims to provide therapeutic information about glucocorticoids and glucocorticoid therapy. It was posted on January 16, 2012. The information available on the website is documented and based on the recent medical literature. The website is made of 43 pages divided into five main sections (generalities about glucocorticoids, adverse events, measures associated with glucocorticoid therapy, discontinuation of glucocorticoids and, situations requiring attention). The website traffic between February 1st, 2012 and January 4, 2013 was analyzed using Google Analytics. During the study period, the website was visited by 67,496 people (average number of visitors per day: 33 in February 2012, 326 in December 2012). The number of page views was 230,496 or an average of 3.5 pages per visitor. Of these 230,496 page views, 145,431 (63.1%) were related to adverse events and 37,722 (16.4%) were related to generalities about glucocorticoids (e.g., what is cortisone? For which disease? How does it work?). Information particularly sought by visitors was related to the diet to follow during glucocorticoid therapy (page accessed 11,946 times), data about what cortisone is (page accessed 11,829 times) and the effects of glucocorticoids on weight (page accessed 10,442 times). Knowledge of glucocorticoid-treated patients' expectations may help physicians to optimize information they give, thereby helping to reduce patients' concerns about glucocorticoids and to improve adherence to the treatment. Copyright © 2013 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  15. Large-scale structure in mimetic Horndeski gravity

    Science.gov (United States)

    Arroja, Frederico; Okumura, Teppei; Bartolo, Nicola; Karmakar, Purnendu; Matarrese, Sabino

    2018-05-01

    In this paper, we propose to use the mimetic Horndeski model as a model for the dark universe. Both cold dark matter (CDM) and dark energy (DE) phenomena are described by a single component, the mimetic field. In linear theory, we show that this component effectively behaves like a perfect fluid with zero sound speed and clusters on all scales. For the simpler mimetic cubic Horndeski model, if the background expansion history is chosen to be identical to a perfect fluid DE (PFDE) then the mimetic model predicts the same power spectrum of the Newtonian potential as the PFDE model with zero sound speed. In particular, if the background is chosen to be the same as that of LCDM, then also in this case the power spectrum of the Newtonian potential in the mimetic model becomes indistinguishable from the power spectrum in LCDM on linear scales. A different conclusion may be found in the case of non-adiabatic perturbations. We also discuss the distinguishability, using power spectrum measurements from LCDM N-body simulations as a proxy for future observations, between these mimetic models and other popular models of DE. For instance, we find that if the background has an equation of state equal to ‑0.95 then we will be able to distinguish the mimetic model from the PFDE model with unity sound speed. On the other hand, it will be hard to do this distinction with respect to the LCDM model.

  16. Glucocorticoid control of gene transcription in neural tissue

    NARCIS (Netherlands)

    Morsink, Maarten Christian

    2007-01-01

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

  17. Deposition of intranasal glucocorticoids--preliminary study.

    Science.gov (United States)

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

    2015-01-01

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

  18. The Mimetic Principle in the Underground Economy

    Directory of Open Access Journals (Sweden)

    Cristina Voicu

    2009-08-01

    Full Text Available There has been in the recent years an increased preoccupation at international level for the research of the mechanism of development of the underground economy. The numerous vain attempts to measure the dimension of the underground economy persuaded us to embark on a qualitative research of this economic phenomenon. In our investigation on the roots of the underground economy we drew very close to the psychological and sociological aspects of the phenomenon itself. The process of humanizing that has at its origin components of the mimetic principle, like acquisitive mimesis, prompt us to ponder over J.M. Keynes’ words: „The avoidance of taxes is the only intellectual ambition that one feels rewarded for.”

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

    NARCIS (Netherlands)

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

    2015-01-01

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

  20. The mimetic finite difference method for elliptic problems

    CERN Document Server

    Veiga, Lourenço Beirão; Manzini, Gianmarco

    2014-01-01

    This book describes the theoretical and computational aspects of the mimetic finite difference method for a wide class of multidimensional elliptic problems, which includes diffusion, advection-diffusion, Stokes, elasticity, magnetostatics and plate bending problems. The modern mimetic discretization technology developed in part by the Authors allows one to solve these equations on unstructured polygonal, polyhedral and generalized polyhedral meshes. The book provides a practical guide for those scientists and engineers that are interested in the computational properties of the mimetic finite difference method such as the accuracy, stability, robustness, and efficiency. Many examples are provided to help the reader to understand and implement this method. This monograph also provides the essential background material and describes basic mathematical tools required to develop further the mimetic discretization technology and to extend it to various applications.

  1. Differential targeting of brain stress circuits with a selective glucocorticoid receptor modulator

    NARCIS (Netherlands)

    Zalachoras, I.; Houtman, R.; Atucha, E.; Devos, R.; Tijssen, A.M.I.; Hu, P.; Lockey, P.M.; Datson, N.A.; Belanoff, J.K.; Lucassen, P.J.; Joëls, M.; de Kloet, E.R.; Roozendaal, B.; Hunt, H.; Meijer, O.C.

    2013-01-01

    Glucocorticoid receptor (GR) antagonism may be of considerable therapeutic value in stress-related psychopathology such as depression. However, blockade of all GR-dependent processes in the brain will lead to unnecessary and even counteractive effects, such as elevated endogenous cortisol levels.

  2. Aspartate and glutamate mimetic structures in biologically active compounds.

    Science.gov (United States)

    Stefanic, Peter; Dolenc, Marija Sollner

    2004-04-01

    Glutamate and aspartate are frequently recognized as key structural elements for the biological activity of natural peptides and synthetic compounds. The acidic side-chain functionality of both the amino acids provides the basis for the ionic interaction and subsequent molecular recognition by specific receptor sites that results in the regulation of physiological or pathophysiological processes in the organism. In the development of new biologically active compounds that possess the ability to modulate these processes, compounds offering the same type of interactions are being designed. Thus, using a peptidomimetic design approach, glutamate and aspartate mimetics are incorporated into the structure of final biologically active compounds. This review covers different bioisosteric replacements of carboxylic acid alone, as well as mimetics of the whole amino acid structure. Amino acid analogs presented include those with different distances between anionic moieties, and analogs with additional functional groups that result in conformational restriction or alternative interaction sites. The article also provides an overview of different cyclic structures, including various cycloalkane, bicyclic and heterocyclic analogs, that lead to conformational restriction. Higher di- and tripeptide mimetics in which carboxylic acid functionality is incorporated into larger molecules are also reviewed. In addition to the mimetic structures presented, emphasis in this article is placed on their steric and electronic properties. These mimetics constitute a useful pool of fragments in the design of new biologically active compounds, particularly in the field of RGD mimetics and excitatory amino acid agonists and antagonists.

  3. Optimal glucocorticoid replacement in adrenal insufficiency.

    Science.gov (United States)

    Øksnes, Marianne; Ross, Richard; Løvås, Kristian

    2015-01-01

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

  4. Glucocorticoids as mediators of developmental programming effects.

    Science.gov (United States)

    Khulan, Batbayar; Drake, Amanda J

    2012-10-01

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

  5. Contribution of glucocorticoids and glucocorticoid receptors to the regulation of neurodegenerative processes.

    Science.gov (United States)

    Vyas, Sheela; Maatouk, Layal

    2013-12-01

    Isolation of glucocorticoids (GCs) from adrenal glands followed by synthesis led rapidly to their first clinical application, about 70 years ago, for treatment of rheumatoid arthritis. To this day GCs are used in diseases that have an inflammatory component. However, their use is carefully monitored because of harmful side effects. GCs are also synonymous with stress and adaptation. In CNS, GC binds and activates high affinity mineralocorticoid receptor (MR) and low affinity glucocorticoid receptor (GR). GR, whose expression is ubiquitous, is only activated when GC levels rise as during circadian peak and in response to stress. Numerous recent studies have yielded important and new insights on the mechanisms concerning pulsatile secretory pattern of GCs as well as various processes that tightly control their synthesis via hypothalamic-pituitary-adrenal (HPA) axis involving regulated release of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) from hypothalamus and pituitary, respectively. GR modulates neuronal functions and viability through both genomic and non-genomic actions, and importantly its transcriptional regulatory activity is tightly locked with GC secretory pattern. There is increasing evidence pointing to involvement of GC-GR in neurodegenerative disorders. Patients with Alzheimer's or Parkinson's or Huntington's disease show chronically high cortisol levels suggesting changes occurring in controls of HPA axis. In experimental models of these diseases, chronic stress or GC treatment was found to exacerbate both the clinical symptoms and neurodegenerative processes. However, recent evidence also shows that GC-GR can exert neuroprotective effects. Thus, for any potential therapeutic strategies in these neurodegenerative diseases we need to understand the precise modifications both in HPA axis and in GR activity and find ways to harness their protective actions.

  6. Glucocorticoids, vitamin D and bone : a pathophysiologic and therapeutic study of glucocorticoid-induced bone disease

    NARCIS (Netherlands)

    J.J. Braun (Jacob Johannes)

    1984-01-01

    textabstractMooser's report ( 1921) of a patient with osteoporosis and obesity is one of the first descriptions of endogenous hypercortisolism. Later Cushing (1932) described the syndrome as a clinical entity and Albright et al. (1941) reported 9 patients who at autopsy all appeared to have

  7. Circumvention of glucocorticoid resistance in childhood leukemia.

    Science.gov (United States)

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

    2008-09-01

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

  8. Exenatide improves glucocorticoid-induced glucose intolerance in mice

    Directory of Open Access Journals (Sweden)

    Ruiying Zhao

    2011-01-01

    Full Text Available Ruiying Zhao1,2*, Enrique Fuentes-Mattei1,2*, Guermarie Velazquez-Torres1,3, Chun-Hui Su1,2, Jian Chen1, Mong-Hong Lee1,2, Sai-Ching Jim Yeung4,51Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Program in Genes and Development, 3Program in Cancer Biology, Graduate School of Biomedical Sciences, University of Texas Health Science Center in Houston, Houston, TX, USA; 4Department of Endocrine Neoplasia and Hormonal Disorders, 5Department of Emergency Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA *Both authors contributed equally.Abstract: Exenatide is an incretin mimetic that is recently available in the US for the treatment of diabetes. There is a paucity of information on the effects of exenatide in glucocorticoid (GC-induced diabetes. Although the effect of continuous intravenous infusion of exenatide on GC-induced glucose intolerance has been investigated before in healthy human males receiving oral prednisolone, we investigated the efficacy of a single subcutaneous dose of exenatide (3 µg/kg in lowering blood glucose in GC-induced glucose intolerance in C57BL/6 mice. In a longitudinal experiment, the area under the curve (AUC of oral glucose tolerance tests (OGTT significantly increased after dexamethasone (P = 0.004, which was subsequently decreased by exenatide (P < 0.001. A cross-sectional experiment showed that exenatide improved glucose tolerance compared with placebo in a mouse model of dexamethasone-induced glucose intolerance. AUC of OGTT in the exenatide group were significantly (P < 0.001 lower than in the placebo group. Insulin tolerance tests (ITT demonstrated that exenatide decreased the ability of the mice to tolerate insulin compared with placebo. The AUC of ITT in the exenatide group were also significantly (P = 0.006 lower than in the placebo group. In conclusion, a single dose of exenatide was able to decrease glucose intolerance and

  9. Glucocorticoids are ineffective in alcoholic hepatitis

    DEFF Research Database (Denmark)

    Christensen, E; Gluud, C

    1995-01-01

    The aim of this study was to perform a meta-analysis of controlled clinical trials of glucocorticoid treatment in clinical alcoholic hepatitis, adjusting for prognostic variables and their possible interaction with therapy, because these trials have given appreciably different results. Weighted...... logistic regression analysis was applied using the summarised descriptive data (for example, % with encephalopathy, mean bilirubin value) of the treatment and control groups of 12 controlled trials that gave this information. Despite evidence of publication bias favouring glucocorticoid treatment, its...... overall effect on mortality was not statistically significant (p = 0.20)--the relative risk (steroid/control) was 0.78 (95% confidence intervals 0.51, 1.18). There was indication of interaction between glucocorticoid therapy and gender, but not encephalopathy. Thus, the effect of glucocorticoid treatment...

  10. Molecular mechanisms of glucocorticoid receptor signaling

    Directory of Open Access Journals (Sweden)

    Marta Labeur

    2010-10-01

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

  11. Glucocorticoids and fetal programming part 2: Mechanisms.

    Science.gov (United States)

    Moisiadis, Vasilis G; Matthews, Stephen G

    2014-07-01

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

  12. Copper Complexes of Nicotinic-Aromatic Carboxylic Acids as Superoxide Dismutase Mimetics

    Directory of Open Access Journals (Sweden)

    Virapong Prachayasittikul

    2008-12-01

    Full Text Available Nicotinic acid (also known as vitamin B3 is a dietary element essential for physiological and antihyperlipidemic functions. This study reports the synthesis of novel mixed ligand complexes of copper with nicotinic and other select carboxylic acids (phthalic, salicylic and anthranilic acids. The tested copper complexes exhibited superoxide dismutase (SOD mimetic activity and antimicrobial activity against Bacillus subtilis ATCC 6633, with a minimum inhibition concentration of 256 μg/mL. Copper complex of nicotinic-phthalic acids (CuNA/Ph was the most potent with a SOD mimetic activity of IC50 34.42 μM. The SOD activities were observed to correlate well with the theoretical parameters as calculated using density functional theory (DFT at the B3LYP/LANL2DZ level of theory. Interestingly, the SOD activity of the copper complex CuNA/Ph was positively correlated with the electron affinity (EA value. The two quantum chemical parameters, highest occupied molecular orbital (HOMO and lowest unoccupied molecular orbital (LUMO, were shown to be appropriate for understanding the mechanism of the metal complexes as their calculated energies show good correlation with the SOD activity. Moreover, copper complex with the highest SOD activity were shown to possess the lowest HOMO energy. These findings demonstrate a great potential for the development of value-added metallovitamin-based therapeutics.

  13. A membrane glucocorticoid receptor mediates the rapid/non-genomic actions of glucocorticoids in mammalian skeletal muscle fibres.

    Science.gov (United States)

    Pérez, María Hernández-Alcalá; Cormack, Jonathan; Mallinson, David; Mutungi, Gabriel

    2013-10-15

    Glucocorticoids (GCs) are steroid hormones released from the adrenal gland in response to stress. They are also some of the most potent anti-inflammatory and immunosuppressive drugs currently in clinical use. They exert most of their physiological and pharmacological actions through the classical/genomic pathway. However, they also have rapid/non-genomic actions whose physiological and pharmacological functions are still poorly understood. Therefore, the primary aim of this study was to investigate the rapid/non-genomic effects of two widely prescribed glucocorticoids, beclomethasone dipropionate (BDP) and prednisolone acetate (PDNA), on force production in isolated, intact, mouse skeletal muscle fibre bundles. The results show that the effects of both GCs on maximum isometric force (Po) were fibre-type dependent. Thus, they increased Po in the slow-twitch fibre bundles without significantly affecting that of the fast-twitch fibre bundles. The increase in Po occurred within 10 min and was insensitive to the transcriptional inhibitor actinomycin D. Also, it was maximal at ∼250 nM and was blocked by the glucocorticoid receptor (GCR) inhibitor RU486 and a monoclonal anti-GCR, suggesting that it was mediated by a membrane (m) GCR. Both muscle fibre types expressed a cytosolic GCR. However, a mGCR was present only in the slow-twitch fibres. The receptor was more abundant in oxidative than in glycolytic fibres and was confined mainly to the periphery of the fibres where it co-localised with laminin. From these findings we conclude that the rapid/non-genomic actions of GCs are mediated by a mGCR and that they are physiologically/therapeutically beneficial, especially in slow-twitch muscle fibres.

  14. 11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

    Science.gov (United States)

    Chapman, Karen; Holmes, Megan

    2013-01-01

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

  15. Bio-Mimetic Sensors Based on Molecularly Imprinted Membranes

    Science.gov (United States)

    Algieri, Catia; Drioli, Enrico; Guzzo, Laura; Donato, Laura

    2014-01-01

    An important challenge for scientific research is the production of artificial systems able to mimic the recognition mechanisms occurring at the molecular level in living systems. A valid contribution in this direction resulted from the development of molecular imprinting. By means of this technology, selective molecular recognition sites are introduced in a polymer, thus conferring it bio-mimetic properties. The potential applications of these systems include affinity separations, medical diagnostics, drug delivery, catalysis, etc. Recently, bio-sensing systems using molecularly imprinted membranes, a special form of imprinted polymers, have received the attention of scientists in various fields. In these systems imprinted membranes are used as bio-mimetic recognition elements which are integrated with a transducer component. The direct and rapid determination of an interaction between the recognition element and the target analyte (template) was an encouraging factor for the development of such systems as alternatives to traditional bio-assay methods. Due to their high stability, sensitivity and specificity, bio-mimetic sensors-based membranes are used for environmental, food, and clinical uses. This review deals with the development of molecularly imprinted polymers and their different preparation methods. Referring to the last decades, the application of these membranes as bio-mimetic sensor devices will be also reported. PMID:25196110

  16. Bio-Mimetic Sensors Based on Molecularly Imprinted Membranes

    Directory of Open Access Journals (Sweden)

    Catia Algieri

    2014-07-01

    Full Text Available An important challenge for scientific research is the production of artificial systems able to mimic the recognition mechanisms occurring at the molecular level in living systems. A valid contribution in this direction resulted from the development of molecular imprinting. By means of this technology, selective molecular recognition sites are introduced in a polymer, thus conferring it bio-mimetic properties. The potential applications of these systems include affinity separations, medical diagnostics, drug delivery, catalysis, etc. Recently, bio-sensing systems using molecularly imprinted membranes, a special form of imprinted polymers, have received the attention of scientists in various fields. In these systems imprinted membranes are used as bio-mimetic recognition elements which are integrated with a transducer component. The direct and rapid determination of an interaction between the recognition element and the target analyte (template was an encouraging factor for the development of such systems as alternatives to traditional bio-assay methods. Due to their high stability, sensitivity and specificity, bio-mimetic sensors-based membranes are used for environmental, food, and clinical uses. This review deals with the development of molecularly imprinted polymers and their different preparation methods. Referring to the last decades, the application of these membranes as bio-mimetic sensor devices will be also reported.

  17. Characterization of a novel non-steroidal glucocorticoid receptor antagonist

    Energy Technology Data Exchange (ETDEWEB)

    Li, Qun-Yi; Zhang, Meng [The National Center for Drug Screening, Shanghai (China); State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China); Hallis, Tina M.; DeRosier, Therese A. [Cell Systems Division, Invitrogen, Madison, WI (United States); Yue, Jian-Min; Ye, Yang [State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China); Mais, Dale E. [The National Center for Drug Screening, Shanghai (China); MPI Research, Mattawan, MI (United States); Wang, Ming-Wei, E-mail: wangmw@mail.shcnc.ac.cn [The National Center for Drug Screening, Shanghai (China); State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China)

    2010-01-15

    Selective antagonists of the glucocorticoid receptor (GR) are desirable for the treatment of hypercortisolemia associated with Cushing's syndrome, psychic depression, obesity, diabetes, neurodegenerative diseases, and glaucoma. NC3327, a non-steroidal small molecule with potent binding affinity to GR (K{sub i} = 13.2 nM), was identified in a high-throughput screening effort. As a full GR antagonist, NC3327 greatly inhibits the dexamethasone (Dex) induction of marker genes involved in hepatic gluconeogenesis, but has a minimal effect on matrix metalloproteinase 9 (MMP-9), a GR responsive pro-inflammatory gene. Interestingly, the compound recruits neither coactivators nor corepressors to the GR complex but competes with glucocorticoids for the interaction between GR and a coactivator peptide. Moreover, NC3327 does not trigger GR nuclear translocation, but significantly blocks Dex-induced GR transportation to the nucleus, and thus appears to be a 'competitive' GR antagonist. Therefore, the non-steroidal compound, NC3327, may represent a new class of GR antagonists as potential therapeutics for a variety of cortisol-related endocrine disorders.

  18. Glucocorticoid augmentation of prolonged exposure therapy: rationale and case report

    Directory of Open Access Journals (Sweden)

    Laura Pratchett

    2010-12-01

    Full Text Available Rationale: Prolonged exposure (PE therapy has been found to reduce symptoms of posttraumatic stress disorder (PTSD; however, it is difficult for many patients to engage fully in the obligatory retelling of their traumatic experiences. This problem is compounded by the fact that habituation and cognitive restructuring – the main mechanisms through which PE is hypothesized to work – are not instantaneous processes, and often require several weeks before the distress associated with imaginal exposure abates. Case reports: Two cases are described that respectively illustrate the use of hydrocortisone and placebo, in combination with PE, for the treatment of combat-related PTSD. Based on known effects of glucocorticoids on learning and memory performance, we hypothesized that augmentation with hydrocortisone would improve the therapeutic effects of PE by hastening “new” learning and facilitating decreases in the emotional impact of fear memories during the course of treatment. The veteran receiving hydrocortisone augmentation of PE displayed an accelerated and ultimately greater decline in PTSD symptoms than the veteran receiving placebo. Conclusions: While no general conclusion can be derived from comparison of two patients, the findings are consistent with the rationale for augmentation. These case reports support the potential for an appropriately designed and powered clinical trial to examine the efficacy of glucocorticoids in augmenting the effects of psychotherapy for PTSD.

  19. Characterization of a novel non-steroidal glucocorticoid receptor antagonist

    International Nuclear Information System (INIS)

    Li, Qun-Yi; Zhang, Meng; Hallis, Tina M.; DeRosier, Therese A.; Yue, Jian-Min; Ye, Yang; Mais, Dale E.; Wang, Ming-Wei

    2010-01-01

    Selective antagonists of the glucocorticoid receptor (GR) are desirable for the treatment of hypercortisolemia associated with Cushing's syndrome, psychic depression, obesity, diabetes, neurodegenerative diseases, and glaucoma. NC3327, a non-steroidal small molecule with potent binding affinity to GR (K i = 13.2 nM), was identified in a high-throughput screening effort. As a full GR antagonist, NC3327 greatly inhibits the dexamethasone (Dex) induction of marker genes involved in hepatic gluconeogenesis, but has a minimal effect on matrix metalloproteinase 9 (MMP-9), a GR responsive pro-inflammatory gene. Interestingly, the compound recruits neither coactivators nor corepressors to the GR complex but competes with glucocorticoids for the interaction between GR and a coactivator peptide. Moreover, NC3327 does not trigger GR nuclear translocation, but significantly blocks Dex-induced GR transportation to the nucleus, and thus appears to be a 'competitive' GR antagonist. Therefore, the non-steroidal compound, NC3327, may represent a new class of GR antagonists as potential therapeutics for a variety of cortisol-related endocrine disorders.

  20. Elaborate Mimetic Vocal Displays by Female Superb Lyrebirds

    Directory of Open Access Journals (Sweden)

    Anastasia H Dalziell

    2016-04-01

    Full Text Available Some of the most striking vocalizations in birds are made by males that incorporate vocal mimicry in their sexual displays. Mimetic vocalization in females is largely undescribed, but it is unclear whether this is because of a lack of selection for vocal mimicry in females, or whether the phenomenon has simply been overlooked. These issues are thrown into sharp relief in the superb lyrebird, Menura novaehollandiae, a basal oscine passerine with a lek-like mating system and female uniparental care. The spectacular mimetic song display produced by courting male lyrebirds is a textbook example of a sexually selected trait, but the vocalizations of female lyrebirds are largely unknown. Here, we provide the first analysis of the structure and context of the vocalizations of female lyrebirds. Female lyrebirds were completely silent during courtship; however, females regularly produced sophisticated vocal displays incorporating both lyrebird-specific vocalizations and imitations of sounds within their environment. The structure of female vocalizations varied significantly with context. While foraging, females mostly produced a complex lyrebird-specific song, whereas they gave lyrebird-specific alarm calls most often during nest defense. Within their vocal displays females also included a variety of mimetic vocalizations, including imitations of the calls of dangerous predators, and of alarm calls and song of harmless heterospecifics. Females gave more mimetic vocalizations during nest defense than while foraging, and the types of sounds they imitated varied between these contexts, suggesting that mimetic vocalizations have more than one function. These results are inconsistent with previous portrayals of vocalizations by female lyrebirds as rare, functionless by-products of sexual selection on males. Instead, our results support the hypotheses that complex female vocalizations play a role in nest defense and mediate female-female competition for

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

    Science.gov (United States)

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

    2015-01-01

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

  2. The BH3 Mimetic Obatoclax Accumulates in Lysosomes and Causes Their Alkalinization.

    Science.gov (United States)

    Stamelos, Vasileios A; Fisher, Natalie; Bamrah, Harnoor; Voisey, Carolyn; Price, Joshua C; Farrell, William E; Redman, Charles W; Richardson, Alan

    2016-01-01

    Obatoclax belongs to a class of compounds known as BH3 mimetics which function as antagonists of Bcl-2 family apoptosis regulators. It has undergone extensive preclinical and clinical evaluation as a cancer therapeutic. Despite this, it is clear that obatoclax has additional pharmacological effects that contribute to its cytotoxic activity. It has been claimed that obatoclax, either alone or in combination with other molecularly targeted therapeutics, induces an autophagic form of cell death. In addition, obatoclax has been shown to inhibit lysosomal function, but the mechanism of this has not been elucidated. We have evaluated the mechanism of action of obatoclax in eight ovarian cancer cell lines. Consistent with its function as a BH3 mimetic, obatoclax induced apoptosis in three cell lines. However, in the remaining cell lines another form of cell death was evident because caspase activation and PARP cleavage were not observed. Obatoclax also failed to show synergy with carboplatin and paclitaxel, chemotherapeutic agents which we have previously shown to be synergistic with authentic Bcl-2 family antagonists. Obatoclax induced a profound accumulation of LC-3 but knockdown of Atg-5 or beclin had only minor effects on the activity of obatoclax in cell growth assays suggesting that the inhibition of lysosomal function rather than stimulation of autophagy may play a more prominent role in these cells. To evaluate how obatoclax inhibits lysosomal function, confocal microscopy studies were conducted which demonstrated that obatoclax, which contains two basic pyrrole groups, accumulates in lysosomes. Studies using pH sensitive dyes demonstrated that obatoclax induced lysosomal alkalinization. Furthermore, obatoclax was synergistic in cell growth/survival assays with bafilomycin and chloroquine, two other drugs which cause lysosomal alkalinization. These studies explain, for the first time, how obatoclax inhibits lysosomal function and suggest that lysosomal

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

    DEFF Research Database (Denmark)

    Lunn, T H; Kehlet, H

    2013-01-01

    with systemic glucocorticoid. Pain was reduced with high-dose systemic and local glucocorticoid, but not with low-dose systemic glucocorticoid. Systemic inflammatory markers were reduced with low-dose and high-dose systemic glucocorticoid, and with local glucocorticoid. Functional recovery was improved...... with local glucocorticoid. All studies were small-sized and none sufficiently powered to meaningfully evaluate uncommon adverse events. Most of the local administration studies had poor scientific quality (high risk of bias). Due to clinical heterogeneity and poor scientific quality, no meta......-analysis was performed. In conclusion, in addition to PONV reduction with low-dose systemic glucocorticoid, this review supports high-dose systemic glucocorticoid to ameliorate post-operative pain after hip and knee surgery. However, large-scale safety and dose-finding studies are warranted before final recommendations....

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

    NARCIS (Netherlands)

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

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

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

    NARCIS (Netherlands)

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

    2014-01-01

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

  6. Adverse Consequences of Glucocorticoid Medication : Psychological, Cognitive, and Behavioral Effects

    NARCIS (Netherlands)

    Judd, Lewis L.; Schettler, Pamela J.; Brown, E. Sherwood; Wolkowitz, Owen M.; Sternberg, Esther M.; Bender, Bruce G.; Bulloch, Karen; Cidlowski, John A.; de Kloet, E. Ronald; Fardet, Laurence; Joëls, Marian; Leung, Donald Y. M.; McEwen, Bruce S.; Roozendaal, Benno; Van Rossum, Elisabeth F. C.; Ahn, Junyoung; Brown, David W.; Plitt, Aaron; Singh, Gagandeep

    2014-01-01

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

  7. Glucocorticoids and fetal programming part 1: Outcomes.

    Science.gov (United States)

    Moisiadis, Vasilis G; Matthews, Stephen G

    2014-07-01

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

  8. Exogenous glucocorticoids and adverse cerebral effects in children

    DEFF Research Database (Denmark)

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

    2011-01-01

    of the glucocorticoid receptor, which is associated with unfavorable cellular outcomes. Prenatal treatment with glucocorticoids can compromise brain growth and is associated with periventricular leukomalacia, attentions deficits and poorer cognitive performance. In the neonatal period exposure to glucocorticoids....... Glucocortioids affect several cellular structures and functions, which may explain the observed adverse effects. Glucocorticoids can impair neuronal glucose uptake, decrease excitability, cause atrophy of dendrites, compromise development of myelin-producing oligodendrocytes and disturb important cellular...

  9. Islet-cell dysfunction induced by glucocorticoid treatment

    DEFF Research Database (Denmark)

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

    2013-01-01

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

  10. Apolipoprotein E Mimetic Promotes Functional and Histological Recovery in Lysolecithin-Induced Spinal Cord Demyelination in Mice.

    Science.gov (United States)

    Gu, Zhen; Li, Fengqiao; Zhang, Yi Ping; Shields, Lisa B E; Hu, Xiaoling; Zheng, Yiyan; Yu, Panpan; Zhang, Yongjie; Cai, Jun; Vitek, Michael P; Shields, Christopher B

    2013-04-01

    Considering demyelination is the pathological hallmark of multiple sclerosis (MS), reducing demyelination and/or promoting remyelination is a practical therapeutic strategy to improve functional recovery for MS. An apolipoprotein E (apoE)-mimetic peptide COG112 has previously demonstrated therapeutic efficacy on functional and histological recovery in a mouse experimental autoimmune encephalomyelitis (EAE) model of human MS. In the current study, we further investigated whether COG112 promotes remyelination and improves functional recovery in lysolecithin induced focal demyelination in the white matter of spinal cord in mice. A focal demyelination model was created by stereotaxically injecting lysolecithin into the bilateral ventrolateral funiculus (VLF) of T8 and T9 mouse spinal cords. Immediately after lysolecithin injection mice were treated with COG112, prefix peptide control or vehicle control for 21 days. The locomotor function of the mice was measured by the beam walking test and Basso Mouse Scale (BMS) assessment. The nerve transmission of the VLF of mice was assessed in vivo by transcranial magnetic motor evoked potentials (tcMMEPs). The histological changes were also examined by by eriochrome cyanine staining, immunohistochemistry staining and electron microscopy (EM) method. The area of demyelination in the spinal cord was significantly reduced in the COG112 group. EM examination showed that treatment with COG112 increased the thickness of myelin sheaths and the numbers of surviving axons in the lesion epicenter. Locomotor function was improved in COG112 treated animals when measured by the beam walking test and BMS assessment compared to controls. TcMMEPs also demonstrated the COG112-mediated enhancement of amplitude of evoked responses. The apoE-mimetic COG112 demonstrates a favorable combination of activities in suppressing inflammatory response, mitigating demyelination and in promoting remyelination and associated functional recovery in animal model

  11. Eco-Cognitive Computationalism: From Mimetic Minds to Morphology-Based Enhancement of Mimetic Bodies

    Directory of Open Access Journals (Sweden)

    Lorenzo Magnani

    2018-06-01

    Full Text Available Eco-cognitive computationalism sees computation in context, exploiting the ideas developed in those projects that have originated the recent views on embodied, situated, and distributed cognition. Turing’s original intellectual perspective has already clearly depicted the evolutionary emergence in humans of information, meaning, and of the first rudimentary forms of cognition, as the result of a complex interplay and simultaneous coevolution, in time, of the states of brain/mind, body, and external environment. This cognitive process played a fundamental heuristic role in Turing’s invention of the universal logical computing machine. It is by extending this eco-cognitive perspective that we can see that the recent emphasis on the simplification of cognitive and motor tasks generated in organic agents by morphological aspects implies the construction of appropriate “mimetic bodies”, able to render the accompanied computation simpler, according to a general appeal to the “simplexity” of animal embodied cognition. I hope it will become clear that eco-cognitive computationalism does not aim at furnishing a final and stable definition of the concept of computation, such as a textbook or a different epistemological approach could provide: I intend to take into account the historical and dynamical character of the concept, to propose an intellectual framework that depicts how we can understand not only the change of its meaning, but also the “emergence” of new forms of computations.

  12. Myostatin Suppression of Akirin1 Mediates Glucocorticoid-Induced Satellite Cell Dysfunction

    Science.gov (United States)

    Dong, Yanjun; Pan, Jenny S.; Zhang, Liping

    2013-01-01

    Glucocorticoids production is increased in many pathological conditions that are associated with muscle loss, but their role in causing muscle wasting is not fully understood. We have demonstrated a new mechanism of glucocorticoid-induced muscle atrophy: Dexamethasone (Dex) suppresses satellite cell function contributing to the development of muscle atrophy. Specifically, we found that Dex decreases satellite cell proliferation and differentiation in vitro and in vivo. The mechanism involved Dex-induced upregulation of myostatin and suppression of Akirin1, a promyogenic gene. When myostatin was inhibited in Dex-treated mice, Akirin1 expression increased as did satellite cell activity, muscle regeneration and muscle growth. In addition, silencing myostatin in myoblasts or satellite cells prevented Dex from suppressing Akirin1 expression and cellular proliferation and differentiation. Finally, overexpression of Akirin1 in myoblasts increased their expression of MyoD and myogenin and improved cellular proliferation and differentiation, theses improvements were no longer suppressed by Dex. We conclude that glucocorticoids stimulate myostatin which inhibits Akirin1 expression and the reparative functions of satellite cells. These responses attribute to muscle atrophy. Thus, inhibition of myostatin or increasing Akirin1 expression could lead to therapeutic strategies for improving satellite cell activation and enhancing muscle growth in diseases associated with increased glucocorticoid production. PMID:23516508

  13. Myostatin suppression of Akirin1 mediates glucocorticoid-induced satellite cell dysfunction.

    Directory of Open Access Journals (Sweden)

    Yanjun Dong

    Full Text Available Glucocorticoids production is increased in many pathological conditions that are associated with muscle loss, but their role in causing muscle wasting is not fully understood. We have demonstrated a new mechanism of glucocorticoid-induced muscle atrophy: Dexamethasone (Dex suppresses satellite cell function contributing to the development of muscle atrophy. Specifically, we found that Dex decreases satellite cell proliferation and differentiation in vitro and in vivo. The mechanism involved Dex-induced upregulation of myostatin and suppression of Akirin1, a promyogenic gene. When myostatin was inhibited in Dex-treated mice, Akirin1 expression increased as did satellite cell activity, muscle regeneration and muscle growth. In addition, silencing myostatin in myoblasts or satellite cells prevented Dex from suppressing Akirin1 expression and cellular proliferation and differentiation. Finally, overexpression of Akirin1 in myoblasts increased their expression of MyoD and myogenin and improved cellular proliferation and differentiation, theses improvements were no longer suppressed by Dex. We conclude that glucocorticoids stimulate myostatin which inhibits Akirin1 expression and the reparative functions of satellite cells. These responses attribute to muscle atrophy. Thus, inhibition of myostatin or increasing Akirin1 expression could lead to therapeutic strategies for improving satellite cell activation and enhancing muscle growth in diseases associated with increased glucocorticoid production.

  14. Management of glucocorticoids-induced osteoporosis: role of teriparatide

    Directory of Open Access Journals (Sweden)

    Silvia Migliaccio

    2009-04-01

    Full Text Available Silvia Migliaccio1, Marina Brama1, Nazzarena Malavolta21Dipartimento di Fisiopatologia Medica, Policlinico Umberto I, Università degli Studi Sapienza di Roma, Italy; 2Dipartimento di Medicina Interna, Policlinico S Orsola Malpighi, Bologna, ItalyAbstract: Glucocorticoids (GC-induced osteoporosis (GIOP is the most common cause of secondary osteoporosis, which leads to an increased fracture risk in patients. The normal bone turnover depends on a balance between osteoblasts and osteoclasts activity and GC can cause a rapid bone loss, decreasing bone formation and increasing bone resorption. The decreased bone formation is mainly due to the GC-induced apoptosis of both osteoblasts and osteocytes, while the increased bone resorption is due to the increased life-span of pre-existing osteoclasts. Bisphosphonates are clearly effective in preventing and treating GIOP but anabolic therapeutic strategies are the new promising therapeutic alternative. Experimental and clinical studies indicate that teriparatide, the active (1–34 parathyroid hormone (PTH molecule, is efficacious for the treatment of GIOP, being able to induce an increase in bone mass in these patients. Intermittent administration of human PTH (1–34 stimulates bone formation by increasing osteoblast number. Additionally, human PTH (1–34 modulates the level and/or activity of locally produced growth factors and cytokines. Teriparatide has been demonstrated in several clinical studies to significantly decrease the incidence of fractures in patients affected by GIOP. It has recently received an indication for GIOP and its label indication has also been expanded.Keywords: glucocorticoids, osteoblasts, osteoclasts, osteoporosis, teriparatide

  15. Systems Biology of Glucocorticoids in Muscle Disease

    Science.gov (United States)

    2010-10-01

    Introduction Duchenne muscular dystrophy (DMD) is the most common and incurable muscular dystrophy of childhood. Muscle regeneration fails with...SUBJECT TERMS Duchenne Muscular dystrophy , Glucocorticoids, Systems biology, Drug mechanism 16. SECURITY CLASSIFICATION OF: U 17. LIMITATION...better targeted and more effective therapies for Duchenne muscular dystrophy dynamically. This MDA grant proposal is led by Dr. Eric Hoffman, and it

  16. On the retinal toxicity of intraocular glucocorticoids.

    Science.gov (United States)

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

    2010-12-15

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

  17. From receptor balance to rational glucocorticoid therapy.

    Science.gov (United States)

    de Kloet, E Ron

    2014-08-01

    Corticosteroids secreted as end product of the hypothalamic-pituitary-adrenal axis act like a double-edged sword in the brain. The hormones coordinate appraisal processes and decision making during the initial phase of a stressful experience and promote subsequently cognitive performance underlying the management of stress adaptation. This action exerted by the steroids on the initiation and termination of the stress response is mediated by 2 related receptor systems: mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs). The receptor types are unevenly distributed but colocalized in abundance in neurons of the limbic brain to enable these complementary hormone actions. This contribution starts from a historical perspective with the observation that phasic occupancy of GR during ultradian rhythmicity is needed to maintain responsiveness to corticosteroids. Then, during stress, initially MR activation enhances excitability of limbic networks that are engaged in appraisal and emotion regulation. Next, the rising hormone concentration occupies GR, resulting in reallocation of energy to limbic-cortical circuits with a role in behavioral adaptation and memory storage. Upon MR:GR imbalance, dysregulation of the hypothalamic-pituitary-adrenal axis occurs, which can enhance an individual's vulnerability. Imbalance is characteristic for chronic stress experience and depression but also occurs during exposure to synthetic glucocorticoids. Hence, glucocorticoid psychopathology may develop in susceptible individuals because of suppression of ultradian/circadian rhythmicity and depletion of endogenous corticosterone from brain MR. This knowledge generated from testing the balance hypothesis can be translated to a rational glucocorticoid therapy.

  18. Glucocorticoid Regulation of the Vitamin D Receptor

    Science.gov (United States)

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

    2010-01-01

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

  19. Salicylamide and salicylglycine oxidovanadium complexes with insulin-mimetic properties.

    Science.gov (United States)

    Nilsson, Jessica; Shteinman, Albert A; Degerman, Eva; Enyedy, Eva A; Kiss, Tamás; Behrens, Ulrich; Rehder, Dieter; Nordlander, Ebbe

    2011-12-01

    Reaction of N-(2-hydroxybenzyl)-N-(2-picolyl) glycine (H(2)papy) with VOSO(4) in water gives the oxidovanadium(V) oxido-bridged dimer [{(papy)(VO)}(2) μ-O)] (1). Similarly, reaction of N-(2-hydroxybenzyl) glycine (H(2)glysal) with VOSO(4) gives [(glysal)VO(H(2)O)] (2) and reaction of salicylamide (Hsalam) with VOSO(4) in methanol gives [(salam)(2)VO] (3). The crystal structure of the oxido-bridged complex 1 is reported. The insulin-mimetic activity of all three complexes was evaluated with respect to their ability to phosphorylate protein kinase B (PKB). The speciations of complexes 1 and 2 were studied over the pH range 2-10. Complex 1 shows greater stability over the whole pH range but only 2 and 3 exhibit an insulin-mimetic effect. Copyright © 2011 Elsevier Inc. All rights reserved.

  20. Risk of catecholaminergic crisis following glucocorticoid administration in patients with an adrenal mass: a literature review.

    Science.gov (United States)

    Barrett, Catherine; van Uum, Stan H M; Lenders, Jacques W M

    2015-11-01

    Glucocorticoids as diagnostic or therapeutic agents have been reported to carry an increased risk of catecholaminergic crisis (CC) in patients with pheochromocytoma or paraganglioma (PPGL). We searched literature databases using the following terms: pheochromocytoma, paraganglioma, adrenal incidentaloma, steroids, glucocorticoids, dexamethasone suppression test (DST), hypertensive crisis, cosyntropin and CRH. From all published case reports (1962-2013), we reviewed medical history, presenting symptoms, dose and route of steroid administration, location and size of adrenal mass, biochemical phenotype and outcome. Twenty-five case reports describing a CC were identified. Three patients with an adrenal incidentaloma suffered a CC following high-dose DST, and in one case, this was fatal. In two of these patients, biochemical testing missed the diagnosis, and in the third, a DST was done despite elevated urinary metanephrines. No CC has been reported for patients undergoing a low-dose DST. Three of 16 patients who received therapeutic glucocorticoids and four of six patients following cosyntropin testing died. No specific biochemical phenotype was related to adverse events. Although a causal relationship cannot be established from this review, it seems prudent to exclude a PPGL in patients with a large incidentaloma or when high-dose DST is considered in a patient with an incidentaloma of any size. Our literature review does not support the need for biochemical testing for PPGL prior to a low-dose (1 mg) DST. Finally, before starting therapeutic glucocorticoids, any clinical signs or symptoms of a potential PPGL should prompt reliable biochemical testing to rule out a PPGL. © 2015 John Wiley & Sons Ltd.

  1. Membrane-Associated Effects of Glucocorticoid on BACE1 Upregulation and Aβ Generation: Involvement of Lipid Raft-Mediated CREB Activation.

    Science.gov (United States)

    Choi, Gee Euhn; Lee, Sei-Jung; Lee, Hyun Jik; Ko, So Hee; Chae, Chang Woo; Han, Ho Jae

    2017-08-30

    due to intracellular glucocorticoid receptor deficiency. In this respect, the genomic mechanism of glucocorticoid faces difficulties in explaining the consistent amyloid β (Aβ) production. Therefore, it is necessary to investigate the novel pathway of glucocorticoid on Aβ generation to find a more selective therapeutic approach to AD patients. In this study, we revealed the importance of nongenomic pathway induced by glucocorticoid where membrane glucocorticoid receptor plays an important role in Aβ formation. Copyright © 2017 the authors 0270-6474/17/378459-18$15.00/0.

  2. Metal stabilization of collagen and de novo designed mimetic peptides

    OpenAIRE

    Parmar, Avanish S.; Xu, Fei; Pike, Douglas H.; Belure, Sandeep V.; Hasan, Nida F.; Drzewiecki, Kathryn E.; Shreiber, David I.; Nanda, Vikas

    2015-01-01

    We explore the design of metal binding sites to modulate triple-helix stability of collagen and collagen-mimetic peptides. Globular proteins commonly utilize metals to connect tertiary structural elements that are well separated in sequence, constraining structure and enhancing stability. It is more challenging to engineer structural metals into fibrous protein scaffolds, which lack the extensive tertiary contacts seen in globular proteins. In the collagen triple helix, the structural adjacen...

  3. Constitutive differences in glucocorticoid responsiveness to stress are related to variation in aggression and anxiety-related behaviors.

    Science.gov (United States)

    Walker, Sophie E; Zanoletti, Olivia; Guillot de Suduiraut, Isabelle; Sandi, Carmen

    2017-10-01

    Glucocorticoids coordinate responses that enable an individual to cope with stressful challenges and, additionally, mediate adaptation following cessation of a stressor. There are important individual differences in the magnitude of glucocorticoid responsiveness to stressors. However, whether individual differences in glucocorticoid responsiveness to stress are linked to different behavioral strategies in coping with social and non-social challenges is not easily studied, owing to the lack of appropriate animal models. To address this, we generated three lines of Wistar rats selectively bred for the magnitude of their glucocorticoid responses following exposure to a variety of stressors over three consecutive days at juvenility. Here, we present findings following observations of a high level of variation in glucocorticoid responsiveness to stress in outbred Wistar rats, and the strong response to selection for this trait over a few generations. When challenged with different stressful challenges, rats from the three lines differed in their coping behaviors. Strikingly, the line with high glucocorticoid responsiveness to stress displayed enhanced aggression and anxiety-like behaviors. In addition, these rats also showed alterations in the expression of genes within both central and peripheral nodes of the hypothalamic-pituitary-adrenal (HPA) axis and enhanced reactivity to acute stress exposure. Together, these findings strongly link differences in glucocorticoid responsiveness to stress with marked differences in coping styles. The developed rat lines are thus a promising model with which to examine the relationship between variation in reactivity of the HPA axis and stress-related pathophysiology and could be employed to assess the therapeutic potential of treatments modulating stress habituation to ameliorate psychopathology. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. On (in)stabilities of perturbations in mimetic models with higher derivatives

    Energy Technology Data Exchange (ETDEWEB)

    Zheng, Yunlong; Shen, Liuyuan [Department of Physics, Nanjing University, Nanjing 210093 (China); Mou, Yicen; Li, Mingzhe, E-mail: zylakx@163.com, E-mail: sly12271103@163.com, E-mail: moinch@mail.ustc.edu.cn, E-mail: limz@ustc.edu.cn [Interdisciplinary Center for Theoretical Study, University of Science and Technology of China, Hefei, Anhui 230026 (China)

    2017-08-01

    Usually when applying the mimetic model to the early universe, higher derivative terms are needed to promote the mimetic field to be dynamical. However such models suffer from the ghost and/or the gradient instabilities and simple extensions cannot cure this pathology. We point out in this paper that it is possible to overcome this difficulty by considering the direct couplings of the higher derivatives of the mimetic field to the curvature of the spacetime.

  5. Metabolic effects of the incretin mimetic exenatide in the treatment of type 2 diabetes

    Directory of Open Access Journals (Sweden)

    Catherine A Schnabel

    2006-03-01

    Full Text Available Catherine A Schnabel, Matthew Wintle, Orville KoltermanAmylin Pharmaceuticals, Inc, 9360 Towne Centre Drive, Suite 110, San Diego, CA 92121, USAAbstract: Interventional studies have demonstrated the impact of hyperglycemia on the development of vascular complications associated with type 2 diabetes, which underscores the importance of safely lowering glucose to as near-normal as possible. Among the current challenges to reducing the risk of vascular disease associated with diabetes is the management of body weight in a predominantly overweight patient population, and in which weight gain is likely with many current therapies. Exenatide is the first in a new class of agents termed incretin mimetics, which replicate several glucoregulatory effects of the endogenous incretin hormone, glucagon-like peptide-1 (GLP-1. Currently approved in the US as an injectable adjunct to metformin and/or sulfonylurea therapy, exenatide improves glycemic control through multiple mechanisms of action including: glucose-dependent enhancement of insulin secretion that potentially reduces the risk of hypoglycemia compared with insulin secretagogues; restoration of first-phase insulin secretion typically deficient in patients with type 2 diabetes; suppression of inappropriately elevated glucagon secretion to reduce postprandial hepatic output; and slowing the rate of gastric emptying to regulate glucose appearance into the circulation. Clinical trials in patients with type 2 diabetes treated with subcutaneous exenatide twice daily demonstrated sustained improvements in glycemic control, evidenced by reductions in postprandial and fasting glycemia and glycosylated hemoglobin (HbA1c levels. Notably, improvements in glycemic control with exenatide were coupled with progressive reductions in body weight, which represents a distinct therapeutic benefit for patients with type 2 diabetes. Acute effects of exenatide on beta-cell responsiveness along with significant reductions

  6. Glucocorticoid exposure in preterm babies predicts saliva cortisol response to immunization at 4 months.

    Science.gov (United States)

    Glover, Vivette; Miles, Rachel; Matta, Simon; Modi, Neena; Stevenson, James

    2005-12-01

    Preterm babies are exposed to multiple stressors and this may have long-term effects. In particular, high levels of endogenous cortisol might have a programming effect on the hypothalamic-pituitary-adrenal axis as may administered glucocorticoids. In this study, we aimed to test the hypothesis that the level of endogenous and exogenous glucocorticoid exposure during the neonatal period predicts the saliva cortisol response to immunization at 4 mo of age. We followed 45 babies born below 32 wk gestation. We showed that their concentration of plasma cortisol during the first 4 wk was 358, 314, 231, and 195 nmol/L cortisol, respectively (geometric mean). This is four to seven times higher than fetal levels at the same gestational age range. We used routine immunization at 4 mo and 12 mo as a stressor and measured the change in saliva cortisol as the stress response. Mean circulating cortisol in the first 4 wk predicted the cortisol response at 4 but not at 12 mo. Path analysis showed that birthweight for gestational age, therapeutic antenatal steroids, and therapeutic postnatal steroids also contributed to the magnitude of the saliva cortisol response at 4 mo. This provides evidence that the magnitude of glucocorticoid exposure, both endogenous and exogenous, may have an effect on later stress responses.

  7. Independent association of glucocorticoids with damage accrual in SLE.

    Science.gov (United States)

    Apostolopoulos, Diane; Kandane-Rathnayake, Rangi; Raghunath, Sudha; Hoi, Alberta; Nikpour, Mandana; Morand, Eric F

    2016-01-01

    To determine factors associated with damage accrual in a prospective cohort of patients with SLE. Patients with SLE who attended the Lupus Clinic at Monash Health, Australia, between 2007 and 2013 were studied. Clinical variables included disease activity (Systemic Lupus Erythematosus Disease Activity Index-2K, SLEDAI-2K), time-adjusted mean SLEDAI, cumulative glucocorticoid dose and organ damage (Systemic Lupus International Collaborating Clinics Damage Index (SDI)). Multivariate logistic regression analyses were performed to identify factors associated with damage accrual. A total of 162 patients were observed over a median (IQR) 3.6 (2.0-4.7) years. Seventy-five per cent (n=121) of patients received glucocorticoids. Damage accrual was significantly more frequent in glucocorticoid-exposed patients (42% vs 15%, p<0.01). Higher glucocorticoid exposure was independently associated with overall damage accrual after controlling for factors including ethnicity and disease activity and was significant at time-adjusted mean doses above 4.42 mg prednisolone/day; the OR of damage accrual in patients in the highest quartile of cumulative glucocorticoid exposure was over 10. Glucocorticoid exposure was independently associated with damage accrual in glucocorticoid-related and non-glucocorticoid related domains of the SDI. Glucocorticoid use is independently associated with the accrual of damage in SLE, including in non-glucocorticoid related domains.

  8. Activity of antimicrobial peptide mimetics in the oral cavity: II. Activity against periopathogenic biofilms and anti-inflammatory activity

    Science.gov (United States)

    Hua, J; Scott, R.W.; Diamond, G

    2011-01-01

    Whereas periodontal disease is ultimately of bacterial etiology, from multispecies biofilms of gram-negative anaerobic microorganisms, much of the deleterious effects are caused by the resultant epithelial inflammatory response. Hence, development of a treatment that combines anti-biofilm antibiotic activity with anti-inflammatory activity would be of great utility. Antimicrobial peptides (AMPs) such as defensins are naturally occurring peptides that exhibit broad-spectrum activity as well as a variety of immunomodulatory activities. Furthermore, bacteria do not readily develop resistance to these agents. However, clinical studies have suggested that they do not represent optimal candidates for exogenous therapeutic agents. Small-molecule mimetics of these AMPs exhibit similar activities to the parent peptides, in addition to having low toxicity, high stability and low cost. To determine whether AMP mimetics have the potential for treatment of periodontal disease, we examined the activity of one mimetic, mPE, against biofilm cultures of Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis. Metabolic assays as well as culture and biomass measurement assays demonstrated that mPE exhibits potent activity against biofilm cultures of both species. Furthermore, as little as 2 µg ml−1 mPE was sufficient to inhibit interleukin-1β-induced secretion of interleukin-8 in both gingival epithelial cells and THP-1 cells. This anti-inflammatory activity is associated with a reduction in activation of nuclear factor-κB, suggesting that mPE can act both as an anti-biofilm agent in an anaerobic environment and as an anti-inflammatory agent in infected tissues. PMID:21040516

  9. Glucocorticoid Availability in Colonic Inflammation of Rat

    Czech Academy of Sciences Publication Activity Database

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

    2008-01-01

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

  10. Biochemical endpoints of glucocorticoid hormone action

    Energy Technology Data Exchange (ETDEWEB)

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

    1978-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Christel Gumy

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

  12. Reproductive isolation related to mimetic divergence in the poison frog Ranitomeya imitator

    DEFF Research Database (Denmark)

    Twomey, Evan; Vestergaard, Jacob Schack; Summers, Kyle

    2014-01-01

    study the Peruvian poison frog Ranitomeya imitator, a species that has undergone a mimetic radiation into four distinct morphs. Using a combination of colour–pattern analysis, landscape genetics and mate-choice experiments, we show that a mimetic shift in R. imitator is associated with a narrow...

  13. Glucocorticoid actions on L6 muscle cells in culture

    International Nuclear Information System (INIS)

    Max, S.R.; Konagaya, M.; Konagaya, Y.

    1986-01-01

    Glucocorticoids exert striking catabolic effects on skeletal muscle. The mechanism of these effects remains poorly understood. They employed L6 muscle cells in culture to ascertain whether intracellular glucocorticoid receptors are involved. Studies in vitro permit exploration of glucocorticoid effects in the absence of other hormonal influences. L6 myoblasts were induced to form differentiated myotubes by growth in 1% serum. L6 myotubes were found to possess a high-affinity, limited capacity intracellular glucocorticoid receptor (apparent K/sub D/ = 5 x 10 -10 M; B/sub max/ = 711 pmols/g protein) with ligand specificity similar to that of glucocorticoid receptors from classical glucocorticoid target tissues. Further, [ 3 H] triamcinolone acetonide specific binding to L6 cell homogenates was blocked by a glucocorticoid antagonist, RU38486 (11β-(4-dimethyl-aminophenyl)-17β-hydroxy-17α-(prop-l-ynyl)-estra-4,9-dien-3-one). Dexamethasone (10 -5 M) caused a 10-fold increase in the activity of gluatmine synthetase in L6 myotubes; this increase was prevented by RU38486. Similarly, dexamethasone (10 -5 M) caused a 20% decrease in [ 12 C] leucine incorporation into protein. This effect also was blocked by RU38486. Thus, induction of glutamine synthetase and diminution of protein synthesis by dexamethasone require intracellular glucocorticoid receptors. L6 cells should prove particularly valuable for further studies of glucocorticoid actions on skeletal muscle

  14. Mimetic Finite Differences for Flow in Fractures from Microseismic Data

    KAUST Repository

    Al-Hinai, Omar; Srinivasan, Sanjay; Wheeler, Mary F.

    2015-01-01

    We present a method for porous media flow in the presence of complex fracture networks. The approach uses the Mimetic Finite Difference method (MFD) and takes advantage of MFD's ability to solve over a general set of polyhedral cells. This flexibility is used to mesh fracture intersections in two and three-dimensional settings without creating small cells at the intersection point. We also demonstrate how to use general polyhedra for embedding fracture boundaries in the reservoir domain. The target application is representing fracture networks inferred from microseismic analysis.

  15. Board composition, mimetic behaviour and corporate voluntary disclosures

    Directory of Open Access Journals (Sweden)

    Roshayani Arshad

    2008-11-01

    Full Text Available This study examines the effects of board composition and mimetic behaviour on the extent and credibility of corporate voluntary disclosure. The investigation is based on the annual reports of 155 Malaysian listed companies during the period when these companies faced new corporate governance regulation. This study provides evidence that under the influence of dominant owners on board, management voluntary disclosure decisions are driven by incentives to conform when their company is structured to meet expectations of good corporate governance. Such incentive seems to override incentives to disclose credible information to outside investors

  16. Mimetic Finite Differences for Flow in Fractures from Microseismic Data

    KAUST Repository

    Al-Hinai, Omar

    2015-01-01

    We present a method for porous media flow in the presence of complex fracture networks. The approach uses the Mimetic Finite Difference method (MFD) and takes advantage of MFD\\'s ability to solve over a general set of polyhedral cells. This flexibility is used to mesh fracture intersections in two and three-dimensional settings without creating small cells at the intersection point. We also demonstrate how to use general polyhedra for embedding fracture boundaries in the reservoir domain. The target application is representing fracture networks inferred from microseismic analysis.

  17. EPOR-Based Purification and Analysis of Erythropoietin Mimetic Peptides from Human Urine by Cys-Specific Cleavage and LC/MS/MS

    Science.gov (United States)

    Vogel, Matthias; Thomas, Andreas; Schänzer, Wilhelm; Thevis, Mario

    2015-09-01

    The development of a new class of erythropoietin mimetic agents (EMA) for treating anemic conditions has been initiated with the discovery of oligopeptides capable of dimerizing the erythropoietin (EPO) receptor and thus stimulating erythropoiesis. The most promising amino acid sequences have been mounted on various different polymeric structures or carrier molecules to obtain highly active EPO-like drugs exhibiting beneficial and desirable pharmacokinetic profiles. Concomitant with creating new therapeutic options, erythropoietin mimetic peptide (EMP)-based drug candidates represent means to artificially enhance endurance performance and necessitate coverage by sports drug testing methods. Therefore, the aim of the present study was to develop a strategy for the comprehensive detection of EMPs in doping controls, which can be used complementary to existing protocols. Three model EMPs were used to provide proof-of-concept data. Following EPO receptor-facilitated purification of target analytes from human urine, the common presence of the cysteine-flanked core structure of EMPs was exploited to generate diagnostic peptides with the aid of a nonenzymatic cleavage procedure. Sensitive detection was accomplished by targeted-SIM/data-dependent MS2 analysis. Method characterization was conducted for the EMP-based drug peginesatide concerning specificity, linearity, precision, recovery, stability, ion suppression/enhancement, and limit of detection (LOD, 0.25 ng/mL). Additionally, first data for the identification of the erythropoietin mimetic peptides EMP1 and BB68 were generated, demonstrating the multi-analyte testing capability of the presented approach.

  18. A recombinant mimetics of the HIV-1 gp41 prehairpin fusion intermediate fused with human IgG Fc fragment elicits neutralizing antibody response in the vaccinated mice

    International Nuclear Information System (INIS)

    Qi, Zhi; Pan, Chungen; Lu, Hong; Shui, Yuan; Li, Lin; Li, Xiaojuan; Xu, Xueqing; Liu, Shuwen; Jiang, Shibo

    2010-01-01

    Research highlights: → One recombinant mimetics of gp41 prehairpin fusion intermediate (PFI) consisting of gp41 N46 sequence, foldon and IgG Fc, designated N46FdFc, was expressed. → N46FdFc-induced antibodies in mice that neutralized HIV-1 infection, inhibited PIE7 binding to PFI, blocked gp41 six-helix bundle formation, and suppressed HIV-1 mediated cell-cell fusion. → These findings provide an important clue for developing recombinant gp41 PFI mimetics-based HIV vaccines. -- Abstract: HIV-1 gp41 prehairpin fusion intermediate (PFI) composed of three N-terminal heptad repeats (NHR) plays a crucial role in viral fusion and entry and represents an attractive target for anti-HIV therapeutics (e.g., enfuvirtide) and vaccines. In present study, we constructed and expressed two recombinant gp41 PFI mimetics, designated N46Fd and N46FdFc. N46Fd consists of N46 (residues 536-581) in gp41 NHR and foldon (Fd), a trimerization motif. N46FdFc is composed of N46Fd fused with human IgG Fc fragment as an immunoenhancer. We immunized mice with N46 peptide, N46Fd and N46FdFc, respectively, and found that only N46FdFc elicited neutralizing antibody response in mice against infection by HIV-1 strains IIIB (clade B, X4), 92US657 (clade B, R5), and 94UG103 (clade A, X4R5). Anti-N46FdFc antibodies inhibited PIE7 binding to PFI, blocked gp41 six-helix bundle formation, and suppressed HIV-1 mediated cell-cell fusion. These findings provide an important clue for developing recombinant gp41 PFI mimetics-based HIV vaccines.

  19. The Regulation of Muscle Mass by Endogenous Glucocorticoids

    Directory of Open Access Journals (Sweden)

    Daniel L Marks

    2015-02-01

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

  20. The mimetic repertoire of the spotted bowerbird Ptilonorhynchus maculatus

    Science.gov (United States)

    Kelley, Laura A.; Healy, Susan D.

    2011-06-01

    Although vocal mimicry in songbirds is well documented, little is known about the function of such mimicry. One possibility is that the mimic produces the vocalisations of predatory or aggressive species to deter potential predators or competitors. Alternatively, these sounds may be learned in error as a result of their acoustic properties such as structural simplicity. We determined the mimetic repertoires of a population of male spotted bowerbirds Ptilonorhynchus maculatus, a species that mimics predatory and aggressive species. Although male mimetic repertoires contained an overabundance of vocalisations produced by species that were generally aggressive, there was also a marked prevalence of mimicry of sounds that are associated with alarm such as predator calls, alarm calls and mobbing calls, irrespective of whether the species being mimicked was aggressive or not. We propose that it may be the alarming context in which these sounds are first heard that may lead both to their acquisition and to their later reproduction. We suggest that enhanced learning capability during acute stress may explain vocal mimicry in many species that mimic sounds associated with alarm.

  1. Live cell imaging unveils multiple domain requirements for in vivo dimerization of the glucocorticoid receptor.

    Directory of Open Access Journals (Sweden)

    Diego M Presman

    2014-03-01

    Full Text Available Glucocorticoids are essential for life, but are also implicated in disease pathogenesis and may produce unwanted effects when given in high doses. Glucocorticoid receptor (GR transcriptional activity and clinical outcome have been linked to its oligomerization state. Although a point mutation within the GR DNA-binding domain (GRdim mutant has been reported as crucial for receptor dimerization and DNA binding, this assumption has recently been challenged. Here we have analyzed the GR oligomerization state in vivo using the number and brightness assay. Our results suggest a complete, reversible, and DNA-independent ligand-induced model for GR dimerization. We demonstrate that the GRdim forms dimers in vivo whereas adding another mutation in the ligand-binding domain (I634A severely compromises homodimer formation. Contrary to dogma, no correlation between the GR monomeric/dimeric state and transcriptional activity was observed. Finally, the state of dimerization affected DNA binding only to a subset of GR binding sites. These results have major implications on future searches for therapeutic glucocorticoids with reduced side effects.

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

    NARCIS (Netherlands)

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

    1985-01-01

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

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

    NARCIS (Netherlands)

    Kroon, Jan; Kroon, Jan; Puhr, M.; Buijs, J.T.; van der Horst, G.; Hemmer, D.M.; Marijt, K.A.; Hwang, M.S.; Masood, M.; Grimm, S.; Storm, Gerrit; Metselaar, Josbert Maarten; Meijer, O.C.; Culig, Z.; van der Pluijm, M.

    2016-01-01

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

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

    NARCIS (Netherlands)

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

    2016-01-01

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

  5. Using fecal glucocorticoids for stress assessment in Mourning Doves

    Science.gov (United States)

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

    2003-01-01

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

  6. Mimetic Gravity: A Review of Recent Developments and Applications to Cosmology and Astrophysics

    Directory of Open Access Journals (Sweden)

    Lorenzo Sebastiani

    2017-01-01

    Full Text Available Mimetic gravity is a Weyl-symmetric extension of General Relativity, related to the latter by a singular disformal transformation, wherein the appearance of a dust-like perfect fluid can mimic cold dark matter at a cosmological level. Within this framework, it is possible to provide a unified geometrical explanation for dark matter, the late-time acceleration, and inflation, making it a very attractive theory. In this review, we summarize the main aspects of mimetic gravity, as well as extensions of the minimal formulation of the model. We devote particular focus to the reconstruction technique, which allows the realization of any desired expansionary history of the universe by an accurate choice of potential or other functions defined within the theory (as in the case of mimetic f(R gravity. We briefly discuss cosmological perturbation theory within mimetic gravity. As a case study within which we apply the concepts previously discussed, we study a mimetic Hořava-like theory, of which we explore solutions and cosmological perturbations in detail. Finally, we conclude the review by discussing static spherically symmetric solutions within mimetic gravity and apply our findings to the problem of galactic rotation curves. Our review provides an introduction to mimetic gravity, as well as a concise but self-contained summary of recent findings, progress, open questions, and outlooks on future research directions.

  7. Exogenous glucocorticoids and adverse cerebral effects in children

    DEFF Research Database (Denmark)

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

    2011-01-01

    of the glucocorticoid receptor, which is associated with unfavorable cellular outcomes. Prenatal treatment with glucocorticoids can compromise brain growth and is associated with periventricular leukomalacia, attentions deficits and poorer cognitive performance. In the neonatal period exposure to glucocorticoids...... reduces neurogenesis and cerebral volume, impairs memory and increases the incidence of cerebral palsy. Cerebral effects of glucocorticoids in later childhood have been less thoroughly studied, but apparent brain atrophy, reduced size of limbic structures and neuropsychiatric symptoms have been reported....... Glucocortioids affect several cellular structures and functions, which may explain the observed adverse effects. Glucocorticoids can impair neuronal glucose uptake, decrease excitability, cause atrophy of dendrites, compromise development of myelin-producing oligodendrocytes and disturb important cellular...

  8. TREATMENT OF DIABETES MELLITUS IN A GOLDEN LION TAMARIN (LEONTOPITHECUS ROSALIA) WITH THE GLUCAGON-LIKE PEPTIDE-1 MIMETIC EXENATIDE.

    Science.gov (United States)

    Johnson, James G; Langan, Jennifer N; Gilor, Chen

    2016-09-01

    An 8-yr-old male golden lion tamarin ( Leontopithecus rosalia ) was diagnosed with diabetes mellitus based on hyperglycemia and persistent glycosuria. Initial treatment consisted of the oral antihyperglycemic medications glipizide and metformin that resulted in decreased blood glucose concentrations; however, marked glycosuria persisted. Insufficient improvement on oral antihyperglycemic therapy and poor feasibility of daily subcutaneous insulin therapy led to an investigation into an alternative therapy with extended-release exenatide, a glucagon-like peptide-1 (GLP-1) mimetic, at a dosage of 0.13 mg/kg subcutaneously once per month. Following treatment with exenatide, the persistent glycosuria resolved, the animal maintained normal blood glucose concentrations, and had lower serum fructosamine concentrations compared to pretreatment levels. Based on these findings, extended-release exenatide could be considered as a therapeutic option in nonhuman primates with diabetes mellitus that do not respond to oral antihyperglycemics and in which daily subcutaneous insulin is not feasible.

  9. The CNTF-derived peptide mimetic Cintrofin attenuates spatial-learning deficits in a rat post-status epilepticus model

    DEFF Research Database (Denmark)

    Russmann, Vera; Seeger, Natalie; Zellinger, Christina

    2013-01-01

    Ciliary neurotrophic growth factor is considered a potential therapeutic agent for central nervous system diseases. We report first in vivo data of the ciliary neurotrophic growth factor peptide mimetic Cintrofin in a rat post-status epilepticus model. Cintrofin prevented long-term alterations...... in the number of doublecortin-positive neuronal progenitor cells and attenuated the persistence of basal dendrites. In contrast, Cintrofin did neither affect acute status epilepticus-associated alterations in hippocampal cell proliferation and neurogenesis nor reveal any relevant effect on seizure activity....... Whereas status epilepticus caused a significant disturbance in spatial learning in reversed peptide-treated rats, the performance of Cintrofin-treated rats did not differ from controls. The study confirms that Cintrofin comprises an active sequence mimicking effects of its parent molecule. While the data...

  10. Synergistic Interactions of a Synthetic Lubricin-Mimetic with Fibronectin for Enhanced Wear Protection

    Directory of Open Access Journals (Sweden)

    Roberto C. Andresen Eguiluz

    2017-06-01

    Full Text Available Lubricin (LUB, a major mucinous glycoprotein of mammalian synovial fluids, is believed to provide excellent lubrication to cartilage surfaces. Consequently, when joint disease or replacement leads to increased friction and surface damage in the joint, robust synthetic LUB alternatives that could be used therapeutically to improve lubrication and surface protection are needed. Here, we report the characterization of a lubricating multiblock bottlebrush polymer whose architecture was inspired by LUB, and we investigate the role of fibronectin (FN, a glycoprotein found in the superficial zone of cartilage, in mediating the tribological properties of the polymer upon shear between mica surfaces. Our surface forces apparatus (SFA normal force measurements indicate that the lubricin-mimetic (mimLUB could be kept anchored between mica surfaces, even under high contact pressures, when an intermediate layer of FN was present. Additional SFA friction measurements show that FN would also extend the wearless friction regime of the polymer up to pressures of 3.4 MPa while ensuring stable friction coefficients (μ ≈ 0.28. These results demonstrate synergistic interactions between mimLUB and FN in assisting the lubrication and wear protection of ideal (mica substrates upon shear. Collectively, these findings suggest that our proposed mimLUB might be a promising alternative to LUB, as similar mechanisms could potentially facilitate the interaction between the polymer and cartilage surfaces in articular joints and prosthetic implants in vivo.

  11. HDL mimetic CER-001 targets atherosclerotic plaques in patients.

    Science.gov (United States)

    Zheng, Kang He; van der Valk, Fleur M; Smits, Loek P; Sandberg, Mara; Dasseux, Jean-Louis; Baron, Rudi; Barbaras, Ronald; Keyserling, Constance; Coolen, Bram F; Nederveen, Aart J; Verberne, Hein J; Nell, Thijs E; Vugts, Danielle J; Duivenvoorden, Raphaël; Fayad, Zahi A; Mulder, Willem J M; van Dongen, Guus A M S; Stroes, Erik S G

    2016-08-01

    Infusion of high-density lipoprotein (HDL) mimetics aimed at reducing atherosclerotic burden has led to equivocal results, which may relate in part to the inability of HDL mimetics to adequately reach atherosclerotic lesions in humans. This study evaluated delivery of recombinant human apolipoprotein A-I (apoA-I) containing HDL mimetic CER-001 in carotid plaques in patients. CER-001 was radiolabeled with the long-lived positron emitter zirconium-89 ((89)Zr) to enable positron emission tomography with computed tomography (PET/CT) imaging. Eight patients with atherosclerotic carotid artery disease (>50% stenosis) received a single infusion of unlabeled CER-001 (3 mg/kg), co-administered with 10 mg of (89)Zr-labeled CER-001 (18 MBq). Serial PET/CT imaging and contrast enhanced-magnetic resonance imaging (CE-MRI) were performed to evaluate targeted delivery of CER-001. One hour after infusion, mean plasma apoA-I levels increased by 9.9 mg/dL (p = 0.026), with a concomitant relative increase in the plasma cholesterol efflux capacity of 13.8% (p CER-001 expressed as target-to-background ratio (TBRmax) increased significantly 24 h after infusion, and remained increased up to 48 h (TBRmax t = 10 min: 0.98; t = 24 h: 1.14 (p = 0.001); t = 48 h: 1.12 (p = 0.007)). TBRmax was higher in plaque compared with non-plaque segments (1.18 vs. 1.05; p CER-001 increases plasma apoA-I concentration and plasma cholesterol efflux capacity. Our data support the concept that CER-001 targets plaque regions in patients, which correlates with plaque contrast enhancement. These clinical findings may also guide future nanomedicine development using HDL particles for drug delivery in atherosclerosis. Netherlands Trial Registry - NTR5178. http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=5178. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  12. Thick branes with inner structure in mimetic gravity

    Energy Technology Data Exchange (ETDEWEB)

    Zhong, Yi; Zhang, Yu-Peng; Liu, Yu-Xiao [Lanzhou University, Institute of Theoretical Physics, Lanzhou (China); Lanzhou University, Research Center of Gravitation, Lanzhou (China); Zhong, Yuan [Xi' an Jiaotong University, School of Science, Xi' an (China)

    2018-01-15

    In this paper, thick branes generated by mimetic scalar field are investigated. Three typical thick brane models are constructed and the linear tensor and scalar perturbations are analyzed. These branes have different inner structures, some of which are absent in general relativity. For each brane model, the solution is stable under both tensor and scalar perturbations. The tensor zero modes are localized on the branes, while the scalar perturbations do not propagate and they are not localized on the brane. As the branes split into multi sub-branes for specific parameters, the potentials of the tensor perturbations also split into multi-wells, and this may lead to new phenomenon in the resonance of the tensor perturbation and the localization of matter fields. (orig.)

  13. Ancient homology underlies adaptive mimetic diversity across butterflies

    Science.gov (United States)

    Gallant, Jason R.; Imhoff, Vance E.; Martin, Arnaud; Savage, Wesley K.; Chamberlain, Nicola L.; Pote, Ben L.; Peterson, Chelsea; Smith, Gabriella E.; Evans, Benjamin; Reed, Robert D.; Kronforst, Marcus R.; Mullen, Sean P.

    2014-01-01

    Convergent evolution provides a rare, natural experiment with which to test the predictability of adaptation at the molecular level. Little is known about the molecular basis of convergence over macro-evolutionary timescales. Here we use a combination of positional cloning, population genomic resequencing, association mapping and developmental data to demonstrate that positionally orthologous nucleotide variants in the upstream region of the same gene, WntA, are responsible for parallel mimetic variation in two butterfly lineages that diverged >65 million years ago. Furthermore, characterization of spatial patterns of WntA expression during development suggests that alternative regulatory mechanisms underlie wing pattern variation in each system. Taken together, our results reveal a strikingly predictable molecular basis for phenotypic convergence over deep evolutionary time. PMID:25198507

  14. Incretin mimetics: a novel therapeutic option for patients with type 2 diabetes - a review

    DEFF Research Database (Denmark)

    Hansen, Katrine Bilberg; Vilsbøll, Tina; Knop, Filip K

    2010-01-01

    Type 2 diabetes mellitus is a metabolic disease associated with low quality of life and early death. The goal in diabetes treatment is to prevent these outcomes by tight glycemic control and minimizing vascular risk factors. So far, even intensified combination regimen with the traditional antidi...

  15. Concurrent spinal cord and vertebral bone marrow radionecrosis 8 years after therapeutic irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Warscotte, L.; Sindic, C.J.M. [Department of Neurology, Universite Catholique de Louvain (Belgium); Duprez, T.; Lecouvet, F.E. [Department of Radiology and Medical Imaging, Universite Catholique de Louvain, Brussels (Belgium); Lonneux, M. [Department of Nuclear Medicine, Universite Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels (Belgium); Michaux, L. [Department of Hematology, Universite Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels (Belgium); Renard, L. [Department of Radiation Oncology, Universite Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels (Belgium)

    2002-03-01

    Concurrent radionecrosis within the spinal cord and the bone marrow at the same thoracic level was observed 8 years after localized therapeutic irradiation in a patient who had undergone repeated cycles of radiotherapy, glucocorticoid treatment, and chemotherapy for a non-Hodgkin's lymphoma. Mechanisms combining radiotoxic potentialization by glucocorticoids/alkylating agents and delayed radiation-induced vasculitis involving the common arterial pathways to the spinal cord and to the vertebrae were speculated to have acted in a synergistic way. (orig.)

  16. Concurrent spinal cord and vertebral bone marrow radionecrosis 8 years after therapeutic irradiation

    International Nuclear Information System (INIS)

    Warscotte, L.; Sindic, C.J.M.; Duprez, T.; Lecouvet, F.E.; Lonneux, M.; Michaux, L.; Renard, L.

    2002-01-01

    Concurrent radionecrosis within the spinal cord and the bone marrow at the same thoracic level was observed 8 years after localized therapeutic irradiation in a patient who had undergone repeated cycles of radiotherapy, glucocorticoid treatment, and chemotherapy for a non-Hodgkin's lymphoma. Mechanisms combining radiotoxic potentialization by glucocorticoids/alkylating agents and delayed radiation-induced vasculitis involving the common arterial pathways to the spinal cord and to the vertebrae were speculated to have acted in a synergistic way. (orig.)

  17. Identification of novel small-molecule Ulex europaeus I mimetics for targeted drug delivery.

    Science.gov (United States)

    Hamashin, Christa; Spindler, Lisa; Russell, Shannon; Schink, Amy; Lambkin, Imelda; O'Mahony, Daniel; Houghten, Richard; Pinilla, Clemencia

    2003-11-17

    Lectin mimetics have been identified that may have potential application towards targeted drug delivery. Synthetic multivalent polygalloyl constructs effectively competed with Ulex europaeus agglutinin I (UEA1) for binding to intestinal Caco-2 cell membranes.

  18. A mucosa-mimetic material for the mucoadhesion testing of thermogelling semi-solids.

    Science.gov (United States)

    da Silva, Jéssica Bassi; Khutoryanskiy, Vitaliy V; Bruschi, Marcos L; Cook, Michael T

    2017-08-07

    Mucosa-mimetic materials are synthetic substrates which aim to replace animal tissue in mucoadhesion experiments. One potential mucosa-mimetic material is a hydrogel comprised of N-acryloyl-d-glucosamine and 2-hydroxyethylmethacrylate, which has been investigated as a surrogate for animal mucosae in the mucoadhesion testing of tablets and solution formulations. This study aims to investigate the efficacy of this mucosa-mimetic material in the testing of thermogelling semi-solid formulations, which transition from solution to gel upon warming. Two methods for assessing mucoadhesion have been used; tensile testing and a flow-through system, which allow for investigation under dramatically different conditions. It was found that the mucosa-mimetic material was a good surrogate for buccal mucosa using both testing methods. This material may be used to replace animal tissue in these experiments, potentially reducing the number of laboratory animals used in studies of this type. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Addison disease in patients treated with glucocorticoid therapy.

    LENUS (Irish Health Repository)

    Cronin, C C

    2012-02-03

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

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

    DEFF Research Database (Denmark)

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

    2015-01-01

    Glucocorticoidinduced osteoporosis (GIOP) is a widespread clinical complication following glucocorticoid therapy. This irreversible damage to boneforming and resorbing cells is essential in the pathogenesis of osteoporosis. Autophagy is a physiological process involved in the regulation of cells...... and their responses to diverse stimuli, however, the role of autophagy in glucocorticoidinduced damage to bone marrow mesenchymal stem cells (BMSCs) remains unclear. The current study confirmed that glucocorticoid administration impaired the proliferation of BMSCs. Transmission electron microscopy...... that in response to glucocorticoid administration, induced autophagy aids to maintain proliferation and prevent apoptosis of BMSCs. Thus, it is hypothesized that autophagy may be a novel target in the treatment or prevention of osteoporosis....

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

    Science.gov (United States)

    Starkman, Monica N

    2013-09-01

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

  2. Midlife stress alters memory and mood-related behaviors in old age: Role of locally activated glucocorticoids.

    Science.gov (United States)

    Wheelan, Nicola; Kenyon, Christopher J; Harris, Anjanette P; Cairns, Carolynn; Al Dujaili, Emad; Seckl, Jonathan R; Yau, Joyce L W

    2018-03-01

    Chronic exposure to stress during midlife associates with subsequent age-related cognitive decline and may increase the vulnerability to develop psychiatric conditions. Increased hypothalamic-pituitary-adrenal (HPA) axis activity has been implicated in pathogenesis though any causative role for glucocorticoids is unestablished. This study investigated the contribution of local glucocorticoid regeneration by the intracellular enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), in persisting midlife stress-induced behavioral effects in mice. Middle-aged (10 months old) 11β-HSD1-deficient mice and wild-type congenic controls were randomly assigned to 28 days of chronic unpredictable stress or left undisturbed (non-stressed). All mice underwent behavioral testing at the end of the stress/non-stress period and again 6-7 months later. Chronic stress impaired spatial memory in middle-aged wild-type mice. The effects, involving a wide spectrum of behavioral modalities, persisted for 6-7 months after cessation of stress into early senescence. Enduring effects after midlife stress included impaired spatial memory, enhanced contextual fear memory, impaired fear extinction, heightened anxiety, depressive-like behavior, as well as reduced hippocampal glucocorticoid receptor mRNA expression. In contrast, 11β-HSD1 deficient mice resisted both immediate and enduring effects of chronic stress, despite similar stress-induced increases in systemic glucocorticoid activity during midlife stress. In conclusion, chronic stress in midlife exerts persisting effects leading to cognitive and affective dysfunction in old age via mechanisms that depend, at least in part, on brain glucocorticoids generated locally by 11β-HSD1. This finding supports selective 11β-HSD1 inhibition as a novel therapeutic target to ameliorate the long-term consequences of stress-related psychiatric disorders in midlife. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

  3. Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program.

    Science.gov (United States)

    Morrison-Nozik, Alexander; Anand, Priti; Zhu, Han; Duan, Qiming; Sabeh, Mohamad; Prosdocimo, Domenick A; Lemieux, Madeleine E; Nordsborg, Nikolai; Russell, Aaron P; MacRae, Calum A; Gerber, Anthony N; Jain, Mukesh K; Haldar, Saptarsi M

    2015-12-08

    Classic physiology studies dating to the 1930s demonstrate that moderate or transient glucocorticoid (GC) exposure improves muscle performance. The ergogenic properties of GCs are further evidenced by their surreptitious use as doping agents by endurance athletes and poorly understood efficacy in Duchenne muscular dystrophy (DMD), a genetic muscle-wasting disease. A defined molecular basis underlying these performance-enhancing properties of GCs in skeletal muscle remains obscure. Here, we demonstrate that ergogenic effects of GCs are mediated by direct induction of the metabolic transcription factor KLF15, defining a downstream pathway distinct from that resulting in GC-related muscle atrophy. Furthermore, we establish that KLF15 deficiency exacerbates dystrophic severity and muscle GC-KLF15 signaling mediates salutary therapeutic effects in the mdx mouse model of DMD. Thus, although glucocorticoid receptor (GR)-mediated transactivation is often associated with muscle atrophy and other adverse effects of pharmacologic GC administration, our data define a distinct GR-induced gene regulatory pathway that contributes to therapeutic effects of GCs in DMD through proergogenic metabolic programming.

  4. Glucocorticoid treatment, immobility, and constipation are associated with nutritional risk.

    Science.gov (United States)

    Gutzwiller, Jean-Pierre; Aschwanden, Josef; Iff, Samuel; Leuenberger, Michèle; Perrig, Martin; Stanga, Zeno

    2011-12-01

    The hypothesis of this clinical study was to determine whether glucocorticoid use and immobility were associated with in-hospital nutritional risk. One hundred and one patients consecutively admitted to the medical wards were enrolled. Current medical conditions, symptoms, medical history, eating and drinking habits, diagnosis, laboratory findings, medications, and anthropometrics were recorded. The Nutrition Risk Score 2002 (NRS-2002) was used as a screening instrument to identify nutritional risk. The results confirmed that glucocorticoid use and immobility are independently associated with nutritional risk determined by the NRS-2002. Constipation could be determined as an additional cofactor independently associated with nutritional risk. Glucocorticoid treatment, immobility, and constipation are associated with nutritional risk in a mixed hospitalized population. The presence of long-time glucocorticoid use, immobility, or constipation should alert the clinician to check for nutritional status, which is an important factor in mortality and morbidity.

  5. Hypersensitivity Reactions from Excipients in Systemic Glucocorticoid Formulations

    DEFF Research Database (Denmark)

    Calogiuri, Gianfranco; Garvey, Lene H; Romita, Paolo

    2016-01-01

    Glucocorticoids are the most widely used drugs for the treatment of hypersensitivity, however these drugs themselves and the excipients contained in commercial corticosteroid formulations are able to induce severe immediate-type hypersensitivity reactions. Reactions involving excipients have been...

  6. Both mineralocorticoid and glucocorticoid receptors regulate emotional memory in mice

    NARCIS (Netherlands)

    Zhou, M.; Bakker, E.H.M.; Velzing, E.; Berger, S.; Oitzl, M.; Joëls, M.; Krugers, H.J.

    2010-01-01

    Corticosteroid hormones are thought to promote optimal behavioral adaptation under fearful conditions, primarily via glucocorticoid receptors (GRs). Here, we examined - using pharmacological and genetic approaches in mice - if mineralocorticoid receptors (MRs) also play a role in fearful memory

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

    Science.gov (United States)

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

    2018-06-01

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

  8. The role of glucocorticoids in sodium retention in cirrhotic patients

    DEFF Research Database (Denmark)

    Hansen, Martin Højmark; Kristensen, Steffen Skott; Schaffalitzky de Muckadell, Ove B

    2012-01-01

    sodium retention evident in cirrhosis. The aim was to elucidate the role of glucocorticoids in sodium retention in decompensated cirrhotic patients. Methods. A randomized, double-blind, placebo-controlled, crossover study was performed in nine patients with alcoholic cirrhosis of the liver. A washout....... Conclusion. These results indicate that endogenous glucocorticoids contribute to the sodium retention in patients with alcoholic cirrhosis of the liver....

  9. The Pro-inflammatory Effects of Glucocorticoids in the Brain

    Science.gov (United States)

    Duque, Erica de Almeida; Munhoz, Carolina Demarchi

    2016-01-01

    Glucocorticoids are a class of steroid hormones derived from cholesterol. Their actions are mediated by the glucocorticoid and mineralocorticoid receptors, members of the superfamily of nuclear receptors, which, once bound to their ligands, act as transcription factors that can directly modulate gene expression. Through protein–protein interactions with other transcription factors, they can also regulate the activity of many genes in a composite or tethering way. Rapid non-genomic signaling was also demonstrated since glucocorticoids can act through membrane receptors and activate signal transduction pathways, such as protein kinases cascades, to modulate other transcriptions factors and activate or repress various target genes. By all these different mechanisms, glucocorticoids regulate numerous important functions in a large variety of cells, not only in the peripheral organs but also in the central nervous system during development and adulthood. In general, glucocorticoids are considered anti-inflammatory and protective agents due to their ability to inhibit gene expression of pro-inflammatory mediators and other possible damaging molecules. Nonetheless, recent studies have uncovered situations in which these hormones can act as pro-inflammatory agents depending on the dose, chronicity of exposure, and the structure/organ analyzed. In this review, we will provide an overview of the conditions under which these phenomena occur, a discussion that will serve as a basis for exploring the mechanistic foundation of glucocorticoids pro-inflammatory gene regulation in the brain. PMID:27445981

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

    Science.gov (United States)

    Chan, KL; Mok, CC

    2012-01-01

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

  11. Glucocorticoid-induced avascular bone necrosis: diagnosis and management.

    Science.gov (United States)

    Chan, K L; Mok, C C

    2012-01-01

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

  12. Reissner–Nordström Anti-de Sitter Black Holes in Mimetic F(R Gravity

    Directory of Open Access Journals (Sweden)

    V. K. Oikonomou

    2016-05-01

    Full Text Available In this paper, we study under which conditions the Reissner–Nordström anti-de Sitter black hole can be a solution of the vacuum mimetic F ( R gravity with Lagrange multiplier and mimetic scalar potential. As the author demonstrates, the resulting picture in the mimetic F ( R gravity case is a trivial extension of the standard F ( R approach, and in effect, the metric perturbations in the mimetic F ( R gravity case, for the Reissner–Nordström anti-de Sitter black hole metric, at the first order of the perturbed variables are the same at the leading order.

  13. Therapeutic benefits of enhancing permeability barrier for atopic eczema

    Directory of Open Access Journals (Sweden)

    George Man

    2015-06-01

    Full Text Available The regulatory role of epidermal permeability barrier function in cutaneous inflammation has been well appreciated. While barrier disruption induces cutaneous inflammation, improvement of permeability barrier function alleviates inflammation. Studies have demonstrated that improvement of epidermal permeability barrier function not only prevents the development of atopic eczema, but also delays the relapse of these diseases. Moreover, enhancing the epidermal permeability barrier also alleviates atopic eczema. Furthermore, co-applications of barrier enhancing products with glucocorticoids can increase the therapeutic efficacy and reduce the adverse effects of glucocorticoids in the treatment of atopic eczema. Therefore, utilization of permeability barrier enhancing products alone or in combination with glucocorticoids could be a valuable approach in the treatment of atopic eczema. In this review, we discuss the benefits of improving the epidermal permeability barrier in the management of atopic eczema.

  14. Glycosaminoglycan-Mimetic Signals Direct the Osteo/Chondrogenic Differentiation of Mesenchymal Stem Cells in a Three-Dimensional Peptide Nanofiber Extracellular Matrix Mimetic Environment.

    Science.gov (United States)

    Arslan, Elif; Guler, Mustafa O; Tekinay, Ayse B

    2016-04-11

    Recent efforts in bioactive scaffold development focus strongly on the elucidation of complex cellular responses through the use of synthetic systems. Designing synthetic extracellular matrix (ECM) materials must be based on understanding of cellular behaviors upon interaction with natural and artificial scaffolds. Hence, due to their ability to mimic both the biochemical and mechanical properties of the native tissue environment, supramolecular assemblies of bioactive peptide nanostructures are especially promising for development of bioactive ECM-mimetic scaffolds. In this study, we used glycosaminoglycan (GAG) mimetic peptide nanofiber gel as a three-dimensional (3D) platform to investigate how cell lineage commitment is altered by external factors. We observed that amount of fetal bovine serum (FBS) presented in the cell media had synergistic effects on the ability of GAG-mimetic nanofiber gel to mediate the differentiation of mesenchymal stem cells into osteogenic and chondrogenic lineages. In particular, lower FBS concentration in the culture medium was observed to enhance osteogenic differentiation while higher amount FBS promotes chondrogenic differentiation in tandem with the effects of the GAG-mimetic 3D peptide nanofiber network, even in the absence of externally administered growth factors. We therefore demonstrate that mesenchymal stem cell differentiation can be specifically controlled by the combined influence of growth medium components and a 3D peptide nanofiber environment.

  15. Determination of superoxide dismutase mimetic activity in common culinary herbs.

    Science.gov (United States)

    Chohan, Magali; Naughton, Declan P; Opara, Elizabeth I

    2014-01-01

    Under conditions of oxidative stress, the removal of superoxide, a free radical associated with chronic inflammation, is catalysed by superoxide dismutase (SOD). Thus in addition to acting as an antioxidant, SOD may also be utilized as an anti-inflammatory agent. Some plant derived foods have been shown to have SOD mimetic (SODm) activity however it is not known if this activity is possessed by culinary herbs which have previously been shown to possess both antioxidant and anti-inflammatory properties. The aim of the study was to ascertain if the culinary herbs rosemary, sage and thyme possess SODm activity, and to investigate the influence of cooking and digestion on this activity. Transition metal ion content was also determined to establish if it could likely contribute to any SODm activity detected. All extracts of uncooked (U), cooked (C) and cooked and digested (C&D) herbs were shown to possess SODm activity, which was significantly correlated with previously determined antioxidant and anti-inflammatory activities of these herbs. SODm activity was significantly increased following (C) and (C&D) for rosemary and sage only. The impact of (C) and (C&D) on the SODm for thyme may have been influenced by its transition metal ion content. SODm activity may contribute to the herbs' antioxidant and anti-inflammatory activities however the source and significance of this activity need to be established.

  16. Membrane mimetic surface functionalization of nanoparticles: Methods and applications

    Science.gov (United States)

    Weingart, Jacob; Vabbilisetty, Pratima; Sun, Xue-Long

    2013-01-01

    Nanoparticles (NPs), due to their size-dependent physical and chemical properties, have shown remarkable potential for a wide range of applications over the past decades. Particularly, the biological compatibilities and functions of NPs have been extensively studied for expanding their potential in areas of biomedical application such as bioimaging, biosensing, and drug delivery. In doing so, surface functionalization of NPs by introducing synthetic ligands and/or natural biomolecules has become a critical component in regards to the overall performance of the NP system for its intended use. Among known examples of surface functionalization, the construction of an artificial cell membrane structure, based on phospholipids, has proven effective in enhancing biocompatibility and has become a viable alternative to more traditional modifications, such as direct polymer conjugation. Furthermore, certain bioactive molecules can be immobilized onto the surface of phospholipid platforms to generate displays more reminiscent of cellular surface components. Thus, NPs with membrane-mimetic displays have found use in a range of bioimaging, biosensing, and drug delivery applications. This review herein describes recent advances in the preparations and characterization of integrated functional NPs covered by artificial cell membrane structures and their use in various biomedical applications. PMID:23688632

  17. Metal Stabilization of Collagen and de Novo Designed Mimetic Peptides.

    Science.gov (United States)

    Parmar, Avanish S; Xu, Fei; Pike, Douglas H; Belure, Sandeep V; Hasan, Nida F; Drzewiecki, Kathryn E; Shreiber, David I; Nanda, Vikas

    2015-08-18

    We explore the design of metal binding sites to modulate triple-helix stability of collagen and collagen-mimetic peptides. Globular proteins commonly utilize metals to connect tertiary structural elements that are well separated in sequence, constraining structure and enhancing stability. It is more challenging to engineer structural metals into fibrous protein scaffolds, which lack the extensive tertiary contacts seen in globular proteins. In the collagen triple helix, the structural adjacency of the carboxy-termini of the three chains makes this region an attractive target for introducing metal binding sites. We engineered His3 sites based on structural modeling constraints into a series of designed homotrimeric and heterotrimeric peptides, assessing the capacity of metal binding to improve stability and in the case of heterotrimers, affect specificity of assembly. Notable enhancements in stability for both homo- and heteromeric systems were observed upon addition of zinc(II) and several other metal ions only when all three histidine ligands were present. Metal binding affinities were consistent with the expected Irving-Williams series for imidazole. Unlike other metals tested, copper(II) also bound to peptides lacking histidine ligands. Acetylation of the peptide N-termini prevented copper binding, indicating proline backbone amide metal-coordination at this site. Copper similarly stabilized animal extracted Type I collagen in a metal-specific fashion, highlighting the potential importance of metal homeostasis within the extracellular matrix.

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

    Directory of Open Access Journals (Sweden)

    Keith Bruce D

    2008-03-01

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

  19. Block of glucocorticoid synthesis during re-activation inhibits extinction of an established fear memory.

    Science.gov (United States)

    Blundell, Jacqueline; Blaiss, Cory A; Lagace, Diane C; Eisch, Amelia J; Powell, Craig M

    2011-05-01

    The pharmacology of traumatic memory extinction has not been fully characterized despite its potential as a therapeutic target for established, acquired anxiety disorders, including post-traumatic stress disorder (PTSD). Here we examine the role of endogenous glucocorticoids in traumatic memory extinction. Male C57BL/6J mice were injected with corticosterone (10 mg/kg, i.p.) or metyrapone (50 mg/kg, s.c.) during re-activation of a contextual fear memory, and compared to vehicle groups (N=10-12 per group). To ensure that metyrapone was blocking corticosterone synthesis, we measured corticosterone levels following re-activation of a fear memory in metyrapone- and vehicle-treated animals. Corticosterone administration following extinction trials caused a long-lasting inhibition of the original fear memory trace. In contrast, blockade of corticosteroid synthesis with metyrapone prior to extinction trials enhanced retrieval and prevented extinction of context-dependent fear responses in mice. Further behavioral analysis suggested that the metyrapone enhancement of retrieval and prevention of extinction were not due to non-specific alterations in locomotor or anxiety-like behavior. In addition, the inhibition of extinction by metyrapone was rescued by exogenous administration of corticosterone following extinction trials. Finally, we confirmed that the rise in corticosterone during re-activation of a contextual fear memory was blocked by metyrapone. We demonstrate that extinction of a classical contextual fear memory is dependent on endogenous glucocorticoid synthesis during re-activation of a fear memory. Our data suggest that decreased glucocorticoids during fear memory re-activation may contribute to the inability to extinguish a fear memory, thus contributing to one of the core symptoms of PTSD. Copyright © 2011 Elsevier Inc. All rights reserved.

  20. Progesterone attenuates airway remodeling and glucocorticoid resistance in a murine model of exposing to ozone.

    Science.gov (United States)

    Zhang, Xue; Bao, Wuping; Fei, Xia; Zhang, Yingying; Zhang, Guoqing; Zhou, Xin; Zhang, Min

    2018-04-01

    Airway remodeling is a vital component of chronic obstructive pulmonary disease (COPD). Despite the broad anti-inflammation effects of glucocorticoids, they exhibit relatively little therapeutic benefit in COPD, indicating the accelerating demands of new agents for COPD. We aim to explore the effect of progesterone on airway remodeling in a murine modeling of exposing to ozone and to further examine the potential effect of progesterone on glucocorticoid insensitivity. C57/BL6 mice were exposed to ozone for 12 times over 6 weeks, and were administered with progesterone alone or combined with budesonide (BUD) after each exposure until the 10th week. The peribronchial collagen deposition was measured. The protein levels of MMP8 and MMP9 in bronchoalveolar lavage fluid (BALF) and lungs were assessed. Western blot analysis was used to detect the levels of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), a-smooth muscle actin (α-SMA), glycogen synthase kinase-3β (GSK-3β). The expression of VEGF and histone deacetylase 2 (HDAC2) in the lung were determined by Immunohistochemical analyses. We observe that progesterone attenuates the peribronchial collagen deposition, as well as the expression of MMP8, MMP9, HIF-1α, VEGF, α-SMA, and GSK-3β in BALF or lung tissues. Progesterone or BUD monotherapy has no effect on HDAC2 production. Progesterone combines with BUD induce dramatically enhanced effects. Thus, these results demonstrate novel roles of progesterone for the pathogenesis and airway remodeling in COPD. Progesterone plus BUD administration exerts more significant inhibition on airway remodeling with dose-independent. Additionally, progesterone may, to some extent, improve the glucocorticoid insensitivity. Copyright © 2018. Published by Elsevier Ltd.

  1. Glucocorticoid resistance in two key models of acute lymphoblastic leukemia occurs at the level of the glucocorticoid receptor.

    Science.gov (United States)

    Schmidt, Stefan; Irving, Julie A E; Minto, Lynne; Matheson, Elizabeth; Nicholson, Lindsay; Ploner, Andreas; Parson, Walther; Kofler, Anita; Amort, Melanie; Erdel, Martin; Hall, Andy; Kofler, Reinhard

    2006-12-01

    Glucocorticoids (GCs) specifically induce apoptosis in malignant lymphoblasts and are thus pivotal in the treatment of acute lymphoblastic leukemia (ALL). However, GC-resistance is a therapeutic problem with an unclear molecular mechanism. We generated approximately 70 GC-resistant sublines from a GC-sensitive B- and a T-ALL cell line and investigated their mechanisms of resistance. In response to GCs, all GC-resistant subclones analyzed by real-time polymerase chain reaction (PCR) showed a deficient up-regulation of the GC-receptor (GR) and its downstream target, GC-induced leucine zipper. This deficiency in GR up-regulation was confirmed by Western blotting and on retroviral overexpression of GR in resistant subclones GC-sensitivity was restored. All GC-resistant subclones were screened for GR mutations using denaturing high-pressure liquid chromatography (DHPLC), DNA-fingerprinting, and fluorescence in situ hybridization (FISH). Among the identified mutations were some previously not associated with GC resistance: A484D, P515H, L756N, Y663H, L680P, and R714W. This approach revealed three genotypes, complete loss of functional GR in the mismatch repair deficient T-ALL model, apparently normal GR genes in B-ALLs, and heterozygosity in both. In the first genotype, deficiency in GR up-regulation was fully explained by mutational events, in the second by a putative regulatory defect, and in the third by a combination thereof. In all instances, GC-resistance occurred at the level of the GR in both models.

  2. Glucocorticoid regulation of astrocytic fate and function.

    Directory of Open Access Journals (Sweden)

    Shuang Yu

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

  3. Hypoxia-mimetic agents inhibit proliferation and alter the morphology of human umbilical cord-derived mesenchymal stem cells

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    Zeng Hui-Lan

    2011-08-01

    Full Text Available Abstract Background The therapeutic efficacy of human mesenchymal stem cells (hMSCs for the treatment of hypoxic-ischemic diseases is closely related to level of hypoxia in the damaged tissues. To elucidate the potential therapeutic applications and limitations of hMSCs derived from human umbilical cords, the effects of hypoxia on the morphology and proliferation of hMSCs were analyzed. Results After treatment with DFO and CoCl2, hMSCs were elongated, and adjacent cells were no longer in close contact. In addition, vacuole-like structures were observed within the cytoplasm; the rough endoplasmic reticulum expanded, and expanded ridges were observed in mitochondria. In addition, DFO and CoCl2 treatments for 48 h significantly inhibited hMSCs proliferation in a concentration-dependent manner (P Conclusions The hypoxia-mimetic agents, DFO and CoCl2, alter umbilical cord-derived hMSCs morphology and inhibit their proliferation through influencing the cell cycle.

  4. Elementary dispersion analysis of some mimetic discretizations on triangular C-grids

    Energy Technology Data Exchange (ETDEWEB)

    Korn, P., E-mail: peter.korn@mpimet.mpg.de [Max Planck Institute for Meteorology, Hamburg (Germany); Danilov, S. [Alfred Wegener Institute for Polar and Marine Research, Bremerhaven (Germany); A.M. Obukhov Institute of Atmospheric Physics, Moscow (Russian Federation)

    2017-02-01

    Spurious modes supported by triangular C-grids limit their application for modeling large-scale atmospheric and oceanic flows. Their behavior can be modified within a mimetic approach that generalizes the scalar product underlying the triangular C-grid discretization. The mimetic approach provides a discrete continuity equation which operates on an averaged combination of normal edge velocities instead of normal edge velocities proper. An elementary analysis of the wave dispersion of the new discretization for Poincaré, Rossby and Kelvin waves shows that, although spurious Poincaré modes are preserved, their frequency tends to zero in the limit of small wavenumbers, which removes the divergence noise in this limit. However, the frequencies of spurious and physical modes become close on shorter scales indicating that spurious modes can be excited unless high-frequency short-scale motions are effectively filtered in numerical codes. We argue that filtering by viscous dissipation is more efficient in the mimetic approach than in the standard C-grid discretization. Lumping of mass matrices appearing with the velocity time derivative in the mimetic discretization only slightly reduces the accuracy of the wave dispersion and can be used in practice. Thus, the mimetic approach cures some difficulties of the traditional triangular C-grid discretization but may still need appropriately tuned viscosity to filter small scales and high frequencies in solutions of full primitive equations when these are excited by nonlinear dynamics.

  5. From Dalek half balls to Daft Punk helmets: Mimetic fandom and the crafting of replicas

    Directory of Open Access Journals (Sweden)

    Matt Hills

    2014-06-01

    Full Text Available Mimetic fandom is a surprisingly understudied mode of (culturally masculinized fan activity in which fans research and craft replica props. Mimetic fandom can be considered as (inauthentic and (immaterial, combining noncommercial status with grassroots marketing or brand reinforcement as well as fusing an emphasis on material artifacts with Web 2.0 collective intelligence. Simply analyzing mimetic fandom as part of fannish material culture fails to adequately assess the nonmaterial aspects of this collaborative creativity. Two fan cultures are taken as case studies: Dalek building groups and Daft Punk helmet constructors. These diverse cases indicate that mimetic fandom has a presence and significance that moves across media fandoms and is not restricted to the science fiction, fantasy, and horror followings with which it is most often associated. Mimetic fandom may be theorized as an oscillatory activity that confuses binaries and constructions of (academic/fan authenticity. This fan practice desires and pursues a kind of ontological bridging or unity—from text to reality—that is either absent or less dominant in many other fan activities such as cosplay, screen-used prop collecting, and geographical pilgrimage. Fan studies may benefit from reassessing the place of mimesis, especially in order to theorize fan practices that are less clearly transformative in character.

  6. Beyond Antibodies as Binding Partners: The Role of Antibody Mimetics in Bioanalysis.

    Science.gov (United States)

    Yu, Xiaowen; Yang, Yu-Ping; Dikici, Emre; Deo, Sapna K; Daunert, Sylvia

    2017-06-12

    The emergence of novel binding proteins or antibody mimetics capable of binding to ligand analytes in a manner analogous to that of the antigen-antibody interaction has spurred increased interest in the biotechnology and bioanalytical communities. The goal is to produce antibody mimetics designed to outperform antibodies with regard to binding affinities, cellular and tumor penetration, large-scale production, and temperature and pH stability. The generation of antibody mimetics with tailored characteristics involves the identification of a naturally occurring protein scaffold as a template that binds to a desired ligand. This scaffold is then engineered to create a superior binder by first creating a library that is then subjected to a series of selection steps. Antibody mimetics have been successfully used in the development of binding assays for the detection of analytes in biological samples, as well as in separation methods, cancer therapy, targeted drug delivery, and in vivo imaging. This review describes recent advances in the field of antibody mimetics and their applications in bioanalytical chemistry, specifically in diagnostics and other analytical methods.

  7. Pharmacokinetic and pharmacodynamic considerations for the next generation protein therapeutics.

    Science.gov (United States)

    Shah, Dhaval K

    2015-10-01

    Increasingly sophisticated protein engineering efforts have been undertaken lately to generate protein therapeutics with desired properties. This has resulted in the discovery of the next generation of protein therapeutics, which include: engineered antibodies, immunoconjugates, bi/multi-specific proteins, antibody mimetic novel scaffolds, and engineered ligands/receptors. These novel protein therapeutics possess unique physicochemical properties and act via a unique mechanism-of-action, which collectively makes their pharmacokinetics (PK) and pharmacodynamics (PD) different than other established biological molecules. Consequently, in order to support the discovery and development of these next generation molecules, it becomes important to understand the determinants controlling their PK/PD. This review discusses the determinants that a PK/PD scientist should consider during the design and development of next generation protein therapeutics. In addition, the role of systems PK/PD models in enabling rational development of the next generation protein therapeutics is emphasized.

  8. Influencia de los glucocorticoides inhalados sobre la densidad mineral ósea y el metabolismo óseo Inhaled glucocorticoids: influence on bone mineral density and bone metabolism

    Directory of Open Access Journals (Sweden)

    Fernando D. Saraví

    2000-04-01

    Full Text Available Los glucocorticoides inhalados (GCI constituyen hoy un tratamiento de primera línea del asma bronquial. Los efectos sistémicos de los GCI, como la supresión del eje hipotalámico- hipofisario-adrenal, son en general menores que los de los glucocorticoides orales. Sin embargo, existe el riesgo de efectos adversos sobre el hueso a largo plazo. El objetivo del presente trabajo fue revisar los datos publicados acerca de los efectos de los GCI sobre los marcadores del metabolismo óseo y la densidad mineral ósea en adultos y en pacientes pediátricos. Aunque los estudios examinados no proporcionan resultados uniformes, en términos generales sugieren que los GCI pueden afectar al metabolismo y a la densidad mineral ósea, en particular 1 cuando se administran a dosis elevadas (más de 400 µg/día en niños y más de 800 µg/día en adultos; 2 en pacientes pediátricos, en los que también pueden afectar al crecimiento en estatura; 3 en pacientes cuya ingesta de calcio y vitamina D es inadecuada, y 4 en mujeres postmenopáusicas sin terapia de reposición hormonal. En general, a dosis terapéuticamente equivalentes, la beclometasona tiene mayor efecto deletéreo sobre el hueso que la budesonida, y esta mayor que la fluticasona. Además de la precaución obvia de utilizar la menor dosis eficaz, se proponen como medidas preventivas: 1 la adecuada instrucción sobre el uso de los aerosoles; 2 el uso de cámaras de inhalación; 3 el enjuague bucal tras la administración de GCI, y 4 ajustes o suplementos dietéticos para asegurar una adecuada ingesta de calcio y vitamina D.Inhaled glucocorticoids (IGs are today the first-line treatment for bronchial asthma. The systemic effects of inhaled glucocorticoids, such as suppressing the hypothalamic-pituitary-adrenal axis, are generally less than those with oral glucocorticoids. However, there is a long-term risk of adverse effects on bone. The objective of this piece was to review the published data on the

  9. Molecular Integration of Incretin and Glucocorticoid Action Reverses Immunometabolic Dysfunction and Obesity.

    Science.gov (United States)

    Quarta, Carmelo; Clemmensen, Christoffer; Zhu, Zhimeng; Yang, Bin; Joseph, Sini S; Lutter, Dominik; Yi, Chun-Xia; Graf, Elisabeth; García-Cáceres, Cristina; Legutko, Beata; Fischer, Katrin; Brommage, Robert; Zizzari, Philippe; Franklin, Bernardo S; Krueger, Martin; Koch, Marco; Vettorazzi, Sabine; Li, Pengyun; Hofmann, Susanna M; Bakhti, Mostafa; Bastidas-Ponce, Aimée; Lickert, Heiko; Strom, Tim M; Gailus-Durner, Valerie; Bechmann, Ingo; Perez-Tilve, Diego; Tuckermann, Jan; Hrabě de Angelis, Martin; Sandoval, Darleen; Cota, Daniela; Latz, Eicke; Seeley, Randy J; Müller, Timo D; DiMarchi, Richard D; Finan, Brian; Tschöp, Matthias H

    2017-10-03

    Chronic inflammation has been proposed to contribute to the pathogenesis of diet-induced obesity. However, scarce therapeutic options are available to treat obesity and the associated immunometabolic complications. Glucocorticoids are routinely employed for the management of inflammatory diseases, but their pleiotropic nature leads to detrimental metabolic side effects. We developed a glucagon-like peptide-1 (GLP-1)-dexamethasone co-agonist in which GLP-1 selectively delivers dexamethasone to GLP-1 receptor-expressing cells. GLP-1-dexamethasone lowers body weight up to 25% in obese mice by targeting the hypothalamic control of feeding and by increasing energy expenditure. This strategy reverses hypothalamic and systemic inflammation while improving glucose tolerance and insulin sensitivity. The selective preference for GLP-1 receptor bypasses deleterious effects of dexamethasone on glucose handling, bone integrity, and hypothalamus-pituitary-adrenal axis activity. Thus, GLP-1-directed glucocorticoid pharmacology represents a safe and efficacious therapy option for diet-induced immunometabolic derangements and the resulting obesity. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. microRNA-379 couples glucocorticoid hormones to dysfunctional lipid homeostasis

    Science.gov (United States)

    de Guia, Roldan M; Rose, Adam J; Sommerfeld, Anke; Seibert, Oksana; Strzoda, Daniela; Zota, Annika; Feuchter, Yvonne; Krones-Herzig, Anja; Sijmonsma, Tjeerd; Kirilov, Milen; Sticht, Carsten; Gretz, Norbert; Dallinga-Thie, Geesje; Diederichs, Sven; Klöting, Nora; Blüher, Matthias; Berriel Diaz, Mauricio; Herzig, Stephan

    2015-01-01

    In mammals, glucocorticoids (GCs) and their intracellular receptor, the glucocorticoid receptor (GR), represent critical checkpoints in the endocrine control of energy homeostasis. Indeed, aberrant GC action is linked to severe metabolic stress conditions as seen in Cushing's syndrome, GC therapy and certain components of the Metabolic Syndrome, including obesity and insulin resistance. Here, we identify the hepatic induction of the mammalian conserved microRNA (miR)-379/410 genomic cluster as a key component of GC/GR-driven metabolic dysfunction. Particularly, miR-379 was up-regulated in mouse models of hyperglucocorticoidemia and obesity as well as human liver in a GC/GR-dependent manner. Hepatocyte-specific silencing of miR-379 substantially reduced circulating very-low-density lipoprotein (VLDL)-associated triglyceride (TG) levels in healthy mice and normalized aberrant lipid profiles in metabolically challenged animals, mediated through miR-379 effects on key receptors in hepatic TG re-uptake. As hepatic miR-379 levels were also correlated with GC and TG levels in human obese patients, the identification of a GC/GR-controlled miRNA cluster not only defines a novel layer of hormone-dependent metabolic control but also paves the way to alternative miRNA-based therapeutic approaches in metabolic dysfunction. PMID:25510864

  11. Fructose, Glucocorticoids and Adipose Tissue: Implications for the Metabolic Syndrome.

    Science.gov (United States)

    Legeza, Balázs; Marcolongo, Paola; Gamberucci, Alessandra; Varga, Viola; Bánhegyi, Gábor; Benedetti, Angiolo; Odermatt, Alex

    2017-04-26

    The modern Western society lifestyle is characterized by a hyperenergetic, high sugar containing food intake. Sugar intake increased dramatically during the last few decades, due to the excessive consumption of high-sugar drinks and high-fructose corn syrup. Current evidence suggests that high fructose intake when combined with overeating and adiposity promotes adverse metabolic health effects including dyslipidemia, insulin resistance, type II diabetes, and inflammation. Similarly, elevated glucocorticoid levels, especially the enhanced generation of active glucocorticoids in the adipose tissue due to increased 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) activity, have been associated with metabolic diseases. Moreover, recent evidence suggests that fructose stimulates the 11β-HSD1-mediated glucocorticoid activation by enhancing the availability of its cofactor NADPH. In adipocytes, fructose was found to stimulate 11β-HSD1 expression and activity, thereby promoting the adipogenic effects of glucocorticoids. This article aims to highlight the interconnections between overwhelmed fructose metabolism, intracellular glucocorticoid activation in adipose tissue, and their metabolic effects on the progression of the metabolic syndrome.

  12. The role of glucocorticoids in emotional memory reconsolidation.

    Science.gov (United States)

    Meir Drexler, Shira; Wolf, Oliver T

    2017-07-01

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

  13. Exercise-mimetic AICAR transiently benefits brain function

    Science.gov (United States)

    Guerrieri, Davide; van Praag, Henriette

    2015-01-01

    Exercise enhances learning and memory in animals and humans. The role of peripheral factors that may trigger the beneficial effects of running on brain function has been sparsely examined. In particular, it is unknown whether AMP-kinase (AMPK) activation in muscle can predict enhancement of brain plasticity. Here we compare the effects of running and administration of AMPK agonist 5-Aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR, 500 mg/kg), for 3, 7 or 14 days in one-month-old male C57BL/6J mice, on muscle AMPK signaling. At the time-points where we observed equivalent running- and AICAR-induced muscle pAMPK levels (7 and 14 days), cell proliferation, synaptic plasticity and gene expression, as well as markers of oxidative stress and inflammation in the dentate gyrus (DG) of the hippocampus and lateral entorhinal cortex (LEC) were evaluated. At the 7-day time-point, both regimens increased new DG cell number and brain-derived neurotrophic factor (BDNF) protein levels. Furthermore, microarray analysis of DG and LEC tissue showed a remarkable overlap between running and AICAR in the regulation of neuronal, mitochondrial and metabolism related gene classes. Interestingly, while similar outcomes for both treatments were stable over time in muscle, in the brain an inversion occurred at fourteen days. The compound no longer increased DG cell proliferation or neurotrophin levels, and upregulated expression of apoptotic genes and inflammatory cytokine interleukin-1β. Thus, an exercise mimetic that produces changes in muscle consistent with those of exercise does not have the same sustainable positive effects on the brain, indicating that only running consistently benefits brain function. PMID:26286955

  14. Prey from the eyes of predators: Color discriminability of aposematic and mimetic butterflies from an avian visual perspective.

    Science.gov (United States)

    Su, Shiyu; Lim, Matthew; Kunte, Krushnamegh

    2015-11-01

    Predation exerts strong selection on mimetic butterfly wing color patterns, which also serve other functions such as sexual selection. Therefore, specific selection pressures may affect the sexes and signal components differentially. We tested three predictions about the evolution of mimetic resemblance by comparing wing coloration of aposematic butterflies and their Batesian mimics: (a) females gain greater mimetic advantage than males and therefore are better mimics, (b) due to intersexual genetic correlations, sexually monomorphic mimics are better mimics than female-limited mimics, and (c) mimetic resemblance is better on the dorsal wing surface that is visible to predators in flight. Using a physiological model of avian color vision, we quantified mimetic resemblance from predators' perspective, which showed that female butterflies were better mimics than males. Mimetic resemblance in female-limited mimics was comparable to that in sexually monomorphic mimics, suggesting that intersexual genetic correlations did not constrain adaptive response to selection for female-limited mimicry. Mimetic resemblance on the ventral wing surface was better than that on the dorsal wing surface, implying stronger natural and sexual selection on ventral and dorsal surfaces, respectively. These results suggest that mimetic resemblance in butterfly mimicry rings has evolved under various selective pressures acting in a sex- and wing surface-specific manner. © 2015 The Author(s). Evolution © 2015 The Society for the Study of Evolution.

  15. Healthy imperfect dark matter from effective theory of mimetic cosmological perturbations

    International Nuclear Information System (INIS)

    Hirano, Shin'ichi; Nishi, Sakine; Kobayashi, Tsutomu

    2017-01-01

    We study the stability of a recently proposed model of scalar-field matter called mimetic dark matter or imperfect dark matter. It has been known that mimetic matter with higher derivative terms suffers from gradient instabilities in scalar perturbations. To seek for an instability-free extension of imperfect dark matter, we develop an effective theory of cosmological perturbations subject to the constraint on the scalar field's kinetic term. This is done by using the unifying framework of general scalar-tensor theories based on the ADM formalism. We demonstrate that it is indeed possible to construct a model of imperfect dark matter which is free from ghost and gradient instabilities. As a side remark, we also show that mimetic F (R) theory is plagued with the Ostrogradsky instability.

  16. A review of underwater bio-mimetic propulsion: cruise and fast-start

    Energy Technology Data Exchange (ETDEWEB)

    Chao, Li-Ming; Cao, Yong-Hui; Pan, Guang, E-mail: PanGuang_010@163.com [School of Marine Science and Technology, Northwestern Polytechnical University, Xian 710072 (China)

    2017-08-15

    This paper reviews recent developments in the understanding of underwater bio-mimetic propulsion. Two impressive models of underwater propulsion are considered: cruise and fast-start. First, we introduce the progression of bio-mimetic propulsion, especially underwater propulsion, where some primary conceptions are touched upon. Second, the understanding of flapping foils, considered as one of the most efficient cruise styles of aquatic animals, is introduced, where the effect of kinematics and the shape and flexibility of foils on generating thrust are elucidated respectively. Fast-start propulsion is always exhibited when predator behaviour occurs, and we provide an explicit introduction of corresponding zoological experiments and numerical simulations. We also provide some predictions about underwater bio-mimetic propulsion. (review)

  17. A review of underwater bio-mimetic propulsion: cruise and fast-start

    Science.gov (United States)

    Chao, Li-Ming; Cao, Yong-Hui; Pan, Guang

    2017-08-01

    This paper reviews recent developments in the understanding of underwater bio-mimetic propulsion. Two impressive models of underwater propulsion are considered: cruise and fast-start. First, we introduce the progression of bio-mimetic propulsion, especially underwater propulsion, where some primary conceptions are touched upon. Second, the understanding of flapping foils, considered as one of the most efficient cruise styles of aquatic animals, is introduced, where the effect of kinematics and the shape and flexibility of foils on generating thrust are elucidated respectively. Fast-start propulsion is always exhibited when predator behaviour occurs, and we provide an explicit introduction of corresponding zoological experiments and numerical simulations. We also provide some predictions about underwater bio-mimetic propulsion.

  18. René Girard and the Mimetic Nature of Eating Disorders.

    Science.gov (United States)

    Strand, Mattias

    2018-03-07

    French historian and literary critic René Girard (1923-2015), most widely known for the concepts of mimetic desire and scapegoating, also engaged in the discussion of the surge of eating disorders in his 1996 essay Eating Disorders and Mimetic Desire. This article explores Girard's ideas on the mimetic nature and origin of eating disorders from a clinical psychiatric perspective and contextualizes them within the field of eating disorders research as well as in relation to broader psychological, sociological and anthropological models of social comparison and non-consumption. Three main themes in Girard's thinking on the topic of eating disorders are identified and explored: the 'end of prohibitions' as a driving force in the emergence of eating disorders, eating disorders as a phenomenon specific to modernity, and the significance of 'conspicuous non-consumption' in the emergence of eating disorders.

  19. Targeting apoptotic machinery as approach for anticancer therapy: Smac mimetics as anticancer agents

    Directory of Open Access Journals (Sweden)

    Nevine M.Y. Elsayed

    2015-06-01

    Full Text Available Apoptosis is a chief regulator of cellular homeostasis. Impairment of apoptotic machinery is a main characteristic of several diseases such as cancer, where the evasion of apoptosis is a cardinal hallmark of cancer. Apoptosis is regulated by contribution of pro- and anti- apoptotic proteins, where caspases are the main executioners of the apoptotic machinery. IAP (inhibitors of apoptosis proteins is a family of endogenous inhibitors of apoptosis, which perform their function through interference with the function of caspases. Smac (second mitochondria-derived activator of caspases is endogenous inhibitor of IAPs, thus it is one of the major proapoptotic endogenous proteins. Thus, the development of Smac mimetics has evolved as an approach for anticancer therapy. Several Smac mimetic agents have been introduced to clinical trial such as birinapanet 12. Herein, the history of development of Smac mimetics along with the recent development in this field is briefly discussed.

  20. Modeling seismic wave propagation using staggered-grid mimetic finite differences

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    Freysimar Solano-Feo

    2017-04-01

    Full Text Available Mimetic finite difference (MFD approximations of continuous gradient and divergence operators satisfy a discrete version of the Gauss-Divergence theorem on staggered grids. On the mimetic approximation of this integral conservation principle, an unique boundary flux operator is introduced that also intervenes on the discretization of a given boundary value problem (BVP. In this work, we present a second-order MFD scheme for seismic wave propagation on staggered grids that discretized free surface and absorbing boundary conditions (ABC with same accuracy order. This scheme is time explicit after coupling a central three-level finite difference (FD stencil for numerical integration. Here, we briefly discuss the convergence properties of this scheme and show its higher accuracy on a challenging test when compared to a traditional FD method. Preliminary applications to 2-D seismic scenarios are also presented and show the potential of the mimetic finite difference method.

  1. Static spherically symmetric solutions in mimetic gravity: rotation curves and wormholes

    International Nuclear Information System (INIS)

    Myrzakulov, Ratbay; Sebastiani, Lorenzo; Vagnozzi, Sunny; Zerbini, Sergio

    2016-01-01

    In this work, we analyse static spherically symmetric solutions in the framework of mimetic gravity, an extension of general relativity where the conformal degree of freedom of gravity is isolated in a covariant fashion. Here we extend previous works by considering, in addition, a potential for the mimetic field. An appropriate choice of such a potential allows for the reconstruction of a number of interesting cosmological and astrophysical scenarios. We explicitly show how to reconstruct such a potential for a general static spherically symmetric space-time. A number of applications and scenarios are then explored, among which are traversable wormholes. Finally, we analytically reconstruct potentials, which leads to solutions to the equations of motion featuring polynomial corrections to the Schwarzschild space-time. Accurate choices for such corrections could provide an explanation for the inferred flat rotation curves of spiral galaxies within the mimetic gravity framework, without the need for particle dark matter. (paper)

  2. Healthy imperfect dark matter from effective theory of mimetic cosmological perturbations

    Energy Technology Data Exchange (ETDEWEB)

    Hirano, Shin' ichi; Nishi, Sakine; Kobayashi, Tsutomu, E-mail: s.hirano@rikkyo.ac.jp, E-mail: sakine@rikkyo.ac.jp, E-mail: tsutomu@rikkyo.ac.jp [Department of Physics, Rikkyo University, Toshima, Tokyo 171-8501 (Japan)

    2017-07-01

    We study the stability of a recently proposed model of scalar-field matter called mimetic dark matter or imperfect dark matter. It has been known that mimetic matter with higher derivative terms suffers from gradient instabilities in scalar perturbations. To seek for an instability-free extension of imperfect dark matter, we develop an effective theory of cosmological perturbations subject to the constraint on the scalar field's kinetic term. This is done by using the unifying framework of general scalar-tensor theories based on the ADM formalism. We demonstrate that it is indeed possible to construct a model of imperfect dark matter which is free from ghost and gradient instabilities. As a side remark, we also show that mimetic F (R) theory is plagued with the Ostrogradsky instability.

  3. Glucocorticoid effects on hippocampal protein synthesis

    International Nuclear Information System (INIS)

    Schlatter, L.K.

    1988-01-01

    Following subcutaneous injection of rats with 5 mg corticosterone, hippocampal slices in vitro show increased [ 35 S]-methionine labeling of a cytosolic protein with an apparent molecular weight (M r ) of 35,000 and an isoelectric point (IEP) of 6.6. This labeling is temporally consistent with a transcriptional event, and is steroid- and tissue-specific. The pear serum concentration of steroid occurs one hour or less following the injection. Maximal labeling of this protein is reached whenever serum corticosterone values are approximately 100 ng/ml. When endogenous corticosterone levels are elevated to 100 ng/ml through stressors or exogenous ACTH injections the same maximal increase in synthesis of the 35,000 M r protein is observed. Adrenalectomy prevents the observed response from occurring following stressor application or ACTH injections. Comparison of the increases observed after administration of the type 2 receptor agonist RU 28362 and aldosterone, which has a higher affinity for the type 1 receptor, shows a 50-fold greater sensitivity of the response to the type 2 receptor agonist. Synthesis of this protein following serum increases of steroid possibly correlates to the theorized function of the type 2 receptor feedback regulation. The similar protein in the liver has an IEP of 6.8 and a slightly higher M r . A second hippocampal protein with an M r of 46,000 and an IEP of 6.2 is also increased in labeling. Two additional liver proteins, one of Mr 53,000 (IEP of 6.2) and the other with an M r of 45,000 (IEP of 8.7-7.8) are increased in the liver following glucocorticoid administration

  4. Salivary cortisol day curves in assessing glucocorticoid replacement therapy in Addison's disease

    NARCIS (Netherlands)

    Smans, L.; Lentjes, E.G.W.M.; Hermus, A.R.; Zelissen, P.M.J.

    2013-01-01

    OBJECTIVE: Patients with Addison's disease require lifelong treatment with glucocorticoids. At present, no glucocorticoid replacement therapy (GRT) can exactly mimic normal physiology. As a consequence, under- and especially overtreatment can occur. Suboptimal GRT may lead to various side effects.

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

    DEFF Research Database (Denmark)

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

    2015-01-01

    Case-reports have made it evident that both inhaled, percutaneous, intranasal, intraarticular and ophthalmic administered glucocorticoids have the potential to cause life threatening adrenal insufficiency. With few and sometimes conflicting data and study methodology the prevalence of adrenal...... insufficiency secondary to locally applied glucocorticoids is not clear. Adrenal insufficiency can only be correctly evaluated by a stimulation test, and has by this procedure been reported in up to 40-50% of patients treated with high-dose inhaled glucocorticoids. Medium- to low-dose inhaled glucocorticoids...... have been shown to cause adrenal suppression in 0-16% of patients. Glucocorticoid creams and nasal glucocorticoids can cause adrenal insufficiency, also when used within prescribed doses, but the frequency seems to be less than with inhaled glucocorticoids. Intraarticularly administered glucocorticoids...

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

    DEFF Research Database (Denmark)

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

    2012-01-01

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

  7. The study of lymphocytes glucocorticoid receptor in severe head injury

    International Nuclear Information System (INIS)

    Li Dapei; Wang Haodan; Zhao Qihuang

    1994-01-01

    Glucocorticoid receptors (GCR) of peripheral lymphocytes from 14 patients with severe head injury and 11 normal volunteers are studied by means of single point method of radioligand binding assay. All these patients receive surgical therapy and glucocorticoid of routine dosage. The results show that the GCR level of these patients is lower than that of the normal, while the plasma cortisol level is much higher. These changes correlate closely to the patients' clinical outcome. It is indicated that the GCR level can reflect the degree of stress of these patients and their response to glucocorticoid therapy. Using peripheral lymphocytes instead of the brain biopsy for the measurement of GCR can reflect the GCR changes of brain tissue, it's more convenient to get the sample and more acceptable to the patients

  8. Glucocorticoid receptor polymorphism in obesity and glucose homeostasis.

    Science.gov (United States)

    Majer-Łobodzińska, Agnieszka; Adamiec-Mroczek, Joanna

    2017-01-01

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

  9. Osteoporosis secundaria y Osteoporosis inducida por glucocorticoides (OIG

    Directory of Open Access Journals (Sweden)

    Elías Forero Illera

    2006-01-01

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

  10. Glucocorticoid receptors in monocytes in type 1 diabetes mellitus

    DEFF Research Database (Denmark)

    Damm, P; Binder, C

    1989-01-01

    Glucocorticoid receptor binding characteristics were investigated in 8 males with poorly controlled Type 1 diabetes mellitus and 14 healthy males. The cell type studied was monocytes, and a method for correction for heterogeneity in glucocorticoid binding in a mononuclear leucocyte population...... or with HbA1c. In conclusion, no major abnormalities in glucocorticoid receptor binding characteristics could be demonstrated in Type 1 diabetes mellitus....... was introduced. The number of receptors and the dissociation constant KD were, respectively, 13,699 and 2.93 X 10(-8) mol/l for the control group and 15,788 and 2.75 X 10(-8) mol/l for diabetics (p greater than 0.05). In diabetics, KD correlated negatively with blood glucose (r = 0.762, p less than 0...

  11. Prevalent glucocorticoid and androgen activity in US water sources.

    Science.gov (United States)

    Stavreva, Diana A; George, Anuja A; Klausmeyer, Paul; Varticovski, Lyuba; Sack, Daniel; Voss, Ty C; Schiltz, R Louis; Blazer, Vicki S; Iwanowicz, Luke R; Hager, Gordon L

    2012-01-01

    Contamination of the environment with endocrine disrupting chemicals (EDCs) is a major health concern. The presence of estrogenic compounds in water and their deleterious effect are well documented. However, detection and monitoring of other classes of EDCs is limited. Here we utilize a high-throughput live cell assay based on sub-cellular relocalization of GFP-tagged glucocorticoid and androgen receptors (GFP-GR and GFP-AR), in combination with gene transcription analysis, to screen for glucocorticoid and androgen activity in water samples. We report previously unrecognized glucocorticoid activity in 27%, and androgen activity in 35% of tested water sources from 14 states in the US. Steroids of both classes impact body development, metabolism, and interfere with reproductive, endocrine, and immune systems. This prevalent contamination could negatively affect wildlife and human populations.

  12. Synthesis of new enantiopure poly(hydroxyaminooxepanes as building blocks for multivalent carbohydrate mimetics

    Directory of Open Access Journals (Sweden)

    Léa Bouché

    2014-01-01

    Full Text Available New compounds with carbohydrate-similar structure (carbohydrate mimetics are presented in this article. Starting from enantiopure nitrones and lithiated TMSE-allene we prepared three 1,2-oxazine derivatives which underwent a highly stereoselective Lewis acid-induced rearrangement to give bicyclic products in good yield. Subsequent reductive transformations delivered a library of new poly(hydroxyaminooxepane derivatives. The crucial final palladium-catalyzed hydrogenolysis of the 1,2-oxazine moiety was optimized resulting in a reasonably efficient approach to a series of new seven-membered carbohydrate mimetics.

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

    Directory of Open Access Journals (Sweden)

    Leonardo Rizzo

    2007-06-01

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

  14. Glucocorticoid-induced myopathy in the intensive care unit

    DEFF Research Database (Denmark)

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

    2015-01-01

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

  15. Quintupling Inhaled Glucocorticoids to Prevent Childhood Asthma Exacerbations.

    Science.gov (United States)

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

    2018-03-08

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

  16. Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program

    DEFF Research Database (Denmark)

    Morrison-Nozik, Alexander; Anand, Priti; Zhu, Han

    2015-01-01

    in Duchenne muscular dystrophy (DMD), a genetic muscle-wasting disease. A defined molecular basis underlying these performance-enhancing properties of GCs in skeletal muscle remains obscure. Here, we demonstrate that ergogenic effects of GCs are mediated by direct induction of the metabolic transcription......Classic physiology studies dating to the 1930s demonstrate that moderate or transient glucocorticoid (GC) exposure improves muscle performance. The ergogenic properties of GCs are further evidenced by their surreptitious use as doping agents by endurance athletes and poorly understood efficacy...... factor KLF15, defining a downstream pathway distinct from that resulting in GC-related muscle atrophy. Furthermore, we establish that KLF15 deficiency exacerbates dystrophic severity and muscle GC-KLF15 signaling mediates salutary therapeutic effects in the mdx mouse model of DMD. Thus, although...

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

    Directory of Open Access Journals (Sweden)

    Marta Labeur

    2010-10-01

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

  18. BH3 mimetics inhibit growth of chondrosarcoma--a novel targeted-therapy for candidate models.

    Science.gov (United States)

    Morii, Takeshi; Ohtsuka, Kouki; Ohnishi, Hiroaki; Mochizuki, Kazuo; Yoshiyama, Akira; Aoyagi, Takayuki; Hornicek, Francis J; Ichimura, Shoichi

    2014-11-01

    Chondrosarcoma is refractory to conventional chemotherapy. BH-3 mimetics ABT-737 and ABT-263 are synthetic small-molecule inhibitors of anti-apoptotic proteins B-cell lymphoma-2 (Bcl2) and Bcl-xL, which play a critical role in survival of chondrosarcoma cells. Chondrosarcoma cell lines SW-1353 and CS-1 were used as the disease model. We used immunoblotting to assess the expression of target molecules Bcl2 and Bcl-xL, and the apoptotic inducers Bcl2-associated X (Bax) and Bcl2-antagonist/killer (Bak). In vitro growth inhibition by BH-3 mimetics was confirmed by photomicroscopic cell counting and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay. Apoptotic induction was confirmed by Enzyme-Linked ImmunoSorbent Assay (ELISA). In vivo growth inhibition was assessed in a non-obese diabetic/severe combined immunodeficient (NOD/SCID) mouse model. Expression of the target and effector molecules was confirmed in chondrosarcoma cell lines. BH3 mimetics significantly inhibited cell growth and induced apoptosis in vitro. Administration of ABT-263 inhibited chondrosarcoma growth and improved survival in a mouse model. BH3 mimetics represent a novel treatment modality for chondrosarcoma. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  19. Discrete conservation properties for shallow water flows using mixed mimetic spectral elements

    NARCIS (Netherlands)

    Lee, D.; Palha, A.; Gerritsma, M.

    2018-01-01

    A mixed mimetic spectral element method is applied to solve the rotating shallow water equations. The mixed method uses the recently developed spectral element histopolation functions, which exactly satisfy the fundamental theorem of calculus with respect to the standard Lagrange basis functions in

  20. Antifungal Potential of Host Defense Peptide Mimetics in a Mouse Model of Disseminated Candidiasis

    Directory of Open Access Journals (Sweden)

    Mobaswar Hossain Chowdhury

    2018-02-01

    Full Text Available Invasive candidiasis caused by Candida albicans and non-albicans Candida (NAC present a serious disease threat. Although the echinocandins are recommended as the first line of antifungal drug class, resistance to these agents is beginning to emerge, demonstrating the need for new antifungal agents. Host defense peptides (HDP exhibit potent antifungal activity, but as drugs they are difficult to manufacture efficiently, and they are often inactivated by serum proteins. HDP mimetics are low molecular weight non-peptide compounds that can alleviate these problems and were shown to be membrane-active against C. albicans and NAC. Here, we expand upon our previous works to describe the in vitro and in vivo activity of 11 new HDP mimetics that are active against C. albicans and NAC that are both sensitive and resistant to standard antifungal drugs. These compounds exhibit minimum inhibitory/fungicidal concentration (MIC/MFC in the µg/mL range in the presence of serum and are inhibited by divalent cations. Rapid propidium iodide influx into the yeast cells following in vitro exposure suggested that these HDP mimetics were also membrane active. The lead compounds were able to kill C. albicans in an invasive candidiasis CD-1 mouse model with some mimetic candidates decreasing kidney burden by 3–4 logs after 24 h in a dose-dependent manner. The data encouraged further development of this new anti-fungal drug class for invasive candidiasis.

  1. Mimetic Divergence and the Speciation Continuum in the Mimic Poison Frog Ranitomeya imitator

    DEFF Research Database (Denmark)

    Twomey, Evan; Vestergaard, Jacob Schack; Venegas, Pablo J.

    2016-01-01

    While divergent ecological adaptation can drive speciation, understanding the factors that facilitate or constrain this process remains a major goal in speciation research. Here, we study two mimetic transition zones in the poison frog Ranitomeya imitator, a species that has undergone a Mullerian...

  2. Comparative Allometric Growth of the Mimetic Ephippid Reef Fishes Chaetodipterus faber and Platax orbicularis.

    Directory of Open Access Journals (Sweden)

    Breno Barros

    Full Text Available Mimesis is a relatively widespread phenomenon among reef fish, but the ontogenetic processes relevant for mimetic associations in fish are still poorly understood. In the present study, the allometric growth of two allopatric leaf-mimetic species of ephippid fishes, Chaetodipterus faber from the Atlantic and Platax orbicularis from the Indo-Pacific, was analyzed using ten morphological variables. The development of fins was considered owing to the importance of these structures for mimetic behaviors during early life stages. Despite the anatomical and behavioral similarities in both juvenile and adult stages, C. faber and P. orbicularis showed distinct patterns of growth. The overall shape of C. faber transforms from a rounded-shape in mimetic juveniles to a lengthened profile in adults, while in P. orbicularis, juveniles present an oblong profile including dorsal and anal fins, with relative fin size diminishing while the overall profile grows rounder in adults. Although the two species are closely-related, the present results suggest that growth patterns in C. faber and P. orbicularis are different, and are probably independent events in ephippids that have resulted from similar selective processes.

  3. Novel thrombopoietin mimetic peptides bind c-Mpl receptor: Synthesis, biological evaluation and molecular modeling.

    Science.gov (United States)

    Liu, Yaquan; Tian, Fang; Zhi, Dejuan; Wang, Haiqing; Zhao, Chunyan; Li, Hongyu

    2017-02-01

    Thrombopoietin (TPO) acts in promoting the proliferation of hematopoietic stem cells and by initiating specific maturation events in megakaryocytes. Now, TPO-mimetic peptides with amino acid sequences unrelated to TPO are of considerable pharmaceutical interest. In the present paper, four new TPO mimetic peptides that bind and activate c-Mpl receptor have been identified, synthesized and tested by Dual-Luciferase reporter gene assay for biological activities. The molecular modeling research was also approached to understand key molecular mechanisms and structural features responsible for peptide binding with c-Mpl receptor. The results presented that three of four mimetic peptides showed significant activities. In addition, the molecular modeling approaches proved hydrophobic interactions were the driven positive forces for binding behavior between peptides and c-Mpl receptor. TPO peptide residues in P7, P13 and P7' positions were identified by the analysis of hydrogen bonds and energy decompositions as the key ones for benefiting better biological activities. Our data suggested the synthesized peptides have considerable potential for the future development of stable and highly active TPO mimetic peptides. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Spectral mimetic least-squares method for div-curl systems

    NARCIS (Netherlands)

    Gerritsma, Marc; Palha, Artur; Lirkov, I.; Margenov, S.

    2018-01-01

    In this paper the spectral mimetic least-squares method is applied to a two-dimensional div-curl system. A test problem is solved on orthogonal and curvilinear meshes and both h- and p-convergence results are presented. The resulting solutions will be pointwise divergence-free for these test

  5. The conversion in the René Girard’s mimetic theory

    Directory of Open Access Journals (Sweden)

    Agustín Moreno Fernández

    2014-12-01

    Full Text Available One of the specific peculiarities of René Girard’s mimetic theory is the recovery of the concept of conversion. In this article we expose, in a detailed way, the three senses of the conversion according to his thinking: novelistic, religious and epistemological. There is an interaction between the three senses and also different significations for each other.

  6. Glucocorticoid stimulates expression of corticotropin-releasing hormone gene in human placenta

    International Nuclear Information System (INIS)

    Robinson, B.G.; Emanuel, R.L.; Frim, D.M.; Majzoub, J.A.

    1988-01-01

    Primary cultures of purified human cytotrophoblasts have been used to examine the expression of the corticotropin-releasing hormone (CRH) gene in placenta. The authors report here that glucocorticoids stimulate placental CRH synthesis and secretion in primary cultures of human placenta. This stimulation is in contrast to the glucocorticoid suppression of CRH expression in hypothalamus. The positive regulation of CRH by glucocorticoids suggests that the rise in CRH preceding parturition could result from the previously described rise in fetal glucocorticoids. Furthermore, this increase in placental CRH could stimulate, via adrenocorticotropic hormone, a further rise in fetal glucocorticoids, completing a positive feedback loop that would be terminated by delivery

  7. Temperature-sensitive elastin-mimetic dendrimers: Effect of peptide length and dendrimer generation to temperature sensitivity.

    Science.gov (United States)

    Kojima, Chie; Irie, Kotaro; Tada, Tomoko; Tanaka, Naoki

    2014-06-01

    Dendrimers are synthetic macromolecules with unique structure, which are a potential scaffold for peptides. Elastin is one of the main components of extracellular matrix and a temperature-sensitive biomacromolecule. Previously, Val-Pro-Gly-Val-Gly peptides have been conjugated to a dendrimer for designing an elastin-mimetic dendrimer. In this study, various elastin-mimetic dendrimers using different length peptides and different dendrimer generations were synthesized to control the temperature dependency. The elastin-mimetic dendrimers formed β-turn structure by heating, which was similar to the elastin-like peptides. The elastin-mimetic dendrimers exhibited an inverse phase transition, largely depending on the peptide length and slightly depending on the dendrimer generation. The elastin-mimetic dendrimers formed aggregates after the phase transition. The endothermal peak was observed in elastin-mimetic dendrimers with long peptides, but not with short ones. The peptide length and the dendrimer generation are important factors to tune the temperature dependency on the elastin-mimetic dendrimer. Copyright © 2013 Wiley Periodicals, Inc.

  8. The Glucocorticoid Receptor Controls Hepatic Dyslipidemia through Hes1

    NARCIS (Netherlands)

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

    2008-01-01

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

  9. CINRG: Systems Biology of Glucocorticoids in Muscle Disease

    Science.gov (United States)

    2013-10-01

    Contract W81XWH-09-1-0726 SYSTEMS BIOLOGY OF GLUCOCORTICOIDS IN MUSCLE DISEASE Introduction Duchenne muscular dystrophy (DMD) is the most... muscle and enable the development of better targeted and more effective therapies for Duchenne muscular dystrophy dynamically. This MDA grant...common and incurable muscular dystrophy of childhood. Muscle regeneration fails with advancing age, leading to considerable fibrosis. Corticosteroid

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

    International Nuclear Information System (INIS)

    Halloran, B.P.; Bikle, D.D.; Cone, C.M.; Morey-Holton, E.

    1988-01-01

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

  11. General effect of endotoxin on glucocorticoid receptors in mammalian tissues

    International Nuclear Information System (INIS)

    Stith, R.D.; McCallum, R.E.

    1986-01-01

    Considering the ubiquitous nature of glucocorticoid actions and the fact that endotoxin inhibits glucocorticoid action in the liver, we proposed to examine whether endotoxin affected extrahepatic actions of glucocorticoids. Fasted C57BL/6J mice were injected intraperitoneally with endotoxin (LD50) at 0800 and were killed 6 h later. Control mice were injected with an equal volume of saline. 3 H-dexamethasone binding, measured by a new cytosol exchange assay utilizing molybdate plus dithiothreitol, in liver, kidney, skeletal muscle, spleen, lung, and heart tissue was significantly lower in treated than in control mice. The equilibrium dissociation constants were not significantly different, but the number of available binding sites in each tissue was reduced by endotoxin treatment. Phosphoenolpyruvate carboxykinase activity was significantly reduced in liver but not in kidney. Endotoxin treatment lowered glycogen content in liver but not in skeletal muscle. The reduction observed in the a form of liver glycogen synthase due to endotoxin was not seen in skeletal muscle glycogen synthase a. These data support the proposal that endotoxin or a mediator of its action inhibits systemic glucocorticoid action. The results also emphasize the central role of the liver in the metabolic disturbances of the endotoxin-treated mouse

  12. Uso de glucocorticoides en enfermedades alérgicas

    Directory of Open Access Journals (Sweden)

    M Rodríguez-González

    2017-01-01

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

  13. Adrenocorticotropic Hormone Secreting Pheochromocytoma Underlying Glucocorticoid Induced Pheochromocytoma Crisis

    Directory of Open Access Journals (Sweden)

    Gil A. Geva

    2018-01-01

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

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

    African Journals Online (AJOL)

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

  15. Chronic Glucocorticoid Hypersecretion in Cushing's Syndrome Exacerbates Cognitive Aging

    Science.gov (United States)

    Michaud, Kathy; Forget, Helene; Cohen, Henri

    2009-01-01

    Cumulative exposure to glucocorticoid hormones (GC) over the lifespan has been associated with cognitive impairment and may contribute to physical and cognitive degeneration in aging. The objective of the present study was to examine whether the pattern of cognitive deficits in patients with Cushing's syndrome (CS), a disorder characterized by…

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

    NARCIS (Netherlands)

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

    2008-01-01

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

  17. Postreactivation glucocorticoids impair recall of established fear memory.

    Science.gov (United States)

    Cai, Wen-Hui; Blundell, Jacqueline; Han, Jie; Greene, Robert W; Powell, Craig M

    2006-09-13

    Pavlovian fear conditioning provides one of the best rodent models of acquired anxiety disorders, including posttraumatic stress disorder. Injection of a variety of drugs after training in fear-conditioning paradigms can impair consolidation of fear memories. Indeed, early clinical trials suggest that immediate administration of such drugs after a traumatic event may decrease the risk of developing posttraumatic stress disorder in humans (Pitman et al., 2002; Vaiva et al., 2003). The use of such a treatment is limited by the difficulty of treating every patient at risk and by the difficulty in predicting which patients will experience chronic adverse consequences. Recent clinical trials suggest that administration of glucocorticoids may have a beneficial effect on established posttraumatic stress disorder (Aerni et al., 2004) and specific phobia (Soravia et al., 2006). Conversely, glucocorticoid administration after training is known to enhance memory consolidation (McGaugh and Roozendaal, 2002; Roozendaal, 2002). From a clinical perspective, enhancement of a fear memory or a reactivated fear memory would not be desirable. We report here that when glucocorticoids are administered immediately after reactivation of a contextual fear memory, subsequent recall is significantly diminished. Additional experiments support the interpretation that glucocorticoids not only decrease fear memory retrieval but, in addition, augment consolidation of fear memory extinction rather than decreasing reconsolidation. These findings provide a rodent model for a potential treatment of established acquired anxiety disorders in humans, as suggested by others (Aerni et al., 2004; Schelling et al., 2004), based on a mechanism of enhanced extinction.

  18. Selective replication of oncolytic virus M1 results in a bystander killing effect that is potentiated by Smac mimetics.

    Science.gov (United States)

    Cai, Jing; Lin, Yuan; Zhang, Haipeng; Liang, Jiankai; Tan, Yaqian; Cavenee, Webster K; Yan, Guangmei

    2017-06-27

    Oncolytic virotherapy is a treatment modality that uses native or genetically modified viruses that selectively replicate in and kill tumor cells. Viruses represent a type of pathogen-associated molecular pattern and thereby induce the up-regulation of dozens of cytokines via activating the host innate immune system. Second mitochondria-derived activator of caspases (Smac) mimetic compounds (SMCs), which antagonize the function of inhibitor of apoptosis proteins (IAPs) and induce apoptosis, sensitize tumor cells to multiple cytokines. Therefore, we sought to determine whether SMCs sensitize tumor cells to cytokines induced by the oncolytic M1 virus, thus enhancing a bystander killing effect. Here, we report that SMCs potentiate the oncolytic effect of M1 in vitro, in vivo, and ex vivo. This strengthened oncolytic efficacy resulted from the enhanced bystander killing effect caused by the M1 virus via cytokine induction. Through a microarray analysis and subsequent validation using recombinant cytokines, we identified IL-8, IL-1A, and TRAIL as the key cytokines in the bystander killing effect. Furthermore, SMCs increased the replication of M1, and the accumulation of virus protein induced irreversible endoplasmic reticulum stress- and c-Jun N-terminal kinase-mediated apoptosis. Nevertheless, the combined treatment with M1 and SMCs had little effect on normal and human primary cells. Because SMCs selectively and significantly enhance the bystander killing effect and the replication of oncolytic virus M1 specifically in cancer cells, this combined treatment may represent a promising therapeutic strategy.

  19. Sera from Children with Autism Induce Autistic Features Which Can Be Rescued with a CNTF Small Peptide Mimetic in Rats

    Science.gov (United States)

    Kazim, Syed Faraz; Cardenas-Aguayo, Maria del Carmen; Arif, Mohammad; Blanchard, Julie; Fayyaz, Fatima; Grundke-Iqbal, Inge; Iqbal, Khalid

    2015-01-01

    Autism is a neurodevelopmental disorder characterized clinically by impairments in social interaction and verbal and non-verbal communication skills as well as restricted interests and repetitive behavior. It has been hypothesized that altered brain environment including an imbalance in neurotrophic support during early development contributes to the pathophysiology of autism. Here we report that sera from children with autism which exhibited abnormal levels of various neurotrophic factors induced cell death and oxidative stress in mouse primary cultured cortical neurons. The effects of sera from autistic children were rescued by pre-treatment with a ciliary neurotrophic factor (CNTF) small peptide mimetic, Peptide 6 (P6), which was previously shown to exert its neuroprotective effect by modulating CNTF/JAK/STAT pathway and LIF signaling and by enhancing brain derived neurotrophic factor (BDNF) expression. Similar neurotoxic effects and neuroinflammation were observed in young Wistar rats injected intracerebroventricularly with autism sera within hours after birth. The autism sera injected rats demonstrated developmental delay and deficits in social communication, interaction, and novelty. Both the neurobiological changes and the behavioral autistic phenotype were ameliorated by P6 treatment. These findings implicate the involvement of neurotrophic imbalance during early brain development in the pathophysiology of autism and a proof of principle of P6 as a potential therapeutic strategy for autism. PMID:25769033

  20. Sera from children with autism induce autistic features which can be rescued with a CNTF small peptide mimetic in rats.

    Science.gov (United States)

    Kazim, Syed Faraz; Cardenas-Aguayo, Maria Del Carmen; Arif, Mohammad; Blanchard, Julie; Fayyaz, Fatima; Grundke-Iqbal, Inge; Iqbal, Khalid

    2015-01-01

    Autism is a neurodevelopmental disorder characterized clinically by impairments in social interaction and verbal and non-verbal communication skills as well as restricted interests and repetitive behavior. It has been hypothesized that altered brain environment including an imbalance in neurotrophic support during early development contributes to the pathophysiology of autism. Here we report that sera from children with autism which exhibited abnormal levels of various neurotrophic factors induced cell death and oxidative stress in mouse primary cultured cortical neurons. The effects of sera from autistic children were rescued by pre-treatment with a ciliary neurotrophic factor (CNTF) small peptide mimetic, Peptide 6 (P6), which was previously shown to exert its neuroprotective effect by modulating CNTF/JAK/STAT pathway and LIF signaling and by enhancing brain derived neurotrophic factor (BDNF) expression. Similar neurotoxic effects and neuroinflammation were observed in young Wistar rats injected intracerebroventricularly with autism sera within hours after birth. The autism sera injected rats demonstrated developmental delay and deficits in social communication, interaction, and novelty. Both the neurobiological changes and the behavioral autistic phenotype were ameliorated by P6 treatment. These findings implicate the involvement of neurotrophic imbalance during early brain development in the pathophysiology of autism and a proof of principle of P6 as a potential therapeutic strategy for autism.

  1. Caloric restriction mimetic 2-deoxyglucose maintains cytoarchitecture and reduces tau phosphorylation in primary culture of mouse hippocampal pyramidal neurons.

    Science.gov (United States)

    Bele, M S; Gajare, K A; Deshmukh, A A

    2015-06-01

    Typical form of neurons is crucially important for their functions. This is maintained by microtubules and associated proteins like tau. Hyperphosphorylation of tau is a major concern in neurodegenerative diseases. Glycogen synthase kinase3β (GSK3β) and cyclin-dependent protein kinase 5 (Cdk5) are the enzymes that govern tau phosphorylation. Currently, efforts are being made to target GSK3β and Cdk5 as possible therapeutic avenues to control tau phosphorylation and treat neurodegenerative diseases related to taupathies. In a number of studies, caloric restriction mimetic 2-deoxyglucose (C6H12O5) was found to be beneficial in improving the brain functions. However, no reports are available on the effect of 2-deoxyglucose 2-DG on tau phosphorylation. In the present study, hippocampal pyramidal neurons from E17 mouse embryos were isolated and cultured on poly-L-lysine-coated coverslips. Neurons from the experimental group were treated with 10 mM 2-deoxyglucose. The treatment of 2-DG resulted in healthier neuronal morphology in terms of significantly lower number of cytoplasmic vacuoles, little or no membrane blebbings, maintained axon hillock and intact neurites. There were decreased immunofluorescence signals for GSK3β, pTau at Ser262, Cdk5 and pTau at Ser235 suggesting decreased tau phosphorylation, which was further confirmed by Western blotting. The results indicate the beneficial effects of 2-DG in controlling the tau phosphorylation and maintaining the healthy neuronal cytoarchitecture.

  2. Social variables exert selective pressures in the evolution and form of primate mimetic musculature.

    Science.gov (United States)

    Burrows, Anne M; Li, Ly; Waller, Bridget M; Micheletta, Jerome

    2016-04-01

    Mammals use their faces in social interactions more so than any other vertebrates. Primates are an extreme among most mammals in their complex, direct, lifelong social interactions and their frequent use of facial displays is a means of proximate visual communication with conspecifics. The available repertoire of facial displays is primarily controlled by mimetic musculature, the muscles that move the face. The form of these muscles is, in turn, limited by and influenced by phylogenetic inertia but here we use examples, both morphological and physiological, to illustrate the influence that social variables may exert on the evolution and form of mimetic musculature among primates. Ecomorphology is concerned with the adaptive responses of morphology to various ecological variables such as diet, foliage density, predation pressures, and time of day activity. We present evidence that social variables also exert selective pressures on morphology, specifically using mimetic muscles among primates as an example. Social variables include group size, dominance 'style', and mating systems. We present two case studies to illustrate the potential influence of social behavior on adaptive morphology of mimetic musculature in primates: (1) gross morphology of the mimetic muscles around the external ear in closely related species of macaque (Macaca mulatta and Macaca nigra) characterized by varying dominance styles and (2) comparative physiology of the orbicularis oris muscle among select ape species. This muscle is used in both facial displays/expressions and in vocalizations/human speech. We present qualitative observations of myosin fiber-type distribution in this muscle of siamang (Symphalangus syndactylus), chimpanzee (Pan troglodytes), and human to demonstrate the potential influence of visual and auditory communication on muscle physiology. In sum, ecomorphologists should be aware of social selective pressures as well as ecological ones, and that observed morphology might

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

    DEFF Research Database (Denmark)

    Dinsen, Stina; Baslund, Bo; Klose, Marianne

    2013-01-01

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

  4. Glucocorticoid receptors in anorexia nervosa and Cushing's disease.

    Science.gov (United States)

    Invitti, C; Redaelli, G; Baldi, G; Cavagnini, F

    1999-06-01

    Patients with anorexia nervosa do not display cushingoid features in spite of elevated cortisol plasma levels. Whether a cortisol resistance or a reduced availability of the metabolic substrates necessary to develop the effect of glucocorticoids is responsible for this has not been established. Twenty-two patients with severe restrictive anorexia nervosa, 10 patients with active Cushing's disease, and 24 healthy volunteers without psychiatric disorders or mood alterations were investigated. Glucocorticoid receptor characteristics were examined on mononuclear leukocytes by measuring [3H]dexamethasone binding and the effect of dexamethasone on [3H]thymidine incorporation, which represents an index of DNA synthesis. The number of glucocorticoid receptors on mononuclear leukocytes (MNL) was comparable in patients with anorexia nervosa, patients with active Cushing's disease, and normal subjects (binding capacity 3.3 +/- 0.23 vs. 3.7 +/- 0.30 and 3.5 +/- 0.20 fmol/10(6) cells). Conversely, glucocorticoid receptor affinity was significantly decreased in anorexia nervosa as well as in Cushing's patients compared to control subjects (dissociation constant 4.0 +/- 0.31 and 4.1 +/- 0.34 vs. 2.9 +/- 0.29 nmol/L, p Cushing's patients compared to control subjects (p Cushing's disease. In patients with anorexia nervosa, the incorporation of [3H]thymidine into the MNL was inversely correlated with urinary free cortisol levels. These data indicate that the lack of cushingoid features in patients with anorexia nervosa is not ascribable to a reduced sensitivity to glucocorticoids but is more likely due to the paucity of metabolic substrates.

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

    Science.gov (United States)

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

    2016-03-01

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

  6. Insulin-mimetic activity of stevioside on diabetic rats: biochemical ...

    African Journals Online (AJOL)

    Biochemical, molecular and histopathological studies have been done to evaluate the therapeutic effect of stevioside on minimizing levels of glucose and its ... For mRNA expression, stevioside up-regulated the expressions of PK and IRS-1 genes, which are down-regulated in diabetic rats, and was very effective in the ...

  7. HDL-mimetic PLGA nanoparticle to target atherosclerosis plaque macrophages

    NARCIS (Netherlands)

    Sanchez-Gaytan, Brenda L.; Fay, Francois; Lobatto, Mark E.; Tang, Jun; Ouimet, Mireille; Kim, Yongtae; van der Staay, Susanne E. M.; van Rijs, Sarian M.; Priem, Bram; Zhang, Liangfang; Fisher, Edward A.; Moore, Kathryn J.; Langer, Robert; Fayad, Zahi A.; Mulder, Willem J. M.

    2015-01-01

    High-density lipoprotein (HDL) is a natural nanoparticle that exhibits an intrinsic affinity for atherosclerotic plaque macrophages. Its natural targeting capability as well as the option to incorporate lipophilic payloads, e.g., imaging or therapeutic components, in both the hydrophobic core and

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

    Science.gov (United States)

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

    2013-04-01

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

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

    Science.gov (United States)

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

    1991-10-01

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

  10. Antimicrobial Peptides for Therapeutic Applications: A Review

    Directory of Open Access Journals (Sweden)

    Tsogbadrakh Mishig-Ochir

    2012-10-01

    Full Text Available Antimicrobial peptides (AMPs have been considered as potential therapeutic sources of future antibiotics because of their broad-spectrum activities and different mechanisms of action compared to conventional antibiotics. Although AMPs possess considerable benefits as new generation antibiotics, their clinical and commercial development still have some limitations, such as potential toxicity, susceptibility to proteases, and high cost of peptide production. In order to overcome those obstacles, extensive efforts have been carried out. For instance, unusual amino acids or peptido-mimetics are introduced to avoid the proteolytic degradation and the design of short peptides retaining antimicrobial activities is proposed as a solution for the cost issue. In this review, we focus on small peptides, especially those with less than twelve amino acids, and provide an overview of the relationships between their three-dimensional structures and antimicrobial activities. The efforts to develop highly active AMPs with shorter sequences are also described.

  11. N-myristoylated ubiquitin ligase Cbl-b inhibitor prevents on glucocorticoid-induced atrophy in mouse skeletal muscle.

    Science.gov (United States)

    Ochi, Arisa; Abe, Tomoki; Nakao, Reiko; Yamamoto, Yoriko; Kitahata, Kanako; Takagi, Marina; Hirasaka, Katsuya; Ohno, Ayako; Teshima-Kondo, Shigetada; Taesik, Gwag; Choi, Inho; Kawamura, Tomoyuki; Nemoto, Hisao; Mukai, Rie; Terao, Junji; Nikawa, Takeshi

    2015-03-15

    A DGpYMP peptide mimetic of tyrosine(608)-phosphorylated insulin receptor substrate-1 (IRS-1), named Cblin, was previously shown to significantly inhibit Cbl-b-mediated IRS-1 ubiquitination. In the present study, we developed N-myristoylated Cblin and investigated whether it was effective in preventing glucocorticoid-induced muscle atrophy. Using HEK293 cells overexpressing Cbl-b, IRS-1 and ubiquitin, we showed that the 50% inhibitory concentrations of Cbl-b-mediated IRS-1 ubiquitination by N-myristoylated Cblin and Cblin were 30 and 120 μM, respectively. Regarding the DEX-induced atrophy of C2C12 myotubes, N-myristoylated Cblin was more effective than Cblin for inhibiting the DEX-induced decreases in C2C12 myotube diameter and IRS-1 degradation. The inhibitory efficacy of N-myristoylated Cblin on IRS-1 ubiquitination in C2C12 myotubes was approximately fourfold larger than that of Cblin. Furthermore, N-myristoylation increased the incorporation of Cblin into HEK293 cells approximately 10-folds. Finally, we demonstrated that N-myristoylated Cblin prevented the wet weight loss, IRS-1 degradation, and MAFbx/atrogin-1 and MuRF-1 expression in gastrocnemius muscle of DEX-treated mice approximately fourfold more effectively than Cblin. Taken together, these results suggest that N-myristoylated Cblin prevents DEX-induced skeletal muscle atrophy in vitro and in vivo, and that N-myristoylated Cblin more effectively prevents muscle atrophy than unmodified Cblin. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Quadrupling Inhaled Glucocorticoid Dose to Abort Asthma Exacerbations.

    Science.gov (United States)

    McKeever, Tricia; Mortimer, Kevin; Wilson, Andrew; Walker, Samantha; Brightling, Christopher; Skeggs, Andrew; Pavord, Ian; Price, David; Duley, Lelia; Thomas, Mike; Bradshaw, Lucy; Higgins, Bernard; Haydock, Rebecca; Mitchell, Eleanor; Devereux, Graham; Harrison, Timothy

    2018-03-08

    Asthma exacerbations are frightening for patients and are occasionally fatal. We tested the concept that a plan for patients to manage their asthma (self-management plan), which included a temporary quadrupling of the dose of inhaled glucocorticoids when asthma control started to deteriorate, would reduce the incidence of severe asthma exacerbations among adults and adolescents with asthma. We conducted a pragmatic, unblinded, randomized trial involving adults and adolescents with asthma who were receiving inhaled glucocorticoids, with or without add-on therapy, and who had had at least one exacerbation in the previous 12 months. We compared a self-management plan that included an increase in the dose of inhaled glucocorticoids by a factor of 4 (quadrupling group) with the same plan without such an increase (non-quadrupling group), over a period of 12 months. The primary outcome was the time to a first severe asthma exacerbation, defined as treatment with systemic glucocorticoids or an unscheduled health care consultation for asthma. A total of 1922 participants underwent randomization, of whom 1871 were included in the primary analysis. The number of participants who had a severe asthma exacerbation in the year after randomization was 420 (45%) in the quadrupling group as compared with 484 (52%) in the non-quadrupling group, with an adjusted hazard ratio for the time to a first severe exacerbation of 0.81 (95% confidence interval, 0.71 to 0.92; P=0.002). The rate of adverse effects, which were related primarily to local effects of inhaled glucocorticoids, was higher in the quadrupling group than in the non-quadrupling group. In this trial involving adults and adolescents with asthma, a personalized self-management plan that included a temporary quadrupling of the dose of inhaled glucocorticoids when asthma control started to deteriorate resulted in fewer severe asthma exacerbations than a plan in which the dose was not increased. (Funded by the Health Technology

  13. Cancer cell-selective promoter recognition accompanies antitumor effect by glucocorticoid receptor-targeted gold nanoparticle

    Science.gov (United States)

    Sau, Samaresh; Agarwalla, Pritha; Mukherjee, Sudip; Bag, Indira; Sreedhar, Bojja; Pal-Bhadra, Manika; Patra, Chitta Ranjan; Banerjee, Rajkumar

    2014-05-01

    Nanoparticles, such as gold nanoparticles (GNP), upon convenient modifications perform multi tasks catering to many biomedical applications. However, GNP or any other type of nanoparticles is yet to achieve the feat of intracellular regulation of endogenous genes of choice such as through manipulation of a gene-promoter in a chromosome. As for gene modulation and delivery, GNP (or other nanoparticles) showed only limited gene therapy potential, which relied on the delivery of `exogenous' genes invoking gene knockdown or replacement. Practically, there are no instances for the nanoparticle-mediated promoter regulation of `endogenous' genes, more so, as a cancer selective phenomenon. In this regard, we report the development of a simple, easily modifiable GNP-formulation, which promoted/up-regulated the expression of a specific category of `endogenous' genes, the glucocorticoid responsive genes. This genetic up-regulation was induced in only cancer cells by modified GNP-mediated transcriptional activation of its cytoplasmic receptor, glucocorticoid receptor (GR). Normal cells and their GR remained primarily unperturbed by this GNP-formulation. The most potent gene up-regulating GNP-formulation down-regulated a cancer-specific proliferative signal, phospho-Akt in cancer cells, which accompanied retardation of tumor growth in the murine melanoma model. We show that GR-targeted GNPs may find potential use in the targeting and modulation of genetic information in cancer towards developing novel anticancer therapeutics.Nanoparticles, such as gold nanoparticles (GNP), upon convenient modifications perform multi tasks catering to many biomedical applications. However, GNP or any other type of nanoparticles is yet to achieve the feat of intracellular regulation of endogenous genes of choice such as through manipulation of a gene-promoter in a chromosome. As for gene modulation and delivery, GNP (or other nanoparticles) showed only limited gene therapy potential, which relied

  14. Effect of cAMP signaling on expression of glucocorticoid receptor, Bim and Bad in glucocorticoid-sensitive and resistant leukemic and multiple myeloma cells.

    Science.gov (United States)

    Dong, Hongli; Carlton, Michael E; Lerner, Adam; Epstein, Paul M

    2015-01-01

    Stimulation of cAMP signaling induces apoptosis in glucocorticoid-sensitive and resistant CEM leukemic and MM.1 multiple myeloma cell lines, and this effect is enhanced by dexamethasone in both glucocorticoid-sensitive cell types and in glucocorticoid-resistant CEM cells. Expression of the mRNA for the glucocorticoid receptor alpha (GR) promoters 1A3, 1B and 1C, expression of mRNA and protein for GR, and the BH3-only proapoptotic proteins, Bim and Bad, and the phosphorylation state of Bad were examined following stimulation of the cAMP and glucocorticoid signaling pathways. Expression levels of GR promoters were increased by cAMP and glucocorticoid signaling, but GR protein expression was little changed in CEM and decreased in MM.1 cells. Stimulation of these two signaling pathways induced Bim in CEM cells, induced Bad in MM.1 cells, and activated Bad, as indicated by its dephosphorylation on ser112, in both cell types. This study shows that leukemic and multiple myeloma cells, including those resistant to glucocorticoids, can be induced to undergo apoptosis by stimulating the cAMP signaling pathway, with enhancement by glucocorticoids, and the mechanism by which this occurs may be related to changes in Bim and Bad expression, and in all cases, to activation of Bad.

  15. Glucocorticoid resistance is reverted by LCK inhibition in pediatric T-cell acute lymphoblastic leukemia.

    Science.gov (United States)

    Serafin, Valentina; Capuzzo, Giorgia; Milani, Gloria; Minuzzo, Sonia Anna; Pinazza, Marica; Bortolozzi, Roberta; Bresolin, Silvia; Porcù, Elena; Frasson, Chiara; Indraccolo, Stefano; Basso, Giuseppe; Accordi, Benedetta

    2017-12-21

    Pediatric T-acute lymphoblastic leukemia (T-ALL) patients often display resistance to glucocorticoid (GC) treatment. These patients, classified as prednisone poor responders (PPR), have poorer outcome than do the other pediatric T-ALL patients receiving a high-risk adapted therapy. Because glucocorticoids are administered to ALL patients during all the different phases of therapy, GC resistance represents an important challenge to improving the outcome for these patients. Mechanisms underlying resistance are not yet fully unraveled; thus our research focused on the identification of deregulated signaling pathways to point out new targeted approaches. We first identified, by reverse-phase protein arrays, the lymphocyte cell-specific protein-tyrosine kinase (LCK) as aberrantly activated in PPR patients. We showed that LCK inhibitors, such as dasatinib, bosutinib, nintedanib, and WH-4-023, are able to induce cell death in GC-resistant T-ALL cells, and remarkably, cotreatment with dexamethasone is able to reverse GC resistance, even at therapeutic drug concentrations. This was confirmed by specific LCK gene silencing and ex vivo combined treatment of cells from PPR patient-derived xenografts. Moreover, we observed that LCK hyperactivation in PPR patients upregulates the calcineurin/nuclear factor of activated T cells signaling triggering to interleukin-4 ( IL-4 ) overexpression. GC-sensitive cells cultured with IL-4 display an increased resistance to dexamethasone, whereas the inhibition of IL-4 signaling could increase GC-induced apoptosis in resistant cells. Treatment with dexamethasone and dasatinib also impaired engraftment of leukemia cells in vivo. Our results suggest a quickly actionable approach to supporting conventional therapies and overcoming GC resistance in pediatric T-ALL patients. © 2017 by The American Society of Hematology.

  16. Glucocorticoids Protect Neonatal Rat Brain in Model of Hypoxic-Ischemic Encephalopathy (HIE

    Directory of Open Access Journals (Sweden)

    Benjamin Harding

    2016-12-01

    Full Text Available Hypoxic-ischemic encephalopathy (HIE resulting from asphyxia in the peripartum period is the most common cause of neonatal brain damage and can result in significant neurologic sequelae, including cerebral palsy. Currently therapeutic hypothermia is the only accepted treatment in addition to supportive care for infants with HIE, however, many additional neuroprotective therapies have been investigated. Of these, glucocorticoids have previously been shown to have neuroprotective effects. HIE is also frequently compounded by infectious inflammatory processes (sepsis and as such, the infants may be more amenable to treatment with an anti-inflammatory agent. Thus, the present study investigated dexamethasone and hydrocortisone treatment given after hypoxic-ischemic (HI insult in neonatal rats via intracerebroventricular (ICV injection and intranasal administration. In addition, we examined the effects of hydrocortisone treatment in HIE after lipopolysaccharide (LPS sensitization in a model of HIE and sepsis. We found that dexamethasone significantly reduced rat brain infarction size when given after HI treatment via ICV injection; however it did not demonstrate any neuroprotective effects when given intranasally. Hydrocortisone after HI insult also significantly reduced brain infarction size when given via ICV injection; and the intranasal administration showed to be protective of brain injury in male rats at a dose of 300 µg. LPS sensitization did significantly increase the brain infarction size compared to controls, and hydrocortisone treatment after LPS sensitization showed a significant decrease in brain infarction size when given via ICV injection, as well as intranasal administration in both genders at a dose of 300 µg. To conclude, these results show that glucocorticoids have significant neuroprotective effects when given after HI injury and that these effects may be even more pronounced when given in circumstances of additional

  17. Macromolecular therapeutics.

    Science.gov (United States)

    Yang, Jiyuan; Kopeček, Jindřich

    2014-09-28

    This review covers water-soluble polymer-drug conjugates and macromolecules that possess biological activity without attached low molecular weight drugs. The main design principles of traditional and backbone degradable polymer-drug conjugates as well as the development of a new paradigm in nanomedicines - (low molecular weight) drug-free macromolecular therapeutics are discussed. To address the biological features of cancer, macromolecular therapeutics directed to stem/progenitor cells and the tumor microenvironment are deliberated. Finally, the future perspectives of the field are briefly debated. Copyright © 2014 Elsevier B.V. All rights reserved.

  18. A radioreceptor assay for measurement of plasma glucocorticoid binding activity

    International Nuclear Information System (INIS)

    Fan Jie

    1990-01-01

    A radioreceptor assay (RRA) for plasma glucocorticoid binding activity (GCBA) has been developed using glucocorticoid receptor in rat thymocytes. Unlike other assays for natural and certain synthetic corticosteroids, RRA measures the GCBA of all natural and synthetic GC in plasma. The range of standard curve was 0 ∼ 1.00 mg/L. The sensitivity was 0.01 mg/l. The recovery rate was 92.1%, and the intra and inter assay CV was 0.7% (n = 3) and 4.4% (n = 3) respectively. The level of corticosterone in 9 rat plasma samples was determined by RRA and CBG-isotope binding assay. There was a general correlation over a wide range between the values determined by the two assays (r = 0.95; P < 0.001). The measuring condition was described in detail

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

    Directory of Open Access Journals (Sweden)

    Dinushan Nesan

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

  20. Chronic Stress and Glucocorticoids: From Neuronal Plasticity to Neurodegeneration

    Directory of Open Access Journals (Sweden)

    Sheela Vyas

    2016-01-01

    Full Text Available Stress and stress hormones, glucocorticoids (GCs, exert widespread actions in central nervous system, ranging from the regulation of gene transcription, cellular signaling, modulation of synaptic structure, and transmission and glial function to behavior. Their actions are mediated by glucocorticoid and mineralocorticoid receptors which are nuclear receptors/transcription factors. While GCs primarily act to maintain homeostasis by inducing physiological and behavioral adaptation, prolonged exposure to stress and elevated GC levels may result in neuro- and psychopathology. There is now ample evidence for cause-effect relationships between prolonged stress, elevated GC levels, and cognitive and mood disorders while the evidence for a link between chronic stress/GC and neurodegenerative disorders such as Alzheimer’s (AD and Parkinson’s (PD diseases is growing. This brief review considers some of the cellular mechanisms through which stress and GC may contribute to the pathogenesis of AD and PD.

  1. Effect of glucocorticoids and gamma radiation on epidermal Langerhans cells

    International Nuclear Information System (INIS)

    Belsito, D.V.; Baer, R.L.; Thorbecke, G.J.; Gigli, I.

    1984-01-01

    The effect of 750 rads of gamma radiation on the rate of return of epidermal Langerhans cells (LC) following suppressive doses of topical glucorticoids was studied in guinea pigs. Gamma radiation alone had no effect on the LC as assessed by staining for cell membrane ATPase activity and Ia antigen. It did, however, delay the expected return of Ia but not ATPase surface markers on the LC after perturbation with glucocorticoids. The delayed return of surface Ia antigen is possibly related to a radiation-induced defect in the production of a required lymphokine and/or in intracellular Ia transport. Although our data do not rule out a cytolytic effect of steroids on the LC, they do strongly suggest that, at least in part, glucocorticoids act on the LC by altering cell surface characteristics

  2. Gastroprotective role of glucocorticoids during NSAID-induced gastropathy.

    Science.gov (United States)

    Filaretova, Ludmila

    2013-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) make significant contributions to gastric ulcer disease which remains widespread. Although several factors have been postulated as pathogenic elements of the gastric injury induced by NSAIDs, it is, however believed that prostaglandin deficiency plays a critical role in the pathogenesis of this injury. During prostaglandin deficiency, other defensive mechanisms might operate to attenuate NSAID-induced gastropathy. According to our results, NSAIDs, similar to stress, induce an increase in glucocorticoid production that in turn helps the gastric mucosa to resist the harmful actions of these drugs. In this article, we review our experimental data suggesting that glucocorticoids may play a role as natural defensive factors in maintaining the integrity of the gastric mucosa during NSAID therapy and might operate to attenuate NSAID-induced gastropathy.

  3. Locomotor therapy with extended-release crystalline glucocorticoids

    Directory of Open Access Journals (Sweden)

    Vladimir Vasilyevich Badokin

    2013-01-01

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

  4. Bioactive Mimetics of Conotoxins and other Venom Peptides

    Directory of Open Access Journals (Sweden)

    Peter J. Duggan

    2015-10-01

    Full Text Available Ziconotide (Prialt®, a synthetic version of the peptide ω-conotoxin MVIIA found in the venom of a fish-hunting marine cone snail Conus magnus, is one of very few drugs effective in the treatment of intractable chronic pain. However, its intrathecal mode of delivery and narrow therapeutic window cause complications for patients. This review will summarize progress in the development of small molecule, non-peptidic mimics of Conotoxins and a small number of other venom peptides. This will include a description of how some of the initially designed mimics have been modified to improve their drug-like properties.

  5. Pathogenesis of Graves' disease and therapeutic implications

    International Nuclear Information System (INIS)

    Seif, F.J.

    1997-01-01

    Graves' disease presents itself clinically mainly as hyperthyroidism and infiltrative ophthalmopathy and to a minimal extent also as dermopathy and acropachy. Autoimmune processes are the basic pathogenesis. Stimulating antibodies against the TSH receptor cause hyperthyroidism. Autoantibodies and autoreactive T lymphocytes against primarily thyroidal antigens cross-react with similar antigens of the eye muscles and orbital connective tissue, thus spreading the disease from the thyroid to the eyes. The therapeutic goal comprises not only the treatment of hyperthyroidism, but also the induction of a steady immuntolerance in order to minimize the irreversible damage to the eye. The therapeutic armamentarium is formed by antithyroid drugs, glucocorticoids, retrobulbar radition and thyroid ablation, either by nearly total thyroidectomy or by radioiodine. The different indications for both ablative procedures are discussed. (orig.) [de

  6. Mimetic Theory for Cell-Centered Lagrangian Finite Volume Formulation on General Unstructured Grids

    Energy Technology Data Exchange (ETDEWEB)

    Sambasivan, Shiv Kumar [Los Alamos National Laboratory; Shashkov, Mikhail J. [Los Alamos National Laboratory; Burton, Donald E. [Los Alamos National Laboratory; Christon, Mark A. [Los Alamos National Laboratory

    2012-07-19

    A finite volume cell-centered Lagrangian scheme for solving large deformation problems is constructed based on the hypo-elastic model and using the mimetic theory. Rigorous analysis in the context of gas and solid dynamics, and arbitrary polygonal meshes, is presented to demonstrate the ability of cell-centered schemes in mimicking the continuum properties and principles at the discrete level. A new mimetic formulation based gradient evaluation technique and physics-based, frame independent and symmetry preserving slope limiters are proposed. Furthermore, a physically consistent dissipation model is employed which is both robust and inexpensive to implement. The cell-centered scheme along with these additional new features are applied to solve solids undergoing elasto-plastic deformation.

  7. Synthesis and evaluation of di- and trimeric hydroxylamine-based β-(1→3)-glucan mimetics.

    Science.gov (United States)

    Ferry, Angélique; Malik, Gaëlle; Guinchard, Xavier; Vĕtvička, Václav; Crich, David

    2014-10-22

    Di- and trimeric hydroxylamine-based mimetics of β-(1→3)-glucans have been accessed by an asymmetric synthesis route featuring an iterative double ring-closing reductive amination reaction. These oligomeric hydroxylamines are demonstrated to inhibit the staining of human neutrophils and of mouse macrophages by fluorescent anti-CR3 and anti-dectin-1 antibodies, respectively, and to stimulate phagocytosis, all in a linkage-dependent manner suggestive of binding to the lectin domains of complement receptor 3 (CR3) and dectin-1. The ability of these relatively short mimetics to bind to CR3 and dectin-1, as compared to the greater degree of polymerization required in β-(1→3)-glucans, is discussed in terms of the increased hydrophobicity of the α-face on replacement of the glycosidic bond by the hydroxylamine linkage.

  8. Serum and Glucocorticoid Regulated Kinase 1 (SGK1) Regulates Neutrophil Clearance During Inflammation Resolution

    Science.gov (United States)

    Burgon, Joseph; Robertson, Anne L.; Sadiku, Pranvera; Wang, Xingang; Hooper-Greenhill, Edward; Prince, Lynne R.; Walker, Paul; Hoggett, Emily E.; Ward, Jonathan R.; Farrow, Stuart N.; Zuercher, William J.; Jeffrey, Philip; Savage, Caroline O.; Ingham, Philip W.; Hurlstone, Adam F.; Whyte, Moira K. B.; Renshaw, Stephen A.

    2013-01-01

    The inflammatory response is integral to maintaining health, by functioning to resist microbial infection and repair tissue damage. Large numbers of neutrophils are recruited to inflammatory sites to neutralise invading bacteria through phagocytosis and the release of proteases and reactive oxygen species into the extracellular environment. Removal of the original inflammatory stimulus must be accompanied by resolution of the inflammatory response, including neutrophil clearance, to prevent inadvertent tissue damage. Neutrophil apoptosis and its temporary inhibition by survival signals provides a target for anti-inflammatory therapeutics, making it essential to better understand this process. GM-CSF, a neutrophil survival factor, causes a significant increase in mRNA levels for the known anti-apoptotic protein Serum and Glucocorticoid Regulated Kinase 1 (SGK1). We have characterised the expression patterns and regulation of SGK family members in human neutrophils, and shown that inhibition of SGK activity completely abrogates the anti-apoptotic effect of GM-CSF. Using a transgenic zebrafish model, we have disrupted sgk1 gene function and shown this specifically delays inflammation resolution, without altering neutrophil recruitment to inflammatory sites in vivo. These data suggest SGK1 plays a key role in regulating neutrophil survival signalling, and thus may prove a valuable therapeutic target for the treatment of inflammatory disease. PMID:24431232

  9. Serum and glucocorticoid-regulated kinase 1 regulates neutrophil clearance during inflammation resolution.

    Science.gov (United States)

    Burgon, Joseph; Robertson, Anne L; Sadiku, Pranvera; Wang, Xingang; Hooper-Greenhill, Edward; Prince, Lynne R; Walker, Paul; Hoggett, Emily E; Ward, Jonathan R; Farrow, Stuart N; Zuercher, William J; Jeffrey, Philip; Savage, Caroline O; Ingham, Philip W; Hurlstone, Adam F; Whyte, Moira K B; Renshaw, Stephen A

    2014-02-15

    The inflammatory response is integral to maintaining health by functioning to resist microbial infection and repair tissue damage. Large numbers of neutrophils are recruited to inflammatory sites to neutralize invading bacteria through phagocytosis and the release of proteases and reactive oxygen species into the extracellular environment. Removal of the original inflammatory stimulus must be accompanied by resolution of the inflammatory response, including neutrophil clearance, to prevent inadvertent tissue damage. Neutrophil apoptosis and its temporary inhibition by survival signals provides a target for anti-inflammatory therapeutics, making it essential to better understand this process. GM-CSF, a neutrophil survival factor, causes a significant increase in mRNA levels for the known anti-apoptotic protein serum and glucocorticoid-regulated kinase 1 (SGK1). We have characterized the expression patterns and regulation of SGK family members in human neutrophils and shown that inhibition of SGK activity completely abrogates the antiapoptotic effect of GM-CSF. Using a transgenic zebrafish model, we have disrupted sgk1 gene function and shown this specifically delays inflammation resolution, without altering neutrophil recruitment to inflammatory sites in vivo. These data suggest SGK1 plays a key role in regulating neutrophil survival signaling and thus may prove a valuable therapeutic target for the treatment of inflammatory disease.

  10. Glucocorticoids at the Olympic Games: state-of-the-art review.

    Science.gov (United States)

    Fitch, Ken

    2016-10-01

    In this state-of-the-art review, the author discusses the history of prohibiting glucocorticoids (GCs) and how this has occurred over nearly three decades at the Olympic Games. He relates how prohibiting systemic GCs in sport was a major factor in the development of therapeutic use exemptions and the fluctuating status of non-systemic GCs (banned, not banned). Concern is expressed that for 2017, the World Anti-Doping Agency (WADA) is proposing to prohibit injecting GCs shortly prior to competition. The author notes that in 1986, when GCs were first prohibited, analytical chemistry techniques could not distinguish the route of GC administration from its urinary concentration. Thirty years later, this remains the case. Importantly, this article discusses how the desired pharmacological effects of injecting GCs locally and intra-articularly can be achieved and why exercising vigorously immediately or shortly after a GC injection is therapeutically unsound. The review concludes by agreeing that injecting GCs shortly prior to strenuous training or competition is medically unwise but stresses that this is a clinical matter that sport-not WADA-needs to address. Cycling and rowing have managed this successfully for the past 5 years. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  11. Therapeutic Nanodevices

    Science.gov (United States)

    Lee, Stephen; Ruegsegger, Mark; Barnes, Philip; Smith, Bryan; Ferrari, Mauro

    Therapeutic nanotechnology offers minimally invasive therapies with high densities of function concentrated in small volumes, features that may reduce patient morbidity and mortality. Unlike other areas of nanotechnology, novel physical properties associated with nanoscale dimensionality are not the raison d'être of therapeutic nanotechnology, whereas the aggregation of multiple biochemical (or comparably precise) functions into controlled nanoarchitectures is. Multifunctionality is a hallmark of emerging nanotherapeutic devices, and multifunctionality can allow nanotherapeutic devices to perform multistep work processes, with each functional component contributing to one or more nanodevice subroutine such that, in aggregate, subroutines sum to a cogent work process. Cannonical nanotherapeutic subroutines include tethering (targeting) to sites of disease, dispensing measured doses of drug (or bioactive compound), detection of residual disease after therapy and communication with an external clinician/operator. Emerging nanotherapeutics thus blur the boundaries between medical devices and traditional pharmaceuticals. Assembly of therapeutic nanodevices generally exploits either (bio)material self-assembly properties or chemoselective bioconjugation techniques, or both. Given the complexity, composition, and the necessity for their tight chemical and structural definition inherent in the nature of nanotherapeutics, their cost of goods (COGs) might exceed that of (already expensive) biologics. Early therapeutic nanodevices will likely be applied to disease states which exhibit significant unmet patient need (cancer and cardiovascular disease), while application to other disease states well-served by conventional therapy may await perfection of nanotherapeutic design and assembly protocols.

  12. Social Regulation of Leukocyte Homeostasis: The Role of Glucocorticoid Sensitivity

    Science.gov (United States)

    Cole, Steve W.

    2010-01-01

    Recent small-scale genomics analyses suggest that physiologic regulation of pro-inflammatory gene expression by endogenous glucocorticoids may be compromised in individuals who experience chronic social isolation. This could potentially contribute to the elevated prevalence of inflammation-related disease previously observed in social isolates. The present study assessed the relationship between leukocyte distributional sensitivity to glucocorticoid regulation and subjective social isolation in a large population-based sample of older adults. Initial analyses confirmed that circulating neutrophil percentages were elevated, and circulating lymphocyte and monocyte percentages were suppressed, in direct proportion to circulating cortisol levels. However, leukocyte distributional sensitivity to endogenous glucocorticoids was abrogated in individuals reporting either occasional or frequent experiences of subjective social isolation. This finding held in both nonparametric univariate analyses and in multivariate linear models controlling for a variety of biological, social, behavioral, and psychological confounders. The present results suggest that social factors may alter immune cell sensitivity to physiologic regulation by the hypothalamic-pituitary-adrenal axis in ways that could ultimately contribute to the increased physical health risks associated with social isolation. PMID:18394861

  13. CHLORPYRIFOS DEVELOPMENTAL NEUROTOXICITY: INTERACTION WITH GLUCOCORTICOIDS IN PC12 CELLS

    Science.gov (United States)

    Slotkin, Theodore A.; Card, Jennifer; Seidler, Frederic J.

    2012-01-01

    Prenatal coexposures to glucocorticoids and organophosphate pesticides are widespread. Glucocorticoids are elevated by maternal stress and are commonly given in preterm labor; organophosphate exposures are virtually ubiquitous. We used PC12 cells undergoing neurodifferentiation in order to assess whether dexamethasone enhances the developmental neurotoxicity of chlorpyrifos, focusing on concentrations relevant to human exposures. By themselves, each agent reduced the number of cells and the combined exposure elicited a correspondingly greater effect than with either agent alone. There was no general cytotoxicity, as cell growth was actually enhanced, and again, the combined treatment evoked greater cellular hypertrophy than with the individual compounds. The effects on neurodifferentiation were more complex. Chlorpyrifos alone had a promotional effect on neuri to genesis whereas dexamethasone impaired it; combined treatment showed an overall impairment greater than that seen with dexamethasone alone. The effect of chlorpyrifos on differentiation into specific neurotransmitter phenotypes was shifted by dexamethasone. Either agent alone promoted differentiation into the dopaminergic phenotype at the expense of the cholinergic phenotype. However, in dexamethasone-primed cells, chlorpyrifos actually enhanced cholinergic neurodifferentiation instead of suppressing this phenotype. Our results indicate that developmental exposure to glucocorticoids, either in the context of stress or the therapy of preterm labor, could enhance the developmental neurotoxicity of organophosphates and potentially of other neurotoxicants, as well as producing neurobehavioral outcomes distinct from those seen with either individual agent. PMID:22796634

  14. Cannabinoids and glucocorticoids modulate emotional memory after stress.

    Science.gov (United States)

    Akirav, Irit

    2013-12-01

    Bidirectional and functional relationships between glucocorticoids and the endocannabinoid system have been demonstrated. Here, I review the interaction between the endocannabinoid and glucocorticoid/stress systems. Specifically, stress is known to produce rapid changes in endocannabinoid signaling in stress-responsive brain regions. In turn, the endocannabinoid system plays an important role in the downregulation and habituation of hypothalamic-pituitary-adrenocortical (HPA) axis activity in response to stress. Glucocorticoids also recruit the endocannabinoid system to exert rapid negative feedback control of the HPA axis during stress. It became increasingly clear, however, that cannabinoid CB1 receptors are also abundantly expressed in the basolateral amygdala (BLA) and other limbic regions where they modulate emotional arousal effects on memory. Enhancing cannabinoids signaling using exogenous CB1 receptor agonists prevent the effects of acute stress on emotional memory. I propose a model suggesting that the ameliorating effects of exogenously administered cannabinoids on emotional learning after acute stress are mediated by the decrease in the activity of the HPA axis via GABAergic mechanisms in the amygdala. Copyright © 2013 Elsevier Ltd. All rights reserved.

  15. Regulation of NAD(P)H:quininone oxidoreductase by glucocorticoids

    International Nuclear Information System (INIS)

    Pinaire, J.A.; Xiao, G.-H.; Falkner, K.C.; Prough, R.A.

    2004-01-01

    Previous studies in neonatal and adolescent rats as well as adrenalectomized rats have demonstrated that glucocorticoids regulate the expression of the rat NAD(P)H:quinone oxidoreductase gene (QOR). We used primary cultures of rat adult hepatocytes to document that added glucorticoids repress both the basal and 1,2-benzanthracene-induced expression of QOR mRNA by 65-70%. QOR enzyme activity and protein were concomitantly suppressed as well. The monotonic concentration response for repression of QOR gene products up to 100 μM DEX concentration demonstrated that the glucocorticoid receptor (GR) was most likely involved in this process. The lack of effect at higher concentration rules out a role for the Pregnane X receptor in this regulation by DEX. In addition, the anti-glucorticoid RU38486 blocked this negative regulation and the protein synthesis inhibitor cycloheximide had no effect on this repression process. Similar results of GR dependence were observed using a luciferase reporter construct containing the 5'-flanking region of the human QOR gene using HepG2 cells. Collectively, these results demonstrate that GR must directly participate in the negative regulation of QOR gene expression by dexamethasone and other glucocorticoids in vivo

  16. Asparaginase Potentiates Glucocorticoid-Induced Osteonecrosis in a Mouse Model.

    Directory of Open Access Journals (Sweden)

    Chengcheng Liu

    Full Text Available Osteonecrosis is a common dose-limiting toxicity of glucocorticoids. Data from clinical trials suggest that other medications can increase the risk of glucocorticoid-induced osteonecrosis. Here we utilized a mouse model to study the effect of asparaginase treatment on dexamethasone-induced osteonecrosis. Mice receiving asparaginase along with dexamethasone had a higher rate of osteonecrosis than those receiving only dexamethasone after 6 weeks of treatment (44% vs. 10%, P = 0.006. Similarly, epiphyseal arteriopathy, which we have shown to be an initiating event for osteonecrosis, was observed in 58% of mice receiving asparaginase and dexamethasone compared to 17% of mice receiving dexamethasone only (P = 0.007. As in the clinic, greater exposure to asparaginase was associated with greater plasma exposure to dexamethasone (P = 0.0001. This model also recapitulated other clinical risk factors for osteonecrosis, including age at start of treatment, and association with the systemic exposure to dexamethasone (P = 0.027 and asparaginase (P = 0.036. We conclude that asparaginase can potentiate the osteonecrotic effect of glucocorticoids.

  17. Effects of Social Isolation on Glucocorticoid Regulation in Social Mammals

    Science.gov (United States)

    Hawkley, Louise C.; Cole, Steve W.; Capitanio, John P.; Norman, Greg J.; Cacioppo, John T.

    2012-01-01

    The regulation and function of the hypothalamic-pituitary-adrenocortical (HPA) axis and glucocorticoids have been well conserved across vertebrate species. Glucocorticoids influence a wide range of physiological functions that include glucose regulation, metabolism, inflammatory control, as well as cardiovascular, reproductive, and neuronal effects. Some of these are relatively quick-acting non-genomic effects, but most are slower-acting genomic effects. Thus, any stimulus that affects HPA function has the potential to exert wide-ranging short-term and long-term effects on much of vertebrate physiology. Here, we review the effects of social isolation on the functioning of the HPA axis in social species, and on glucocorticoid physiology in social mammals in particular. Evidence indicates that objective and perceived social isolation alter HPA regulation, although the nature and direction of the HPA response differs among species and across age. The inconsistencies in the direction and nature of HPA effects have implications for drawing cross-species conclusions about the effects of social isolation, and are particularly problematic for understanding HPA-related physiological processes in humans. The animal and human data are incommensurate because, for example, animal studies of objective isolation have typically not been modeled on, or for comparability with, the subjective experience of isolation in humans. An animal model of human isolation must be taken more seriously if we want to advance our understanding of the mechanisms for the effects of objective and perceived isolation in humans. PMID:22663934

  18. The effects of glucocorticoid on microarchitecture, collagen, mineral and mechanical properties of sheep femur cortical bone

    DEFF Research Database (Denmark)

    Ding, Ming; Danielsen, Carl Christian; Overgaard, Søren

    2011-01-01

    of 3 months without treatment. Group 3 was left untreated and served as controls. All sheep received a restricted diet with low calcium and phosphorus. At sacrifice, cortical bone samples from the femur midshaft of each sheep were harvested, micro-CT scanned and subjected to three-point bending...... and tensile strength testing. Bone collagen and mineral were determined. Cortical porosity was significantly increased in the glucocorticoid-2 compared with the glucocorticoid-1 and control groups. Apparent density was significantly decreased in the glucocorticoid-2 compared with the glucocorticoid-1 group....... Collagen content was significantly increased in the glucocorticoid-2 compared with the glucocorticoid-1 and control groups. Bone mineral content did not differ between the groups. Neither the three-point bending mechanical properties nor the tensile mechanical properties differed significantly between...

  19. iBodies: Modular Synthetic Antibody Mimetics Based on Hydrophilic Polymers Decorated with Functional Moieties

    Czech Academy of Sciences Publication Activity Database

    Šácha, Pavel; Knedlík, Tomáš; Schimer, Jiří; Tykvart, Jan; Parolek, Jan; Navrátil, Václav; Dvořáková, Petra; Sedlák, František; Ulbrich, Karel; Strohalm, Jiří; Majer, Pavel; Šubr, Vladimír; Konvalinka, Jan

    2016-01-01

    Roč. 55, č. 7 (2016), s. 2356-2360 ISSN 1433-7851 R&D Projects: GA ČR GBP208/12/G016; GA MŠk LO1302 Institutional support: RVO:61388963 ; RVO:61389013 Keywords : antibody mimetics * HPMA * molecular recognition * polymer conjugates * protein targeting Subject RIV: CE - Biochemistry; CD - Macromolecular Chemistry (UMCH-V) Impact factor: 11.994, year: 2016 http://onlinelibrary.wiley.com/doi/10.1002/anie.201508642/full

  20. Superstretchable Nacre-Mimetic Graphene/Poly(vinyl alcohol) Composite Film Based on Interfacial Architectural Engineering.

    Science.gov (United States)

    Zhao, Nifang; Yang, Miao; Zhao, Qian; Gao, Weiwei; Xie, Tao; Bai, Hao

    2017-05-23

    Through designing hierarchical structures, particularly optimizing the chemical and architectural interactions at its inorganic/organic interface, nacre has achieved an excellent combination of contradictory mechanical properties such as strength and toughness, which is highly demanded yet difficult to achieve by most synthetic materials. Most techniques applied to develop nacre-mimetic composites have been focused on mimicking the "brick-and-mortar" structure, but the interfacial architectural features, especially the asperities and mineral bridges of "bricks", have been rarely concerned, which are of equal importance for enhancing mechanical properties of nacre. Here, we used a modified bidirectional freezing method followed by uniaxial pressing and chemical reduction to assemble a nacre-mimetic graphene/poly(vinyl alcohol) composite film, with both asperities and bridges introduced in addition to the lamellar layers to mimic the interfacial architectural interactions found in nacre. As such, we have developed a composite film that is not only strong (up to ∼150.9 MPa), but also tough (up to ∼8.50 MJ/m 3 ), and highly stretchable (up to ∼10.44%), difficult to obtain by other methods. This was all achieved by only interfacial architectural engineering within the traditional "brick-and-mortar" structure, without introducing a third component or employing chemical cross-linker as in some other nacre-mimetic systems. More importantly, we believe that the design principles and processing strategies reported here can also be applied to other material systems to develop strong and stretchable materials.

  1. Activity of Potent and Selective Host Defense Peptide Mimetics in Mouse Models of Oral Candidiasis

    Science.gov (United States)

    Ryan, Lisa K.; Freeman, Katie B.; Masso-Silva, Jorge A.; Falkovsky, Klaudia; Aloyouny, Ashwag; Markowitz, Kenneth; Hise, Amy G.; Fatahzadeh, Mahnaz; Scott, Richard W.

    2014-01-01

    There is a strong need for new broadly active antifungal agents for the treatment of oral candidiasis that not only are active against many species of Candida, including drug-resistant strains, but also evade microbial countermeasures which may lead to resistance. Host defense peptides (HDPs) can provide a foundation for the development of such agents. Toward this end, we have developed fully synthetic, small-molecule, nonpeptide mimetics of the HDPs that improve safety and other pharmaceutical properties. Here we describe the identification of several HDP mimetics that are broadly active against C. albicans and other species of Candida, rapidly fungicidal, and active against yeast and hyphal cultures and that exhibit low cytotoxicity for mammalian cells. Importantly, specificity for Candida over commensal bacteria was also evident, thereby minimizing potential damage to the endogenous microbiome which otherwise could favor fungal overgrowth. Three compounds were tested as topical agents in two different mouse models of oral candidiasis and were found to be highly active. Following single-dose administrations, total Candida burdens in tongues of infected animals were reduced up to three logs. These studies highlight the potential of HDP mimetics as a new tool in the antifungal arsenal for the treatment of oral candidiasis. PMID:24752272

  2. Design, synthesis, and evaluation of an alpha-helix mimetic library targeting protein-protein interactions.

    Science.gov (United States)

    Shaginian, Alex; Whitby, Landon R; Hong, Sukwon; Hwang, Inkyu; Farooqi, Bilal; Searcey, Mark; Chen, Jiandong; Vogt, Peter K; Boger, Dale L

    2009-04-22

    The design and solution-phase synthesis of an alpha-helix mimetic library as an integral component of a small-molecule library targeting protein-protein interactions are described. The iterative design, synthesis, and evaluation of the candidate alpha-helix mimetic was initiated from a precedented triaryl template and refined by screening the designs for inhibition of MDM2/p53 binding. Upon identifying a chemically and biologically satisfactory design and consistent with the screening capabilities of academic collaborators, the corresponding complete library was assembled as 400 mixtures of 20 compounds (20 x 20 x 20-mix), where the added subunits are designed to mimic all possible permutations of the naturally occurring i, i + 4, i + 7 amino acid side chains of an alpha-helix. The library (8000 compounds) was prepared using a solution-phase synthetic protocol enlisting acid/base liquid-liquid extractions for purification on a scale that insures its long-term availability for screening campaigns. Screening of the library for inhibition of MDM2/p53 binding not only identified the lead alpha-helix mimetic upon which the library was based, but also suggests that a digestion of the initial screening results that accompany the use of such a comprehensive library can provide insights into the nature of the interaction (e.g., an alpha-helix mediated protein-protein interaction) and define the key residues and their characteristics responsible for recognition.

  3. Role of phosphate on stability and catalase mimetic activity of cerium oxide nanoparticles.

    Science.gov (United States)

    Singh, Ragini; Singh, Sanjay

    2015-08-01

    Cerium oxide nanoparticles (CeNPs) have been recently shown to scavenge reactive oxygen and nitrogen species (ROS and RNS) in different experimental model systems. CeNPs (3+) and CeNPs (4+) have been shown to exhibit superoxide dismutase (SOD) and catalase mimetic activity, respectively. Due to their nanoscale dimension, CeNPs are expected to interact with the components of biologically relevant buffers and medium, which could alter their catalytic properties. We have demonstrated earlier that CeNPs (3+) interact with phosphate and lose the SOD activity. However, very little is known about the interaction of CeNPs (4+) with the phosphate and other anions, predominantly present in biological buffers and their effects on the catalase mimetic-activity of these nanoparticles. In this study, we report that catalase mimetic-activity of CeNPs (4+) is resistant to the phosphate anions, pH changes and composition of cell culture media. Given the abundance of phosphate anions in the biological system, it is likely that internalized CeNPs would be influenced by cytoplasmic and nucleoplasmic concentration of phosphate. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. The reconstruction of f(ϕ)R and mimetic gravity from viable slow-roll inflation

    Science.gov (United States)

    Odintsov, S. D.; Oikonomou, V. K.

    2018-04-01

    In this work, we extend the bottom-up reconstruction framework of F (R) gravity to other modified gravities, and in particular for f (ϕ) R and mimetic F (R) gravities. We investigate which are the important conditions in order for the method to work, and we study several viable cosmological evolutions, focusing on the inflationary era. Particularly, for the f (ϕ) R theory case, we specify the functional form of the Hubble rate and of the scalar-to-tensor ratio as a function of the e-foldings number and accordingly, the rest of the physical quantities and also the slow-roll and the corresponding observational indices can be calculated. The same method is applied in the mimetic F (R) gravity case, and in both cases we thoroughly analyze the resulting free parameter space, in order to show that the viability of the models presented is guaranteed and secondly that there is a wide range of values of the free parameters for which the viability of the models occurs. In addition, the reconstruction method is also studied in the context of mimetic F (R) = R gravity. As we demonstrate, the resulting theory is viable, and also in this case, only the scalar-to-tensor ratio needs to be specified, since the rest follow from this condition. Finally, we discuss in brief how the reconstruction method could function for other modified gravities.

  5. The reconstruction of f(ϕR and mimetic gravity from viable slow-roll inflation

    Directory of Open Access Journals (Sweden)

    S.D. Odintsov

    2018-04-01

    Full Text Available In this work, we extend the bottom-up reconstruction framework of F(R gravity to other modified gravities, and in particular for f(ϕR and mimetic F(R gravities. We investigate which are the important conditions in order for the method to work, and we study several viable cosmological evolutions, focusing on the inflationary era. Particularly, for the f(ϕR theory case, we specify the functional form of the Hubble rate and of the scalar-to-tensor ratio as a function of the e-foldings number and accordingly, the rest of the physical quantities and also the slow-roll and the corresponding observational indices can be calculated. The same method is applied in the mimetic F(R gravity case, and in both cases we thoroughly analyze the resulting free parameter space, in order to show that the viability of the models presented is guaranteed and secondly that there is a wide range of values of the free parameters for which the viability of the models occurs. In addition, the reconstruction method is also studied in the context of mimetic F(R=R gravity. As we demonstrate, the resulting theory is viable, and also in this case, only the scalar-to-tensor ratio needs to be specified, since the rest follow from this condition. Finally, we discuss in brief how the reconstruction method could function for other modified gravities.

  6. Interactions of Bio-Inspired Membranes with Peptides and Peptide-Mimetic Nanoparticles

    Directory of Open Access Journals (Sweden)

    Michael Sebastiano

    2015-08-01

    Full Text Available Via Dissipative Particle Dynamics (DPD and implicit solvent coarse-grained (CG Molecular Dynamics (MD we examine the interaction of an amphiphilic cell-penetrating peptide PMLKE and its synthetic counterpart with a bio-inspired membrane. We use the DPD technique to investigate the interaction of peptide-mimetic nanoparticles, or nanopins, with a three-component membrane. The CG MD approach is used to investigate the interaction of a cell-penetrating peptide PMLKE with single-component membrane. We observe the spontaneous binding and subsequent insertion of peptide and nanopin in the membrane by using CG MD and DPD approaches, respectively. In addition, we find that the insertion of peptide and nanopins is mainly driven by the favorable enthalpic interactions between the hydrophobic components of the peptide, or nanopin, and the membrane. Our study provides insights into the mechanism underlying the interactions of amphiphilic peptide and peptide-mimetic nanoparticles with a membrane. The result of this study can be used to guide the functional integration of peptide and peptide-mimetic nanoparticles with a cell membrane.

  7. Late-time cosmological approach in mimetic f(R, T) gravity

    Energy Technology Data Exchange (ETDEWEB)

    Baffou, E.H. [Institut de Mathematiques et de Sciences Physiques (IMSP), Porto-Novo (Benin); Houndjo, M.J.S. [Institut de Mathematiques et de Sciences Physiques (IMSP), Porto-Novo (Benin); Faculte des Sciences et Techniques de Natitingou, Natitingou (Benin); Hamani-Daouda, M. [Universite de Niamey, Departement de Physique, Niamey (Niger); Alvarenga, F.G. [Universidade Federal do Espirito Santo, Departamento de Engenharia e Ciencias Naturais, CEUNES, Sao Mateus, ES (Brazil)

    2017-10-15

    In this paper, we investigate the late-time cosmic acceleration in mimetic f(R, T) gravity with the Lagrange multiplier and potential in a Universe containing, besides radiation and dark energy, a self-interacting (collisional) matter. We obtain through the modified Friedmann equations the main equation that can describe the cosmological evolution. Then, with several models from Q(z) and the well-known particular model f(R, T), we perform an analysis of the late-time evolution. We examine the behavior of the Hubble parameter, the dark energy equation of state and the total effective equation of state and in each case we compare the resulting picture with the non-collisional matter (assumed as dust) and also with the collisional matter in mimetic f(R, T) gravity. The results obtained are in good agreement with the observational data and show that in the presence of the collisional matter the dark energy oscillations in mimetic f(R, T) gravity can be damped. (orig.)

  8. New therapeutic developments in lipidology

    African Journals Online (AJOL)

    2009-03-20

    Mar 20, 2009 ... combination with statins its effects are additive, with no significant increase in adverse ... Incorporated into foods such as margarine (the only product available in .... modification include infusions of artificial. 'HDL mimetics' or ...

  9. Science review: Mechanisms of impaired adrenal function in sepsis and molecular actions of glucocorticoids

    OpenAIRE

    Prigent, Hélène; Maxime, Virginie; Annane, Djillali

    2004-01-01

    This review describes current knowledge on the mechanisms that underlie glucocorticoid insufficiency in sepsis and the molecular action of glucocorticoids. In patients with severe sepsis, numerous factors predispose to glucocorticoid insufficiency, including drugs, coagulation disorders and inflammatory mediators. These factors may compromise the hypothalamic–pituitary axis (i.e. secondary adrenal insufficiency) or the adrenal glands (i.e. primary adrenal failure), or may impair glucocorticoi...

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

    Directory of Open Access Journals (Sweden)

    Laura Bennet

    2012-01-01

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

  11. Assignment of the human gene for the glucocorticoid receptor to chromosome 5.

    OpenAIRE

    Gehring, U; Segnitz, B; Foellmer, B; Francke, U

    1985-01-01

    Human lymphoblastic leukemia cells of line CEM-C7 are glucocroticoid-sensitive and contain glucocorticoid receptors of wild-type characteristics. EL4 mouse lymphoma cells are resistant to lysis by glucocorticoids due to mutant receptors that exhibit abnormal DNA binding. Hybrids between the two cell lines were prepared and analyzed with respect to glucocorticoid responsiveness and to receptor types by DNA-cellulose chromatrography. Sensitive hybrid cell clones contained the CEM-C7-specific re...

  12. Clinical profiling of BCL-2 family members in the setting of BRAF inhibition offers a rationale for targeting de novo resistance using BH3 mimetics.

    Directory of Open Access Journals (Sweden)

    Dennie T Frederick

    Full Text Available While response rates to BRAF inhibitiors (BRAFi are high, disease progression emerges quickly. One strategy to delay the onset of resistance is to target anti-apoptotic proteins such as BCL-2, known to be associated with a poor prognosis. We analyzed BCL-2 family member expression levels of 34 samples from 17 patients collected before and 10 to 14 days after treatment initiation with either vemurafenib or dabrafenib/trametinib combination. The observed changes in mRNA and protein levels with BRAFi treatment led us to hypothesize that combining BRAFi with a BCL-2 inhibitor (the BH3-mimetic navitoclax would improve outcome. We tested this hypothesis in cell lines and in mice. Pretreatment mRNA levels of BCL-2 negatively correlated with maximal tumor regression. Early increases in mRNA levels were seen in BIM, BCL-XL, BID and BCL2-W, as were decreases in MCL-1 and BCL2A. No significant changes were observed with BCL-2. Using reverse phase protein array (RPPA, significant increases in protein levels were found in BIM and BID. No changes in mRNA or protein correlated with response. Concurrent BRAF (PLX4720 and BCL2 (navitoclax inhibition synergistically reduced viability in BRAF mutant cell lines and correlated with down-modulation of MCL-1 and BIM induction after PLX4720 treatment. In xenograft models, navitoclax enhanced the efficacy of PLX4720. The combination of a selective BRAF inhibitor with a BH3-mimetic promises to be an important therapeutic strategy capable of enhancing the clinical efficacy of BRAF inhibition in many patients that might otherwise succumb quickly to de novo resistance. Trial registrations: ClinicalTrials.gov NCT01006980; ClinicalTrials.gov NCT01107418; ClinicalTrials.gov NCT01264380; ClinicalTrials.gov NCT01248936; ClinicalTrials.gov NCT00949702; ClinicalTrials.gov NCT01072175.

  13. Lipoproteins and lipoprotein mimetics for imaging and drug delivery.

    Science.gov (United States)

    Thaxton, C Shad; Rink, Jonathan S; Naha, Pratap C; Cormode, David P

    2016-11-15

    Lipoproteins are a set of natural nanoparticles whose main role is the transport of fats within the body. While much work has been done to develop synthetic nanocarriers to deliver drugs or contrast media, natural nanoparticles such as lipoproteins represent appealing alternatives. Lipoproteins are biocompatible, biodegradable, non-immunogenic and are naturally targeted to some disease sites. Lipoproteins can be modified to act as contrast agents in many ways, such as by insertion of gold cores to provide contrast for computed tomography. They can be loaded with drugs, nucleic acids, photosensitizers or boron to act as therapeutics. Attachment of ligands can re-route lipoproteins to new targets. These attributes render lipoproteins attractive and versatile delivery vehicles. In this review we will provide background on lipoproteins, then survey their roles as contrast agents, in drug and nucleic acid delivery, as well as in photodynamic therapy and boron neutron capture therapy. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Improved surface bioactivity of stainless steel substrates using osteocalcin mimetic peptide

    International Nuclear Information System (INIS)

    Hosseini, Samaneh; Naderi-Manesh, Hossein; Vali, Hojatollah; Faghihi, Shahab

    2014-01-01

    Although stainless steel has a good biocompatibility for most clinical cases, the higher tissue response (bone bonding property) is required in orthopedic field. In this study, to improve bone-bonding ability of stainless steel substrates, a specific sequence of osteocalcin mimetic peptide is used as bioactive coating material to biochemically modify the surface of metallic samples. This sequence consists of thirteen amino acids present in the first helix of osteocalcin is synthesized in amidic form and physically adsorbed on the surface of 316LS (316 low carbon surgical grade) stainless steel substrates. Atomic force microscopy (AFM) and scanning electron microscopy (SEM) are used to characterize the surface of peptide coated and uncoated substrates. The bioactivity and bone bonding ability of coated and uncoated substrates are assessed by level of hydroxyapatite formation, using transmission electron microscopy (TEM), energy-dispersive x-ray (EDS), and scanning electron microscopy (SEM). The pre-osteoblast cell attachment and proliferation are also evaluated by MTT assay. The results show that the surface of coated sample is homogenously covered by the peptide and display a rougher surface relative to uncoated sample. TEM images reveal the formation of plate-like hydroxyapatite crystals in the presence of the peptide and an amorphous calcium phosphate phase without the peptide. Pre-osteoblast cells proliferation is significantly higher on the surface of peptide coated substrate, while cell attachment remains unaffected by the peptide coatings. Pre-osteoblast cells also demonstrate a higher degree of spreading on the surface of coated sample. It is believed that osteocalcin mimetic peptide improve surface bioactivity and promote hydroxyapatite crystal formation may lead to increased mineralization and bone formation on the surface of metallic biomedical devices. - Graphical abstract: A peptide sequence located in the first helix of OC is selected based on its

  15. Improved surface bioactivity of stainless steel substrates using osteocalcin mimetic peptide

    Energy Technology Data Exchange (ETDEWEB)

    Hosseini, Samaneh [Department of Nanobiotechnology, Faculty of Biological Sciences, Tarbiat Modares University, Tehran (Iran, Islamic Republic of); Tissue Engineering and Biomaterials Division, National Institute of Genetic Engineering and Biotechnology, Tehran 14965/161 (Iran, Islamic Republic of); Naderi-Manesh, Hossein, E-mail: naderman@modares.ac.ir [Department of Nanobiotechnology, Faculty of Biological Sciences, Tarbiat Modares University, Tehran (Iran, Islamic Republic of); Vali, Hojatollah [Department of Anatomy and Cell Biology, McGill University, 3640 University Street, Montréal, QC H3A 0C7 (Canada); Faghihi, Shahab, E-mail: sfaghihi@nigeb.ac.ir [Tissue Engineering and Biomaterials Division, National Institute of Genetic Engineering and Biotechnology, Tehran 14965/161 (Iran, Islamic Republic of)

    2014-02-14

    Although stainless steel has a good biocompatibility for most clinical cases, the higher tissue response (bone bonding property) is required in orthopedic field. In this study, to improve bone-bonding ability of stainless steel substrates, a specific sequence of osteocalcin mimetic peptide is used as bioactive coating material to biochemically modify the surface of metallic samples. This sequence consists of thirteen amino acids present in the first helix of osteocalcin is synthesized in amidic form and physically adsorbed on the surface of 316LS (316 low carbon surgical grade) stainless steel substrates. Atomic force microscopy (AFM) and scanning electron microscopy (SEM) are used to characterize the surface of peptide coated and uncoated substrates. The bioactivity and bone bonding ability of coated and uncoated substrates are assessed by level of hydroxyapatite formation, using transmission electron microscopy (TEM), energy-dispersive x-ray (EDS), and scanning electron microscopy (SEM). The pre-osteoblast cell attachment and proliferation are also evaluated by MTT assay. The results show that the surface of coated sample is homogenously covered by the peptide and display a rougher surface relative to uncoated sample. TEM images reveal the formation of plate-like hydroxyapatite crystals in the presence of the peptide and an amorphous calcium phosphate phase without the peptide. Pre-osteoblast cells proliferation is significantly higher on the surface of peptide coated substrate, while cell attachment remains unaffected by the peptide coatings. Pre-osteoblast cells also demonstrate a higher degree of spreading on the surface of coated sample. It is believed that osteocalcin mimetic peptide improve surface bioactivity and promote hydroxyapatite crystal formation may lead to increased mineralization and bone formation on the surface of metallic biomedical devices. - Graphical abstract: A peptide sequence located in the first helix of OC is selected based on its

  16. Raised urinary glucocorticoid and adrenal androgen precursors in the urine of young hypertensive patients: possible evidence for partial glucocorticoid resistance

    Science.gov (United States)

    Shamim, W; Yousufuddin, M; Francis, D; Gualdiero, P; Honour, J; Anker, S; Coats, A

    2001-01-01

    OBJECTIVE—To evaluate urinary glucocorticoid excretion profiles in a cohort of recently diagnosed young hypertensive patients.
METHODS—After excluding patients with secondary causes, 60 individuals with premature hypertension were recruited (diagnosed by ambulatory blood pressure monitoring before the age of 36 years). In addition, 30 older hypertensive controls (age of onset > 36 years, "middle aged hypertensive controls"), and 30 normal controls (age matched to the young hypertensive group) were studied. All provided 24 hour urine collections for mass spectrometry for total cortisol metabolites and total androgen metabolites by gas chromatography.
RESULTS—Among male patients, those with premature hypertension had higher total urinary excretion of cortisol metabolites (mean (SD), 13 332 (6472) µg/day) than age matched normal controls (7270 (1788) µg/day; p = 0.00001) or middle aged hypertensive controls (8315 (3565) µg/day; p = 0.002). A similar increase was seen among the female patients, although the absolute concentrations were lower. There was no significant difference between middle aged hypertensive patients and normal controls. Urinary total androgen excretion profiles in female patients also showed an unusual increase in the premature hypertension group (2958 (1672) µg/day) compared with the other groups (middle aged hypertensive controls, 1373 (748) µg/day, p = 0.0003; normal controls, 1687 (636) µg/day, p = 0.002). In all subjects, serum sodium and creatinine concentrations were within the normal range; serum potassium concentrations were found to be low before the start of treatment.
CONCLUSIONS—Individuals presenting with premature hypertension have an abnormally high excretion of glucocorticoid metabolites in the urine. While the mechanism remains uncertain, these findings are compatible with partial resistance of the glucocorticoid receptors, with a compensatory increase in cortisol and androgen

  17. HDL-mimetic PLGA nanoparticle to target atherosclerosis plaque macrophages.

    Science.gov (United States)

    Sanchez-Gaytan, Brenda L; Fay, Francois; Lobatto, Mark E; Tang, Jun; Ouimet, Mireille; Kim, YongTae; van der Staay, Susanne E M; van Rijs, Sarian M; Priem, Bram; Zhang, Liangfang; Fisher, Edward A; Moore, Kathryn J; Langer, Robert; Fayad, Zahi A; Mulder, Willem J M

    2015-03-18

    High-density lipoprotein (HDL) is a natural nanoparticle that exhibits an intrinsic affinity for atherosclerotic plaque macrophages. Its natural targeting capability as well as the option to incorporate lipophilic payloads, e.g., imaging or therapeutic components, in both the hydrophobic core and the phospholipid corona make the HDL platform an attractive nanocarrier. To realize controlled release properties, we developed a hybrid polymer/HDL nanoparticle composed of a lipid/apolipoprotein coating that encapsulates a poly(lactic-co-glycolic acid) (PLGA) core. This novel HDL-like nanoparticle (PLGA-HDL) displayed natural HDL characteristics, including preferential uptake by macrophages and a good cholesterol efflux capacity, combined with a typical PLGA nanoparticle slow release profile. In vivo studies carried out with an ApoE knockout mouse model of atherosclerosis showed clear accumulation of PLGA-HDL nanoparticles in atherosclerotic plaques, which colocalized with plaque macrophages. This biomimetic platform integrates the targeting capacity of HDL biomimetic nanoparticles with the characteristic versatility of PLGA-based nanocarriers.

  18. Glucocorticoid administration for Graves' hyperthyroidism treated by radioiodine. A questionnaire survey among members of the European Thyroid Association

    NARCIS (Netherlands)

    Lazarus, J. H.; Bartalena, L.; Marcocci, C.; Kahaly, G. J.; Krassas, G.; Wiersinga, W. M.; Baldeschi, L.; Boboridis, K.; Boschi, A.; Currò, N.; Daumerie, C.; Dickinson, A. J.; Eckstein, A.; Kendall-Taylor, P.; Lane, C. M.; Ludgate, M. E.; Mann, K.; Marinò, M.; Mourits, M. P.; Nardi, M.; Neoh, C.; Orgiazzi, J.; Pearce, S.; Perros, P.; Pinchera, A.; Pitz, S.; Salvi, M.; Sivelli, P.; Stahl, M.; von Arx, G.

    2010-01-01

    Background: Glucocorticoid prophylaxis is required in some instances after radioiodine (RAI) treatment for Graves' hyperthyroidism to prevent progression of Graves' orbitopathy (GO). However, no randomized clinical trial has been performed to ascertain the optimum glucocorticoid therapy. Aim and

  19. Glucocorticoid Effects on Memory Consolidation Depend on Functional Interactions between the Medial Prefrontal Cortex and Basolateral Amygdala

    NARCIS (Netherlands)

    Roozendaal, Benno; McReynolds, Jayme R.; Van der Zee, Eddy A.; Lee, Sangkwan; McGaugh, James L.; McIntyre, Christa K.

    2009-01-01

    Considerable evidence indicates that the basolateral complex of the amygdala (BLA) interacts with efferent brain regions in mediating glucocorticoid effects on memory consolidation. Here, we investigated whether glucocorticoid influences on the consolidation of memory for emotionally arousing

  20. Therapeutic ultrasound

    International Nuclear Information System (INIS)

    Crum, Lawrence A

    2004-01-01

    The use of ultrasound in medicine is now quite commonplace, especially with the recent introduction of small, portable and relatively inexpensive, hand-held diagnostic imaging devices. Moreover, ultrasound has expanded beyond the imaging realm, with methods and applications extending to novel therapeutic and surgical uses. These applications broadly include: tissue ablation, acoustocautery, lipoplasty, site-specific and ultrasound mediated drug activity, extracorporeal lithotripsy, and the enhancement of natural physiological functions such as wound healing and tissue regeneration. A particularly attractive aspect of this technology is that diagnostic and therapeutic systems can be combined to produce totally non-invasive, imageguided therapy. This general lecture will review a number of these exciting new applications of ultrasound and address some of the basic scientific questions and future challenges in developing these methods and technologies for general use in our society. We shall particularly emphasize the use of High Intensity Focused Ultrasound (HIFU) in the treatment of benign and malignant tumors as well as the introduction of acoustic hemostasis, especially in organs which are difficult to treat using conventional medical and surgical techniques. (amum lecture)

  1. Glucocorticoid receptor gene polymorphism and juvenile idiopathic arthritis

    Directory of Open Access Journals (Sweden)

    Scheplyagina Larisa A

    2011-01-01

    Full Text Available Abstract Background The glucocorticoid receptor gene (NR3C1 has been suggested as a candidate gene affecting juvenile idiopathic arthritis (JIA course and prognosis. The purpose of this study is to investigate the glucocorticoid receptor gene BclI polymorphism (rs41423247 in JIA patients, the gene's role in susceptibility to juvenile idiopathic arthritis, and its associations with JIA activity, course and bone mineralization. Methods One hundred twenty-two Caucasian children with JIA and 143 healthy ethnically matched controls were studied. We checked markers of clinical and laboratory activity: morning stiffness, Ritchie Articular Index (RAI, swollen joint count (SJC, tender joint count (TJC, physician's visual analog scale (VAS, hemoglobin level (Hb, leukocyte count (L, platelet count (Pl, Westergren erythrocyte sedimentation rate (ESR, C-reactive protein (CRP, albumin, DAS and DAS28. Bone mineralization was measured by dual-energy X-ray absorptiometry (DXA of lumbar spine L1-L4. Assessments of bone metabolism included osteocalcin, C-terminal telopeptide (CTT, parathyroid hormone (PTH, total and ionized calcium, inorganic phosphate and total alkaline phosphatase (TAP. BclI polymorphism was genotyped by polymerase chain reaction restriction fragment length polymorphism. Results No association was observed between glucocorticoid receptor gene polymorphism and the presence or absence of JIA. In girls with JIA, the presence of the G allele was associated with an unfavorable arthritis course, a younger age of onset of arthritis (p = 0.0017, and higher inflammatory activity. The higher inflammatory activity was demonstrated by the following: increased time of morning stiffness (p = 0.02, VAS (p = 0.014, RAI (p = 0.048, DAS (p = 0.035, DAS28 (p = 0.05, Pl (p = 0.003, L (p = 0.046, CRP (p = 0.01. In addition, these patients had bone metabolism disturbances as follows: decreased BA (p = 0.0001, BMC (p = 0.00007, BMD (0.005 and Z score (p = 0.002; and

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

    Directory of Open Access Journals (Sweden)

    Daniel Beracochea

    2016-10-01

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

  3. Withdrawal of inhaled glucocorticoids and exacerbations of COPD

    DEFF Research Database (Denmark)

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

    2014-01-01

    fluticasone propionate (500 μg twice daily) during a 6-week run-in period. Patients were then randomly assigned to continued triple therapy or withdrawal of fluticasone in three steps over a 12-week period. The primary end point was the time to the first moderate or severe COPD exacerbation. Spirometric......-acting bronchodilators has not been fully explored. METHODS: In this 12-month, double-blind, parallel-group study, 2485 patients with a history of exacerbation of COPD received triple therapy consisting of tiotropium (at a dose of 18 μg once daily), salmeterol (50 μg twice daily), and the inhaled glucocorticoid...

  4. Glucocorticoid resistance as a major drive in sepsis pathology.

    Science.gov (United States)

    Dendoncker, Karen; Libert, Claude

    2017-06-01

    Sepsis is an acute systemic inflammatory disease. Glucocorticoids (GCs), which function by binding to the GC receptor GR have very powerful anti-inflammatory activities, yet they are hardly useful in sepsis. We can thus consider sepsis as a GC resistant disease. We here review the literature which has investigated this GC resistance, and summarize the mechanisms of GC resistance that have been observed in other diseases and in experimental models. We also discuss the importance of GC resistance in sepsis, in terms of the contribution of this phenomenon to the pathogenesis of sepsis. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Glucocorticoids Enhance Taste Aversion Memory via Actions in the Insular Cortex and Basolateral Amygdala

    Science.gov (United States)

    Miranda, Maria Isabel; Quirarte, Gina L.; Rodriguez-Garcia, Gabriela; McGaugh, James L.; Roozendaal, Benno

    2008-01-01

    It is well established that glucocorticoid hormones strengthen the consolidation of hippocampus-dependent spatial and contextual memory. The present experiments investigated glucocorticoid effects on the long-term formation of conditioned taste aversion (CTA), an associative learning task that does not depend critically on hippocampal function.…

  6. Polymorphisms in the glucocorticoid receptor gene and their associations with metabolic parameters and body composition

    NARCIS (Netherlands)

    S.W.J. Lamberts (Steven); E.F.C. van Rossum (Liesbeth)

    2004-01-01

    textabstractMost actions of glucocorticoids (GCs) are mediated by the glucocorticoid receptor (GR). The interindividual response to GCs varies considerably, as demonstrated by a variable suppressive response to 0.25-mg dexamethasone (DEX). Several polymorphisms in the gene coding

  7. Investigation of radioprotective properties of synthetic antagonist of glucocorticoids RU 38 486

    International Nuclear Information System (INIS)

    Sejliev, A.A.; Zvonareva, N.B.; Zhivotovskij, B.D.; Khanson, K.P.; Akademiya Meditsinskikh Nauk SSSR, Leningrad

    1992-01-01

    Radioprotective properties of synthetic antiglucocorticoid RU 38 486 were investigated. It was demonstrated that this antigonist of glucocorticoids possesses radioprotective effect in vitro and in vivo systems. Radioprotective properties at molecular level exhibited in inhibition of postirradiation endonuclease activation and in prevention of internucleosome chromatin degradation. Involvement of cytosol glucocorticoid receptors in initiation of radiation-induced programmed cell death is discussed

  8. Fatal and non-fatal adverse events of glucocorticoid therapy for Graves' orbitopathy

    DEFF Research Database (Denmark)

    Marcocci, Claudio; Watt, Torquil; Altea, Maria Antonietta

    2012-01-01

    The objective of this study was to investigate the side effects of glucocorticoid (GC) therapy observed by European thyroidologists during the treatment of Graves' orbitopathy (GO).......The objective of this study was to investigate the side effects of glucocorticoid (GC) therapy observed by European thyroidologists during the treatment of Graves' orbitopathy (GO)....

  9. Pulsatile thyrotropin secretion in patients with Addison's disease during variable glucocorticoid therapy

    DEFF Research Database (Denmark)

    Hangaard, J; Andersen, M; Grodum, E

    1996-01-01

    , increasing significantly (P glucocorticoids, when the pulse frequency was also significantly reduced (P ... of glucocorticoids on the TSH response to TRH, our data indicate that even physiological serum levels of cortisol have an influence on endogenous TSH secretion, probably caused by regulation of the pituitary sensitivity to TRH....

  10. Live cell imaging unveils multiple domain requirements for in vivo dimerization of the glucocorticoid receptor

    DEFF Research Database (Denmark)

    Presman, Diego M; Ogara, M Florencia; Stortz, Martín

    2014-01-01

    Glucocorticoids are essential for life, but are also implicated in disease pathogenesis and may produce unwanted effects when given in high doses. Glucocorticoid receptor (GR) transcriptional activity and clinical outcome have been linked to its oligomerization state. Although a point mutation wi...

  11. Fecal glucocorticoid response to environmental stressors in green iguanas (Iguana iguana)

    DEFF Research Database (Denmark)

    Kalliokoski, Otto; Timm, Jeanette; Ibsen, Ida

    2012-01-01

    Quantification of glucocorticoid metabolites in feces has been shown to be a powerful tool in evaluating well-being in vertebrates. Little is known however about the hypothalamic–pituitary–adrenal axis response to stressors, and consequent glucocorticoid excretion, in reptiles. In a longitudinal...

  12. Glucocorticoid metabolites in newborns: A marker for traffic noise related stress?

    DEFF Research Database (Denmark)

    Lech Cantuaria, Manuella; Usermann, Jakob; Proietti, Elena

    2018-01-01

    Traffic noise has been associated with an increased risk for several non-auditory health effects, which may be explained by a noise-induced release of stress hormones (e.g. glucocorticoids). Although several studies in children and adults have indicated an increased secretion of glucocorticoids...

  13. Maternal PTSD associates with greater glucocorticoid sensitivity in offspring of Holocaust survivors.

    Science.gov (United States)

    Lehrner, Amy; Bierer, Linda M; Passarelli, Vincent; Pratchett, Laura C; Flory, Janine D; Bader, Heather N; Harris, Iris R; Bedi, Aarti; Daskalakis, Nikolaos P; Makotkine, Iouri; Yehuda, Rachel

    2014-02-01

    Intergenerational effects of trauma have been observed clinically in a wide range of populations, and parental PTSD has been associated with an increased risk for psychopathology in offspring. In studies of Holocaust survivor offspring, parental PTSD, and particularly maternal PTSD, has been associated with increased risk for PTSD, low basal urinary cortisol excretion and enhanced cortisol suppression in response to dexamethasone. Such findings implicate maternally derived glucocorticoid programming in the intergenerational transmission of trauma-related consequences, potentially resulting from in utero influences or early life experiences. This study investigated the relative influence of Holocaust exposure and PTSD in mothers and fathers on glucocorticoid sensitivity in offspring. Eighty Holocaust offspring and 15 offspring of non-exposed Jewish parents completed evaluations and provided blood and urine samples. Glucocorticoid sensitivity was evaluated using the lysozyme suppression test (LST), an in vitro measure of glucocorticoid receptor sensitivity in a peripheral tissue, the dexamethasone suppression test (DST), and 24-h urinary cortisol excretion. Maternal PTSD was associated with greater glucocorticoid sensitivity in offspring across all three measures of glucocorticoid function. An interaction of maternal and paternal PTSD on the DST and 24-h urinary cortisol showed an effect of decreased glucocorticoid sensitivity in offspring with paternal, but not maternal, PTSD. Although indirect, these findings are consistent with the hypothesis that epigenetic programming may be involved in the intergenerational transmission of trauma-related effects on glucocorticoid regulation. Published by Elsevier Ltd.

  14. Scavenger Receptor B1 is a Potential Biomarker of Human Nasopharyngeal Carcinoma and Its Growth is Inhibited by HDL-mimetic Nanoparticles

    Science.gov (United States)

    Zheng, Ying; Liu, Yanyan; Jin, Honglin; Pan, Shaotao; Qian, Yuan; Huang, Chuan; Zeng, Yixin; Luo, Qingming; Zeng, Musheng; Zhang, Zhihong

    2013-01-01

    Nasopharyngeal carcinoma (NPC) is a very regional malignant head and neck cancer that has attracted widespread attention for its unique etiology, epidemiology and therapeutic options. To achieve high cure rates in NPC patients, theranostic approaches are actively being pursued and improved efforts remain desirable in identifying novel biomarkers and establishing effective therapeutic approaches with low long-term toxicities. Here, we discovered that the scavenger receptor class B type I (SR-B1) was overexpressed in all investigated NPC cell lines and 75% of NPC biopsies, demonstrating that SR-B1 is a potential biomarker of NPC. Additional functional analysis showed that SR-B1 has great effect on cell motility while showing no significant impact on cell proliferation. As high-density lipoproteins (HDL) exhibit strong binding affinities to SR-B1 and HDL mimetic peptides are reportedly capable of inhibiting tumor growth, we further examined the SR-B1 targeting ability of a highly biocompatible HDL-mimicking peptide-phospholipid scaffold (HPPS) nanocarrier and investigated its therapeutic effect on NPC. Results show that NPC cells with higher SR-B1 expression have superior ability in taking up the core constituents of HPPS. Moreover, HPPS inhibited the motility and colony formation of 5-8F cells, and significantly suppressed the NPC cell growth in nude mice without inducing tumor cell necrosis or apoptosis. These results indicate that HPPS is not only a NPC-targeting nanocarrier but also an effective anti-NPC drug. Together, the identification of SR-B1 as a potential biomarker and the use of HPPS as an effective anti-NPC agent may shed new light on the diagnosis and therapeutics of NPC. PMID:23843895

  15. The effects of glucocorticoids on the inhibition of emotional information: A dose-response study.

    Science.gov (United States)

    Taylor, Véronique A; Ellenbogen, Mark A; Washburn, Dustin; Joober, Ridha

    2011-01-01

    There is evidence that cortisol influences cognitive and affective processes such as selective attention and memory for emotional events, yet the effects of glucocorticoids on attentional inhibition in humans remain unknown. Consequently, this double-blind study examined dose-dependent effects of exogenous glucocorticoids on the inhibition of emotional information. Sixty-three university students (14 male, 49 female) ingested either a placebo pill or hydrocortisone (10mg or 40mg), and completed a negative priming task assessing the inhibition of pictures depicting angry, sad, and happy faces. The 10mg, but not the 40mg hydrocortisone dose elicited increased inhibition for angry faces relative to placebo. Thus, moderate glucocorticoid elevations may have adaptive effects on emotional information processing, whereas high glucocorticoid elevations appear to attenuate this effect, consistent with the view that there are dose-dependent effects of glucocorticoids on cognition. Copyright © 2010 Elsevier B.V. All rights reserved.

  16. Total brain, cortical and white matter volumes in children previously treated with glucocorticoids

    DEFF Research Database (Denmark)

    Holm, Sara K; Madsen, Kathrine S; Vestergaard, Martin

    2018-01-01

    BACKGROUND: Perinatal exposure to glucocorticoids and elevated endogenous glucocorticoid-levels during childhood can have detrimental effects on the developing brain. Here, we examined the impact of glucocorticoid-treatment during childhood on brain volumes. METHODS: Thirty children and adolescents...... with rheumatic or nephrotic disease previously treated with glucocorticoids and 30 controls matched on age, sex, and parent education underwent magnetic resonance imaging (MRI) of the brain. Total cortical grey and white matter, brain, and intracranial volume, and total cortical thickness and surface area were...... were mainly driven by the children with rheumatic disease. Total cortical thickness and cortical surface area did not significantly differ between groups. We found no significant associations between glucocorticoid-treatment variables and volumetric measures. CONCLUSION: Observed smaller total brain...

  17. Glucocorticoids maintain human osteoclasts in the active mode of their resorption cycle

    DEFF Research Database (Denmark)

    Søe, Kent; Delaissé, Jean-Marie

    2010-01-01

    that glucocorticoids deeply modify this resorptive behavior. First, glucocorticoids gradually induce excavations with a trenchlike morphology while reducing the time-dependent increase in excavation numbers. This indicates that glucocorticoids make osteoclasts elongate the excavations they initiated rather than...... migrating to a new resorption site, as in control conditions. Second, the round excavations in control conditions contain undegraded demineralized collagen as repeatedly reported earlier, whereas the excavations with a trenchlike morphology generated under glucocorticoid exposure appear devoid of leftovers...... of demineralized collagen. This indicates that collagenolysis proceeds generally at a lower rate than demineralization under control conditions, whereas collagenolysis rates are increased up to the level of demineralization rates in the presence of glucocorticoids. Taking these observations together leads...

  18. A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined with Enzalutamide in Castrate Resistant Prostate Cancer

    Science.gov (United States)

    2015-12-01

    AWARD NUMBER: W81XWH-14-1-0021 TITLE: A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined...4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined...way it adapts is by upregulating another hormone receptor, the glucocorticoid receptor (GR), which may compensate for diminished AR activity. The

  19. Expression and function of nuclear receptor coregulators in brain : understanding the cell-specific effects of glucocorticoids

    NARCIS (Netherlands)

    Laan, Siem van der

    2008-01-01

    Currently, the raising awareness of the role of glucocorticoids in the onset of numerous (neuro)-pathologies constitutes the increasing necessity of understanding the mechanisms of action of glucocorticoids in bodily processes and brain functioning. Glucocorticoids mediate their effects by binding

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

    DEFF Research Database (Denmark)

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

    2011-01-01

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

  1. Effects of a new glucocorticoid, oxazacort, on some variables connected with bone metabolism in man: a comparison with prednisone.

    Science.gov (United States)

    Caniggia, A; Marchetti, M; Gennari, C; Vattimo, A; Nicolis, F B

    1977-03-01

    The urinary elimination of calcium, other electrolytes, and hydroxyproline and the oral absorption of 47Ca have been evaluated in three groups of 8 patients before and during a 15-day treatment with prednisone at daily doses of 25 and 50 mg and with oxazacort, a new glucocorticoid, at a daily dose of 50 mg. The results obtained demonstrate that oxazacort in short-term teatment with a high dose has no significant effect on the urinary elimination of calcium and hydroxypyroline in experimental conditions in which prednisone produces statistically significant and clinically relevant increase, both when given at the same dose and when given at half that dose. On the other hand, the oral absorption of 47Ca is decreased by oxazacort, but less than by prednisone at the same dose. As the antirheumatic activity of oxazacort appears to be only slightly lower than that of prednisone (activity ratio of about 0.84: 1), these findings may have interesting therapeutic implications.

  2. Regulation of the glucocorticoid receptor via a BET-dependent enhancer drives antiandrogen resistance in prostate cancer.

    Science.gov (United States)

    Shah, Neel; Wang, Ping; Wongvipat, John; Karthaus, Wouter R; Abida, Wassim; Armenia, Joshua; Rockowitz, Shira; Drier, Yotam; Bernstein, Bradley E; Long, Henry W; Freedman, Matthew L; Arora, Vivek K; Zheng, Deyou; Sawyers, Charles L

    2017-09-11

    In prostate cancer, resistance to the antiandrogen enzalutamide (Enz) can occur through bypass of androgen receptor (AR) blockade by the glucocorticoid receptor (GR). In contrast to fixed genomic alterations, here we show that GR-mediated antiandrogen resistance is adaptive and reversible due to regulation of GR expression by a tissue-specific enhancer. GR expression is silenced in prostate cancer by a combination of AR binding and EZH2-mediated repression at the GR locus, but is restored in advanced prostate cancers upon reversion of both repressive signals. Remarkably, BET bromodomain inhibition resensitizes drug-resistant tumors to Enz by selectively impairing the GR signaling axis via this enhancer. In addition to revealing an underlying molecular mechanism of GR-driven drug resistance, these data suggest that inhibitors of broadly active chromatin-readers could have utility in nuanced clinical contexts of acquired drug resistance with a more favorable therapeutic index.

  3. Targeted recombinant fusion proteins of IFNγ and mimetic IFNγ with PDGFβR bicyclic peptide inhibits liver fibrogenesis in vivo.

    Directory of Open Access Journals (Sweden)

    Ruchi Bansal

    Full Text Available Hepatic stellate cells (HSCs, following transdifferentiation to myofibroblasts plays a key role in liver fibrosis. Therefore, attempts to attenuate this myofibroblastic phenotype would be a promising therapeutic approach. Interferon gamma (IFNγ is a potent anti-fibrotic cytokine, but its pleiotropic receptor expression leading to severe adverse effects has limited its clinical application. Since, activated HSC express high-level of platelet derived growth factor beta receptor (PDGFβR, we investigated the potential of PDGFβR-specific targeting of IFNγ and its signaling peptide that lacks IFNγR binding site (mimetic IFNγ or mimIFNγ in liver fibrosis. We prepared DNA constructs expressing IFNγ, mimIFNγ or BiPPB (PDGFβR-specific bicyclic peptide-IFNγ, BiPPB-mimIFNγ fusion proteins. Both chimeric proteins alongwith IFNγ and mimIFNγ were produced in E.coli. The expressed proteins were purified and analyzed for PDGFβR-specific binding and in vitro effects. Subsequently, these recombinant proteins were investigated for the liver uptake (pSTAT1α signaling pathway, for anti-fibrotic effects and adverse effects (platelet counts in CCl4-induced liver fibrogenesis in mice. The purified HSC-targeted IFNγ and mimIFNγ fusion proteins showed PDGFβR-specific binding and significantly reduced TGFβ-induced collagen-I expression in human HSC (LX2 cells, while mouse IFNγ and mimIFNγ did not show any effect. Conversely, mouse IFNγ and BiPPB-IFNγ induced activation and dose-dependent nitric oxide release in mouse macrophages (express IFNγR while lack PDGFβR, which was not observed with mimIFNγ and BiPPB-mimIFNγ, due to the lack of IFNγR binding sites. In vivo, targeted BiPPB-IFNγ and BiPPB-mimIFNγ significantly activated intrahepatic IFNγ-signaling pathway compared to IFNγ and mimIFNγ suggesting increased liver accumulation. Furthermore, the targeted fusion proteins ameliorated liver fibrogenesis in mice by significantly reducing

  4. Bio-mimetic mineralization potential of collagen hydrolysate obtained from chromium tanned leather waste

    International Nuclear Information System (INIS)

    Banerjee, Pradipta; Madhu, S.; Chandra Babu, N.K.; Shanthi, C.

    2015-01-01

    Hydroxyapatite (HA) ceramics serve as an alternative to autogenous-free bone grafting by virtue of their excellent biocompatibility. However, chemically synthesized HA lacks the strong load-bearing capacity as required by bone. The bio-mimetic growth of HA crystals on collagen surface provides a feasible solution for synthesizing bone substitutes with the desired properties. This study deals with the utilization of the collagen hydrolysate recovered from leather waste as a substrate for promoting HA crystal growth. Bio-mimetic growth of HA was induced by subjecting the hydrolysate to various mineralization conditions. Parameters that would have a direct effect on crystal growth were varied to determine the optimal conditions necessary. Maximum mineralization was achieved with a combination of 10 mM of CaCl 2 , 5 mM of Na 2 HPO 4 , 100 mM of NaCl and 0.575% glutaraldehyde at a pH of 7.4. The metal–protein interactions leading to formation of HA were identified through Fourier-transform infrared (FTIR) spectroscopy and x-ray diffraction (XRD) studies. The crystal dimensions were determined to be in the nanoscale range by atomic force microscopy (AFM) and scanning electron microscopy (SEM). The size and crystallinity of bio-mimetically grown HA indicate that hydrolysate from leather waste can be used as an ideal alternative substrate for bone growth. - Highlights: • Collagen hydrolysate, extracted from leather industry waste is subjected to biomineralization. • Optimal conditions required for HA growth are identified. • FTIR studies reveal higher Ca−COO − and low C−N stretch with higher HA formation. • AFM and SEM studies reveal nanometer ranged HA crystals

  5. Smac mimetic-derived augmentation of chemotherapeutic response in experimental pancreatic cancer

    Directory of Open Access Journals (Sweden)

    Schwarz Margaret A

    2011-01-01

    Full Text Available Abstract Background Pancreatic ductal adenocarcinoma (PDAC is highly resistant to conventional chemotherapy, in part due to the overexpression of inhibitors of apoptosis proteins (IAPs. Smac is an endogenous IAP-antagonist, which renders synthetic Smac mimetics attractive anticancer agents. We evaluated the benefits of combining a Smac mimetic, JP1201 (JP, with conventional chemotherapy agents used for PDAC management. Methods Cell viability assays and protein expression analysis were performed using WST-1 reagent and Western blotting, respectively. Apoptosis was detected by annexin V/propidium iodide staining. In vivo tumor growth and survival studies were performed in murine PDAC xenografts. Results JP and gemcitabine (Gem inhibited PDAC cell proliferation with additive effects in combination. The percentage of early apoptotic cells in controls, JP, Gem and JP + Gem was 17%, 26%, 26% and 38%, respectively. JP-induced apoptosis was accompanied by PARP-1 cleavage. Similar additive anti-proliferative effects were seen for combinations of JP with doxorubicin (Dox and docetaxel (DT. The JP + Gem combination caused a 30% decrease in tumor size in vivo compared to controls. Median animal survival was improved significantly in mice treated with JP + Gem (38 d compared to controls (22 d, JP (28 d or Gem (32 d (p = 0.01. Animal survival was also improved with JP + DT treatment (32 d compared to controls (16 d, JP (21 d or DT alone (27 d. Conclusions These results warrant further exploration of strategies that promote chemotherapy-induced apoptosis of tumors and highlight the potential of Smac mimetics in clinical PDAC therapy.

  6. Mimetic Theory and the evolutionary paradox of schizophrenia: The archetypal scapegoat hypothesis.

    Science.gov (United States)

    Riordan, Daniel Vincent

    2017-10-01

    Schizophrenia poses an evolutionary paradox, being genetically mediated yet associated with reduced fecundity. Numerous hypotheses have attempted to address this, but few describe how the schizophrenic phenotype itself might constitute an evolutionary adaptation. This paper draws on René Girard's theory on human origins, which claims that humans evolved a tendency to mimic both the desires and the behaviours of each other (mimetic theory). This would have promoted social cohesion and co-operation, but at the cost of intra-group rivalry and conflict. The mimetic dynamic would have escalated such conflicts into reciprocal internecine violence, threatening the survival of the entire group. Girard theorised that the "scapegoat mechanism" emerged, by which means such violence was curtailed by the unanimity of "all against one", thus allowing the mimetic impulse to safely evolve further, making language and complex social behaviours possible. Whereas scapegoating may have emerged in the entire population, and any member of a community could be scapegoated if necessary, this paper proposes that the scapegoat mechanism would have worked better in groups containing members who exhibited traits, recognised by all others, which singled them out as victims. Schizophrenia may be a functional adaptation, similar in evolutionary terms to altruism, in that it may have increased inclusive fitness, by providing scapegoat victims, the choice of whom was likely to be agreed upon unanimously, even during internecine conflict, thus restoring order and protecting the group from self-destruction. This evolutionary hypothesis, uses Girardian anthropology to combine the concept of the schizophrenic as religious shaman with that of the schizophrenic as scapegoat. It may help to reconcile divergent philosophical concepts of mental illness, and also help us to better understand, and thus counter, social exclusion and stigmatisation. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Synovial DKK1 expression is regulated by local glucocorticoid metabolism in inflammatory arthritis.

    Science.gov (United States)

    Hardy, Rowan; Juarez, Maria; Naylor, Amy; Tu, Jinwen; Rabbitt, Elizabeth H; Filer, Andrew; Stewart, Paul M; Buckley, Christopher D; Raza, Karim; Cooper, Mark S

    2012-10-18

    Inflammatory arthritis is associated with increased bone resorption and suppressed bone formation. The Wnt antagonist dickkopf-1 (DKK1) is secreted by synovial fibroblasts in response to inflammation and this protein has been proposed to be a master regulator of bone remodelling in inflammatory arthritis. Local glucocorticoid production is also significantly increased during joint inflammation. Therefore, we investigated how locally derived glucocorticoids and inflammatory cytokines regulate DKK1 synthesis in synovial fibroblasts during inflammatory arthritis. We examined expression and regulation of DKK1 in primary cultures of human synovial fibroblasts isolated from patients with inflammatory arthritis. The effect of TNFα, IL-1β and glucocorticoids on DKK1 mRNA and protein expression was examined by real-time PCR and ELISA. The ability of inflammatory cytokine-induced expression of the glucocorticoid-activating enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) to sensitise fibroblasts to endogenous glucocorticoids was explored. Global expression of Wnt signalling and target genes in response to TNFα and glucocorticoids was assessed using a custom array. DKK1 expression in human synovial fibroblasts was directly regulated by glucocorticoids but not proinflammatory cytokines. Glucocorticoids, but not TNFα, regulated expression of multiple Wnt agonists and antagonists in favour of inhibition of Wnt signalling. However, TNFα and IL-1β indirectly stimulated DKK1 production through increased expression of 11β-HSD1. These results demonstrate that in rheumatoid arthritis synovial fibroblasts, DKK1 expression is directly regulated by glucocorticoids rather than TNFα. Consequently, the links between synovial inflammation, altered Wnt signalling and bone remodelling are not direct but are dependent on local activation of endogenous glucocorticoids.

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

    Directory of Open Access Journals (Sweden)

    Gabriele Pizzino

    2017-09-01

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

  9. Yin Yang 1 Promotes Hepatic Gluconeogenesis Through Upregulation of Glucocorticoid Receptor

    Science.gov (United States)

    Lu, Yan; Xiong, Xuelian; Wang, Xiaolin; Zhang, Zhijian; Li, Jin; Shi, Guojun; Yang, Jian; Zhang, Huijie; Ning, Guang; Li, Xiaoying

    2013-01-01

    Gluconeogenesis is critical in maintaining blood glucose levels in a normal range during fasting. In this study, we investigated the role of Yin Yang 1 (YY1), a key transcription factor involved in cell proliferation and differentiation, in the regulation of hepatic gluconeogenesis. Our data showed that hepatic YY1 expression levels were induced in mice during fasting conditions and in a state of insulin resistance. Overexpression of YY1 in livers augmented gluconeogenesis, raising fasting blood glucose levels in C57BL/6 mice, whereas liver-specific ablation of YY1 using adenoviral shRNA ameliorated hyperglycemia in wild-type and diabetic db/db mice. At the molecular level, we further demonstrated that the major mechanism of YY1 in the regulation of hepatic glucose production is to modulate the expression of glucocorticoid receptor. Therefore, our study uncovered for the first time that YY1 participates in the regulation of hepatic gluconeogenesis, which implies that YY1 might serve as a potential therapeutic target for hyperglycemia in diabetes. PMID:23193188

  10. Glucocorticoid inhibition of leptin- and lipopolysaccharide-induced interleukin-6 production in obesity.

    Science.gov (United States)

    Huang, Chun-Jung; Acevedo, Edmund O; Mari, David C; Randazzo, Christopher; Shibata, Yoshimi

    2014-01-01

    Obesity is considered a chronic inflammatory condition that enhances the risk of numerous inflammatory diseases, including diabetes and cardiovascular disease. Glucocorticoids (GCs) and synthetic therapeutic GCs are anti-inflammatory agents, but the exact functions of GCs in obesity-related inflammation are unknown. Therefore, the objective of this study was to examine the inhibitory effect of an exogenous GC (dexamethasone, DEX) on leptin- and lipopolysaccharide (LPS)-induced IL-6 production by peripheral blood mononuclear cells (PBMCs) ex vivo in obese subjects compared to normal-weight subjects. Blood samples were drawn from 14 obese (BMI>30 kg/m(2)) and 14 normal-weight (BMIobese subjects showed greater leptin- and LPS-induced IL-6 production compared to normal-weight subjects. The suppressive effect of DEX on leptin- and LPS-induced IL-6 production (IC50) was not different between the two groups. However, the IC50 of DEX for LPS-induced was correlated with BMI, waist circumference, and hip circumference. These findings suggest that reduced GC sensitivity may be an important mechanism in the up-regulation of selected obese inflammation. Published by Elsevier Inc.

  11. Glucose-induced serum- and glucocorticoid-regulated kinase activation in oncofetal fibronectin expression

    International Nuclear Information System (INIS)

    Khan, Zia A.; Barbin, Yousef P.; Farhangkhoee, Hana; Beier, Norbert; Scholz, Wolfgang; Chakrabarti, Subrata

    2005-01-01

    Preferential expression of oncofetal extra domain-B fibronectin (EDB + FN), a proposed angiogenic marker, has been shown in proliferative diabetic retinopathy. High levels of glucose also increase EDB + FN expression in endothelial cells (ECs) via transforming growth factor-β1 (TGF-β1) and endothelin-1 (ET-1). The present study was aimed at elucidating the role of serum- and glucocorticoid-regulated kinase (SGK-1) in glucose-induced EDB + FN expression. Using human macro- and microvascular ECs, we show that high levels of glucose, TGF-β1, and ET-1 increase the EDB + FN expression via SGK-1 alteration at the mRNA, protein, and activity levels. Inhibition of TGF-β1 and ET-1 prevented glucose-induced SGK-1 activation and the EDB + FN expression. Furthermore, using siRNA-mediated SGK-1 gene silencing, we show that glucose-induced EDB + FN expression can be completely prevented. These findings provide first evidence of glucose-induced SGK-1 activation in altered EDB + FN expression and provide novel avenues for therapeutic modalities

  12. Safety and tolerability of high doses of glucocorticoides

    Directory of Open Access Journals (Sweden)

    Rakić Branislava D.

    2016-01-01

    Full Text Available Introduction: Treatment of acute lymphoblastic leukemia includes the use of high doses of glucocorticoides (prednisone and dexamethasone, which significantly increase the success of therapy due to lymphocytolitic effect. The aim: The aim of the study was to determine tolerability of high doses of prednisone and dexamethasone in children with acute lymphoblastic leukemia and the structure and the intensity of adverse effects, occurred after application of these medicines. Subjects and methods: In a prospective study, we analyzed adverse effects of high doses of glucocorticoides in children suffering acute lymphoblastic leukemia treated in the Institute for Child and Youth Health Care of Vojvodina, since December 2010. until October 2014, were analyzed. This study included 18 patients, aged from 2 to 15 years. Results: Hyperglycemia appeared in 89% of patients treated with prednisone and in 61% of patients treated with dexamethasone. In order to control the high blood glucose level (above 10 mmol /L, in 11% of patients insulin was used. Hypertension appeared in 28% patients treated with prednisone and dexamethasone. Antihypertensives were needed for regulation in 17% patients. Hypopotassemia and hypocalcaemia were significantly more expressed after the use of prednisone in comparison to dexamethasone. In 11% of patients, the treatment with dexamethasone caused depressive behavior, followed by agitation. Conclusion: Adverse effects of dexamethasone and prednisone, administered in high doses in children with ALL were known, expected and reversible. Adverse reactions usually disappeared spontaneously or after short-term symptomatic therapy.

  13. Stabilization of glucocorticoid receptors in isolated rat hepatocytes by radioprotectants

    International Nuclear Information System (INIS)

    Karle, J.M.; Ridder, W.E.; Wright, N.; Olmeda, R.; Nielsen, C.J.

    1986-01-01

    Previous work has shown that glucocorticoid receptors in rat liver homogenate can be stabilized by the addition of MoO 4 plus the sulfhydryl-containing compounds dithiothreitol and WR 1065. The latter is the dephosphorylated, principal metabolite of the radioprotectant WR 2721 (or S-2-(3-aminopropylamino)ethanesphosphorothioic acid). The current work results from applying this knowledge to intact rat hepatocytes. Cells were isolated by collagenase perfusion and incubated in supplemented minimum essential medium at 37 0 C with various concentrations of WR 2721, WR 1065, or vehicle. Samples of these cell suspensions were analyzed at various times for steroid binding capacity by incubating homogenates (27,000 x g supernates) with 50 nM 3 H-triamcinolone acetonide in the presence or absence of excess unlabelled dexamethasone. Concentrations of 10 mM WR 2721 provided marked preservation of the binding capacity (>85% of the initial value at 5 hours) compared to control at 60% of the binding capacity. WR 1065 at 10 mM provided no such protection. This is consistent with the observation that WR 1065 does not pass cell membranes. The authors propose that supplying reducing equivalents to intracellular components such as the glucocorticoid receptor may be one mechanism of the radioprotection afforded by WR 2721

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

    International Nuclear Information System (INIS)

    Aguilar, David; Strom, Joshua; Chen, Qin M.

    2014-01-01

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

  15. Autoimmune hyperthyroidism due to secondary adrenal insufficiency: resolution with glucocorticoids.

    Science.gov (United States)

    Skamagas, Maria; Geer, Eliza B

    2011-01-01

    To describe the course of autoimmune hyperthyroid disease in a patient with corticotropin (ACTH) deficiency treated with glucocorticoids. We report the clinical presentation, laboratory data, imaging studies, and management of a patient with weight loss, fatigue, apathy, hallucinations, and arthritis. Autoimmune hyperthyroidism (positive thyroperoxidase and thyroglobulin antibodies and borderline positive thyrotropin receptor antibody) was diagnosed in a 71-year-old woman. New psychotic symptoms prompted brain magnetic resonance imaging, which revealed a partially empty sella. Undetectable morning cortisol, undetectable ACTH, and failure to stimulate cortisol with synthetic ACTH (cosyntropin 250 mcg) secured the diagnosis of long-standing secondary adrenal insufficiency. Hydrocortisone replacement improved the patient's symptoms, resolved the thyroid disease, and decreased thyroid antibody titers. In retrospect, the patient recalled severe postpartum hemorrhage requiring blood transfusion at age 38 years. A Sheehan event probably occurred 33 years before the patient presented with corticotropin deficiency. Hyperthyroidism accelerated cortisol metabolism and provoked symptoms of adrenal insufficiency. The hypocortisolemic state may precipitate hyperimmunity and autoimmune thyroid disease. Rapid resolution of hyperthyroidism and decreased thyroid antibody titers with glucocorticoid treatment support this hypothesis.

  16. Fecal Glucocorticoid Analysis: Non-invasive Adrenal Monitoring in Equids.

    Science.gov (United States)

    Yarnell, Kelly; Purcell, Rebecca S; Walker, Susan L

    2016-04-25

    Adrenal activity can be assessed in the equine species by analysis of feces for corticosterone metabolites. During a potentially aversive situation, corticotrophin releasing hormone (CRH) is released from the hypothalamus in the brain. This stimulates the release of adrenocorticotrophic hormone (ACTH) from the pituitary gland, which in turn stimulates release of glucocorticoids from the adrenal gland. In horses the glucocorticoid corticosterone is responsible for several adaptations needed to support equine flight behaviour and subsequent removal from the aversive situation. Corticosterone metabolites can be detected in the feces of horses and assessment offers a non-invasive option to evaluate long term patterns of adrenal activity. Fecal assessment offers advantages over other techniques that monitor adrenal activity including blood plasma and saliva analysis. The non-invasive nature of the method avoids sampling stress which can confound results. It also allows the opportunity for repeated sampling over time and is ideal for studies in free ranging horses. This protocol describes the enzyme linked immunoassay (EIA) used to assess feces for corticosterone, in addition to the associated biochemical validation.

  17. Mimetic discretization of the Abelian Chern-Simons theory and link invariants

    Energy Technology Data Exchange (ETDEWEB)

    Di Bartolo, Cayetano; Grau, Javier [Departamento de Física, Universidad Simón Bolívar, Apartado Postal 89000, Caracas 1080-A (Venezuela, Bolivarian Republic of); Leal, Lorenzo [Departamento de Física, Universidad Simón Bolívar, Apartado Postal 89000, Caracas 1080-A (Venezuela, Bolivarian Republic of); Centro de Física Teórica y Computacional, Facultad de Ciencias, Universidad Central de Venezuela, Apartado Postal 47270, Caracas 1041-A (Venezuela, Bolivarian Republic of)

    2013-12-15

    A mimetic discretization of the Abelian Chern-Simons theory is presented. The study relies on the formulation of a theory of differential forms in the lattice, including a consistent definition of the Hodge duality operation. Explicit expressions for the Gauss Linking Number in the lattice, which correspond to their continuum counterparts are given. A discussion of the discretization of metric structures in the space of transverse vector densities is presented. The study of these metrics could serve to obtain explicit formulae for knot an link invariants in the lattice.

  18. Molecular Design, Structures, and Activity of Antimicrobial Peptide-Mimetic Polymers

    Science.gov (United States)

    Takahashi, Haruko; Palermo, Edmund F.; Yasuhara, Kazuma; Caputo, Gregory A.

    2014-01-01

    There is an urgent need for new antibiotics which are effective against drug-resistant bacteria without contributing to resistance development. We have designed and developed antimicrobial copolymers with cationic amphiphilic structures based on the mimicry of naturally occurring antimicrobial peptides. These copolymers exhibit potent antimicrobial activity against a broad spectrum of bacteria including methicillin-resistant Staphylococcus aureus with no adverse hemolytic activity. Notably, these polymers also did not result in any measurable resistance development in E. coli. The peptide-mimetic design principle offers significant flexibility and diversity in the creation of new antimicrobial materials and their potential biomedical applications. PMID:23832766

  19. Cytokine modulation by glucocorticoids: mechanisms and actions in cellular studies.

    Science.gov (United States)

    Brattsand, R; Linden, M

    1996-01-01

    Glucocorticoids inhibit the expression and action of most cytokines. This is part of the in vivo feed-back system between inflammation-derived cytokines and CNS-adrenal produced corticosteroids with the probable physiological relevance to balance parts of the host defence and anti-inflammatory systems of the body. Glucocorticoids modulate cytokine expression by a combination of genomic mechanisms. The activated glucocorticoid-receptor complex can (i) bind to and inactivate key proinflammatory transcription factors (e.g. AP-1, NF kappa B). This takes place at the promotor responsive elements of these factors, but has also been reported without the presence of DNA; (ii) via glucocorticoid responsive elements (GRE), upregulate the expression of cytokine inhibitory proteins, e.g. I kappa B, which inactivates the transcription factor NF kappa B and thereby the secondary expression of a series of cytokines; (iii) reduce the half-life time and utility of cytokine mRNAs. In studies with triggered human blood mononuclear cells in culture, glucocorticoids strongly diminish the production of the 'initial phase' cytokines IL-1 beta and TNF-alpha and the 'immunomodulatory' cytokines IL-2, IL-3, IL-4, IL-5, IL-10, IL-12 and IFN-gamma, as well as of IL-6, IL-8 and the growth factor GM-CSF. While steroid treatment broadly attenuates cytokine production, it cannot modulate it selectively, e.g. just the TH0, the TH1 or the TH2 pathways. The production of the 'anti-inflammatory' IL-10 is also inhibited. The exceptions of steroid down-regulatory activity on cytokine expression seem to affect 'repair phase' cytokines like TGF-beta and PDGF. These are even reported to be upregulated, which may explain the rather weak steroid dampening action on healing and fibrotic processes. Some growth factors, e.g. G-CSF and M-CSF, are only weakly affected. In addition to diminishing the production of a cytokine, steroids can also often inhibit its subsequent actions. Because cytokines work in

  20. Experimental Study on the Effect of Calcitonin in Osteoporosis Induced by the Immobilization and Long-Term Glucocorticoid

    International Nuclear Information System (INIS)

    Park, Dong Jin; Lee, Sang Rae

    1989-01-01

    It is well known that the glucocorticoid induces osteoporosis by suppression of the osteoblast, but its effect on the osteoclast has some controversy whether it activates or suppresses the osteoclast. If the calcitonin, which is known to suppress the osteoclast, prevents the osteoporosis by glucocorticoid, then the suppression of the osteoclast by the glucocorticoid is not so significant. And if the calcitonin increases the osteoblastic activity, Tc-99m MDP uptake will be increased in spite of the glucocorticoid effect on the osteoblast. The immobilization operation was performed to the right leg of male Wistar rats weighing about 200 gm each. For 16 weeks after operation, rats were injected glucocorticoid alone or glucocorticoid and calcitonin. The bone density was measured by means of photodensitometry under reference aluminum step wedge and Tc-99m MDP uptake was available to the index of the osteoblastic activity. 1. The bone density of femoral head was markedly reduced than that of femoral shaft following ratio of cancellous and cortical components in both site. 2. glucocorticoid caused decrease in bone density of spine and femur, and there is significantly increase of it when medication of glucocorticoid and calcitonin injection simultaneously than that of glucocorticoid. 3. Tc-99m MDP uptake was revealed significant reduction in medication of glucocorticoid but increase in glucocorticoid and calcitonin injection simultaneously in later experimental period. 4. There was a slight reduction in plasma osteocalcin in medication of glucocorticoid through experimental periods and an increase in its value in case of giving glucocorticoid and calcitonin simultaneously in later experimental period. From these results, we suggest that osteoporosis by immobilization is more pronounced by glucocorticoid hormone and osteoporosis induced by immobilization and glucocorticoid use is prevented by calcitonin administration with increasing osteoblastic activity.

  1. Cytokine-induced loss of glucocorticoid function: effect of kinase inhibitors, long-acting β(2-adrenoceptor [corrected] agonist and glucocorticoid receptor ligands.

    Directory of Open Access Journals (Sweden)

    Christopher F Rider

    Full Text Available 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

  2. Stick–slip friction of gecko-mimetic flaps on smooth and rough surfaces

    Science.gov (United States)

    Das, Saurabh; Cadirov, Nicholas; Chary, Sathya; Kaufman, Yair; Hogan, Jack; Turner, Kimberly L.; Israelachvili, Jacob N.

    2015-01-01

    The discovery and understanding of gecko ‘frictional-adhesion’ adhering and climbing mechanism has allowed researchers to mimic and create gecko-inspired adhesives. A few experimental and theoretical approaches have been taken to understand the effect of surface roughness on synthetic adhesive performance, and the implications of stick–slip friction during shearing. This work extends previous studies by using a modified surface forces apparatus to quantitatively measure and model frictional forces between arrays of polydimethylsiloxane gecko footpad-mimetic tilted microflaps against smooth and rough glass surfaces. Constant attachments and detachments occur between the surfaces during shearing, as described by an avalanche model. These detachments ultimately result in failure of the adhesion interface and have been characterized in this study. Stick–slip friction disappears with increasing velocity when the flaps are sheared against a smooth silica surface; however, stick–slip was always present at all velocities and loads tested when shearing the flaps against rough glass surfaces. These results demonstrate the significance of pre-load, shearing velocity, shearing distances, commensurability and shearing direction of gecko-mimetic adhesives and provide us a simple model for analysing and/or designing such systems. PMID:25589569

  3. Stick-slip friction of gecko-mimetic flaps on smooth and rough surfaces.

    Science.gov (United States)

    Das, Saurabh; Cadirov, Nicholas; Chary, Sathya; Kaufman, Yair; Hogan, Jack; Turner, Kimberly L; Israelachvili, Jacob N

    2015-03-06

    The discovery and understanding of gecko 'frictional-adhesion' adhering and climbing mechanism has allowed researchers to mimic and create gecko-inspired adhesives. A few experimental and theoretical approaches have been taken to understand the effect of surface roughness on synthetic adhesive performance, and the implications of stick-slip friction during shearing. This work extends previous studies by using a modified surface forces apparatus to quantitatively measure and model frictional forces between arrays of polydimethylsiloxane gecko footpad-mimetic tilted microflaps against smooth and rough glass surfaces. Constant attachments and detachments occur between the surfaces during shearing, as described by an avalanche model. These detachments ultimately result in failure of the adhesion interface and have been characterized in this study. Stick-slip friction disappears with increasing velocity when the flaps are sheared against a smooth silica surface; however, stick-slip was always present at all velocities and loads tested when shearing the flaps against rough glass surfaces. These results demonstrate the significance of pre-load, shearing velocity, shearing distances, commensurability and shearing direction of gecko-mimetic adhesives and provide us a simple model for analysing and/or designing such systems. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

  4. Glycosides from Stevia rebaudiana Bertoni Possess Insulin-Mimetic and Antioxidant Activities in Rat Cardiac Fibroblasts

    Directory of Open Access Journals (Sweden)

    Cecilia Prata

    2017-01-01

    Full Text Available Stevia rebaudiana Bertoni is a shrub having a high content of sweet diterpenoid glycosides in its leaves, mainly stevioside and rebaudioside A, which are used as noncaloric, natural sweeteners. The aim of this study was to deepen the knowledge about the insulin-mimetic effect exerted by four different mixtures of steviol glycosides, rich in stevioside and rebaudioside A, in neonatal rat cardiac fibroblasts. The potential antioxidant activity of these steviol glycosides was also assessed, as oxidative stress is associated with diabetes. Likewise the insulin effect, steviol glycosides caused an increase in glucose uptake into rat fibroblasts by activating the PI3K/Akt pathway, thus inducing Glut4 translocation to the plasma membrane. The presence of S961, an insulin antagonist, completely abolished these effects, allowing to hypothesize that steviol glycosides could act as ligands of the same receptor engaged by insulin. Moreover, steviol glycosides counteracted oxidative stress by increasing reduced glutathione intracellular levels and upregulating expression and activity of the two antioxidant enzymes superoxide dismutase and catalase. The present work unravels the insulin-mimetic effect and the antioxidant property exerted by steviol glycosides, suggesting their potential beneficial role in the cotreatment of diabetes and in health maintenance.

  5. Glycosides from Stevia rebaudiana Bertoni Possess Insulin-Mimetic and Antioxidant Activities in Rat Cardiac Fibroblasts

    Science.gov (United States)

    Prata, Cecilia; Zambonin, Laura; Rizzo, Benedetta; Vieceli Dalla Sega, Francesco

    2017-01-01

    Stevia rebaudiana Bertoni is a shrub having a high content of sweet diterpenoid glycosides in its leaves, mainly stevioside and rebaudioside A, which are used as noncaloric, natural sweeteners. The aim of this study was to deepen the knowledge about the insulin-mimetic effect exerted by four different mixtures of steviol glycosides, rich in stevioside and rebaudioside A, in neonatal rat cardiac fibroblasts. The potential antioxidant activity of these steviol glycosides was also assessed, as oxidative stress is associated with diabetes. Likewise the insulin effect, steviol glycosides caused an increase in glucose uptake into rat fibroblasts by activating the PI3K/Akt pathway, thus inducing Glut4 translocation to the plasma membrane. The presence of S961, an insulin antagonist, completely abolished these effects, allowing to hypothesize that steviol glycosides could act as ligands of the same receptor engaged by insulin. Moreover, steviol glycosides counteracted oxidative stress by increasing reduced glutathione intracellular levels and upregulating expression and activity of the two antioxidant enzymes superoxide dismutase and catalase. The present work unravels the insulin-mimetic effect and the antioxidant property exerted by steviol glycosides, suggesting their potential beneficial role in the cotreatment of diabetes and in health maintenance. PMID:28947927

  6. Fabrication of cell outer membrane mimetic polymer brush on polysulfone surface via RAFT technique

    International Nuclear Information System (INIS)

    Ma Qian; Zhang Hui; Zhao Jiang; Gong Yongkuan

    2012-01-01

    Highlights: ► Cell membrane mimetic antifouling polymer brush was grown on polysulfone surface. ► Graft density and polymerization degree were calculated from XPS results. ► Water contact angle measurements showed an extremely hydrophilic surface. ► Platelet adhesion and protein adsorption results suggested excellent antifouling ability. - Abstract: Cell membrane mimetic antifouling polymer brush was grown on polysulfone (PSF) membrane by surface-induced reversible addition–fragmentation chain transfer (RAFT) polymerization of 2-methacryloyloxyethyl phosphorylcholine (MPC). The RAFT agent immobilized PSF substrate was prepared by successive chloromethylation, amination with ethylenediamine (EDA) and amidation of the amine group of grafted EDA with the carboxylic group of 4-cyanopentanoic acid dithiobenzoate (CPAD). The surface RAFT polymerization of MPC was initiated in aqueous solution by 4,4′-azobis-4-cyanopentanoic acid (ACPA). The formation of PMPC brush coating is evidenced by X-ray photoelectron spectroscopy and water contact angle measurements. The degree of polymerization of PMPC and the polymer grafting density were calculated from the high resolution XPS spectra. The platelet adhesion and protein adsorption results showed that the PMPC-grafted PSF surface has excellent antifouling ability to resist platelet adhesion completely and suppress protein adsorption significantly. This biomimetic and bio-friendly surface RAFT polymerization strategy could be promising for a variety of biomedical applications.

  7. Methods and Experimental Protocols to Design a Simulated Bio-Mimetic Quadruped Robot

    Directory of Open Access Journals (Sweden)

    Hadi El Daou

    2013-05-01

    Full Text Available Abstract This paper presents a bio-mimetic approach to design and simulate a tortoise-like virtual robot. This study takes a multidisciplinary approach: from in vivo and in vitro experiments on animals, data are collected and used to design, control and simulate a bio-mimetic virtual robot using MD ADAMS platform. From the in vitro experiments, the geometrical and inertial properties of body limbs are measured, and a model of tortoise kinematics is derived. From the in vivo experiments the contact forces between each limb and the ground are measured. The contributions of hind and forelimbs in the generation of propelling and braking forces are studied. The motion of the joints between limb segments are recorded and used to solve the inverse kinematics problem. A virtual model of a tortoise-like robot is built; it is a linkage of 15 rigid bodies articulated by 22 degrees of freedom. This model is referred to as TATOR II. It has the inertial and geometrical properties measured during the in vitro experiments. TATOR II motion is achieved using a Proportional-Derivative controller copying the joint angle trajectories calculated from the in vivo experiments.

  8. A mimetic finite difference method for the Stokes problem with elected edge bubbles

    Energy Technology Data Exchange (ETDEWEB)

    Lipnikov, K [Los Alamos National Laboratory; Berirao, L [DIPARTMENTO DI MATERMATICA

    2009-01-01

    A new mimetic finite difference method for the Stokes problem is proposed and analyzed. The unstable P{sub 1}-P{sub 0} discretization is stabilized by adding a small number of bubble functions to selected mesh edges. A simple strategy for selecting such edges is proposed and verified with numerical experiments. The discretizations schemes for Stokes and Navier-Stokes equations must satisfy the celebrated inf-sup (or the LBB) stability condition. The stability condition implies a balance between discrete spaces for velocity and pressure. In finite elements, this balance is frequently achieved by adding bubble functions to the velocity space. The goal of this article is to show that the stabilizing edge bubble functions can be added only to a small set of mesh edges. This results in a smaller algebraic system and potentially in a faster calculations. We employ the mimetic finite difference (MFD) discretization technique that works for general polyhedral meshes and can accomodate non-uniform distribution of stabilizing bubbles.

  9. Differential Effects of Superoxide Dismutase Mimetics after Mechanical Overload of Articular Cartilage

    Directory of Open Access Journals (Sweden)

    Mitchell C. Coleman

    2017-11-01

    Full Text Available Post-traumatic osteoarthritis can develop as a result of the initial mechanical impact causing the injury and also as a result of chronic changes in mechanical loading of the joint. Aberrant mechanical loading initiates excessive production of reactive oxygen species, oxidative damage, and stress that appears to damage mitochondria in the surviving chondrocytes. To probe the benefits of increasing superoxide removal with small molecular weight superoxide dismutase mimetics under severe loads, we applied both impact and overload injury scenarios to bovine osteochondral explants using characterized mechanical platforms with and without GC4403, MnTE-2-PyP, and MnTnBuOE-2-PyP. In impact scenarios, each of these mimetics provides some dose-dependent protection from cell death and loss of mitochondrial content while in repeated overloading scenarios only MnTnBuOE-2-PyP provided a clear benefit to chondrocytes. These results support the hypothesis that superoxide is generated in excess after impact injuries and suggest that superoxide production within the lipid compartment may be a critical mediator of responses to chronic overload. This is an important nuance distinguishing roles of superoxide, and thus superoxide dismutases, in mediating damage to cellular machinery in hyper-acute impact scenarios compared to chronic scenarios.

  10. Tumor-promoting phorbol ester amplifies the inductions of tyrosine aminotransferase and ornithine decarboxylase by glucocorticoid

    International Nuclear Information System (INIS)

    Kido, H.; Fukusen, N.; Katunuma, N.

    1987-01-01

    In adrenalectomized rats, the tumor-promoting phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) markedly enhanced the inductions of tyrosine aminotransferase (TAT) and ornithine decarboxylase by glucocorticoids, even with sufficient concentration of glucocorticoids to have a maximal effect, whereas it had no effect on TAT activity and increased ornithine decarboxylase activity only slightly in the absence of glucocorticoids. Phorbol derivatives and components of TPA such as 4β-phorbol, phorbol 12-tetradecanoate, phorbol 13-acetate, and 4-O-methylphorbol 12-tetradecanoate 13-acetate, which have no tumor-promoting activity or ability to activate protein kinase C, did not have any effect on TAT induction by glucocorticoid. TPA enhanced the induction of TAT by various glucocorticoids but had no effect on induction of TAT by glucagon or insulin and did not enhance the induction of glucose-6-phosphate dehydrogenase by 17β-estradiol. These results suggest that TPA specifically enhances the induction of TAT and ornithine decarboxylase by glucocorticoids. Similar effects of TPA on TAT induction by glucocorticoid were observed in primary cultures of adult rat hepatocytes. Another activator of protein kinase C, rac-1,2-dioctanoylglycerol, was also found to have similar effects on the cells

  11. Radioreceptor assay for evaluation of the plasma glucocorticoid activity of natural and synthetic steroids in man

    International Nuclear Information System (INIS)

    Ballard, P.L.; Carter, J.P.; Graham, B.S.; Baxter, J.D.

    1975-01-01

    An assay for plasma glucocorticoid activity has been developed using specific glucocorticoid receptors. Unlike other assays for cortisol and certain synthetic corticosteroids, this radioreceptor assay measures the glucocorticoid activity of all natural and synthetic steroids. Steroids extracted from as little as 0.05 ml of plasma are incubated with 3 H-dexamethasone and cytosol receptors from cultured rat hepatoma cells. From 0.5 to 50 ng of cortisol are accurately detected. Glucocorticoid activities of adult plasmas determined by the assay correlate closely with corticoid levels obtained in the CBG-isotope and fluorometric assays. Other steroids are measured in proportion to both concentration and potency as glucocorticoids. Relative activities include: cortisol 100, dexamethasone 940, prednisolone 230, prednisone 3, estradiol 1 and androstenedione 1. A similar ranking of steroids was found using receptors from a human source (fetal lung). The assay has been useful in detecting glucocorticoid activity in unidentified medications and in measuring plasma glucocorticoid levels after administration of synthetic corticosteroids. (auth)

  12. Functional interaction between the glucocorticoid receptor and GANP/MCM3AP

    International Nuclear Information System (INIS)

    Osman, Waffa; Laine, Sanna; Zilliacus, Johanna

    2006-01-01

    Glucocorticoids are widely used to treat inflammatory diseases but have a number of side effects that partly are connected to inhibition of cell proliferation. Glucocorticoids mediated their action by binding to the glucocorticoid receptor. In the present study, we have identified by two-hybrid screens the germinal center-associated protein (GANP) and MCM3-associated protein (MCM3AP), a splicing variant of GANP, as glucocorticoid receptor interacting proteins. GANP and MCM3AP can bind to the MCM3 protein involved in initiation of DNA replication. Glutathione-S-transferase-pull-down and co-immunoprecipitation assays showed that the C-terminal domain of GANP, encompassing MCM3AP, interacts with the ligand-binding domain of the glucocorticoid receptor. Characterization of the intracellular localization of GANP revealed that GANP is shuttling between the nucleus and the cytoplasm. Furthermore, we show that glucocorticoids are unable to inhibit DNA replication in HeLa cells overexpressing MCM3AP suggesting a role for both glucocorticoid receptor and GANP/MCM3AP in regulating cell proliferation

  13. A case report: Familial glucocorticoid deficiency associated with familial focal segmental glomerulosclerosis

    Directory of Open Access Journals (Sweden)

    Ram Nanik

    2012-12-01

    Full Text Available Abstract Background Familial glucocorticoid deficiency (FGD is a rare autosomal recessive disorder characterized by isolated glucocorticoid deficiency in the presence of normal plasma renin and aldosterone level. Focal segmental glomerulosclerosis (FSGS is a form of glomerular disease associated with proteinuria and nephritic syndrome. This is the first case of familial glucocorticoid deficiency associated with familial focal segmental glomerulosclerosis. Case presentation An eight month old boy presented with increased genital pigmentation. Initial investigation revealed that he was glucocorticoid deficient and was started on hydrocortisone and fludrocortisone with a diagnosis of primary adrenal insufficiency. Later fludrocortisone was withdrawn and he was diagnosed to have isolated glucocorticoid deficiency. He later developed focal segmental glomerulosclerosis for which he underwent renal transplantation at the age of five years. Now at the age of twelve years, this boy is doing well on hydrocortisone treatment. His two siblings and a first degree cousin also had isolated glucocorticoid deficiency. One of the above two siblings died due to renal failure secondary to focal segmental glomerulosclerosis. Conclusion Patients with familial glucocorticoid deficiency should be carefully followed for development of features of nephrotic syndrome.

  14. Overexpression of Glucocorticoid Receptor β Enhances Myogenesis and Reduces Catabolic Gene Expression.

    Science.gov (United States)

    Hinds, Terry D; Peck, Bailey; Shek, Evan; Stroup, Steven; Hinson, Jennifer; Arthur, Susan; Marino, Joseph S

    2016-02-11

    Unlike the glucocorticoid receptor α (GRα), GR β (GRβ) has a truncated ligand-binding domain that prevents glucocorticoid binding, implicating GRα as the mediator of glucocorticoid-induced skeletal muscle loss. Because GRβ causes glucocorticoid resistance, targeting GRβ may be beneficial in impairing muscle loss as a result of GRα activity. The purpose of this study was to determine how the overexpression of GRβ affects myotube formation and dexamethasone (Dex) responsiveness. We measured GR isoform expression in C₂C12 muscle cells in response to Dex and insulin, and through four days of myotube formation. Next, lentiviral-mediated overexpression of GRβ in C₂C12 was performed, and these cells were characterized for cell fusion and myotube formation, as well as sensitivity to Dex via the expression of ubiquitin ligases. GRβ overexpression increased mRNA levels of muscle regulatory factors and enhanced proliferation in myoblasts. GRβ overexpressing myotubes had an increased fusion index. Myotubes overexpressing GRβ had lower forkhead box O3 (Foxo3a) mRNA levels and a blunted muscle atrophy F-box/Atrogen-1 (MAFbx) and muscle ring finger 1 (MuRF1) response to Dex. We showed that GRβ may serve as a pharmacological target for skeletal muscle growth and protection from glucocorticoid-induced catabolic signaling. Increasing GRβ levels in skeletal muscle may cause a state of glucocorticoid resistance, stabilizing muscle mass during exposure to high doses of glucocorticoids.

  15. Overexpression of Glucocorticoid Receptor β Enhances Myogenesis and Reduces Catabolic Gene Expression

    Directory of Open Access Journals (Sweden)

    Terry D. Hinds

    2016-02-01

    Full Text Available Unlike the glucocorticoid receptor α (GRα, GR β (GRβ has a truncated ligand-binding domain that prevents glucocorticoid binding, implicating GRα as the mediator of glucocorticoid-induced skeletal muscle loss. Because GRβ causes glucocorticoid resistance, targeting GRβ may be beneficial in impairing muscle loss as a result of GRα activity. The purpose of this study was to determine how the overexpression of GRβ affects myotube formation and dexamethasone (Dex responsiveness. We measured GR isoform expression in C2C12 muscle cells in response to Dex and insulin, and through four days of myotube formation. Next, lentiviral-mediated overexpression of GRβ in C2C12 was performed, and these cells were characterized for cell fusion and myotube formation, as well as sensitivity to Dex via the expression of ubiquitin ligases. GRβ overexpression increased mRNA levels of muscle regulatory factors and enhanced proliferation in myoblasts. GRβ overexpressing myotubes had an increased fusion index. Myotubes overexpressing GRβ had lower forkhead box O3 (Foxo3a mRNA levels and a blunted muscle atrophy F-box/Atrogen-1 (MAFbx and muscle ring finger 1 (MuRF1 response to Dex. We showed that GRβ may serve as a pharmacological target for skeletal muscle growth and protection from glucocorticoid-induced catabolic signaling. Increasing GRβ levels in skeletal muscle may cause a state of glucocorticoid resistance, stabilizing muscle mass during exposure to high doses of glucocorticoids.

  16. A role for glucocorticoids in stress-impaired reproduction: beyond the hypothalamus and pituitary.

    Science.gov (United States)

    Whirledge, Shannon; Cidlowski, John A

    2013-12-01

    In addition to the well-characterized role of the sex steroid receptors in regulating fertility and reproduction, reproductive events are also mediated by the hypothalamic-pituitary-adrenal axis in response to an individual's environment. Glucocorticoid secretion in response to stress contributes to the well-characterized suppression of the hypothalamic-pituitary-gonadal axis through central actions in the hypothalamus and pituitary. However, both animal and in vitro studies indicate that other components of the reproductive system are also regulated by glucocorticoids. Furthermore, in the absence of stress, it appears that homeostatic glucocorticoid signaling plays a significant role in reproduction and fertility in all tissues comprising the hypothalamic-pituitary-gonadal axis. Indeed, as central regulators of the immune response, glucocorticoids are uniquely poised to integrate an individual's infectious, inflammatory, stress, nutritional, and metabolic status through glucocorticoid receptor signaling in target tissues. Endocrine signaling between tissues regulating the immune and stress response and those determining reproductive status provides an evolutionary advantage, facilitating the trade-off between reproductive investment and offspring fitness. This review focuses on the actions of glucocorticoids in tissues important for fertility and reproduction, highlighting recent studies that show glucocorticoid signaling plays a significant role throughout the hypothalamic-pituitary-gonadal axis and characterizing these effects as permissive or inhibitory in terms of facilitating reproductive success.

  17. Cell-specific expression of the glucocorticoid receptor within granular convoluted tubules of the rat submaxillary gland

    International Nuclear Information System (INIS)

    Antakly, T.; Zhang, C.X.; Sarrieau, A.; Raquidan, D.

    1991-01-01

    The submaxillary gland, a heterogeneous tissue composed essentially of two functionally distinct cell types (tubular epithelial and acinar), offers an interesting system in which to study the mechanisms of steroid-dependent growth and differentiation. One cell type, the granular convoluted tubular (GCT) cell, secretes a large number of physiologically important polypeptides, including epidermal and nerve growth factors. Two steroids, androgens and glucocorticoids, greatly influence the growth, differentiation, and secretory activity of GCT cells. Because glucocorticoids can partially mimic or potentiate androgen effects, it has been thought that glucocorticoids act via androgen receptors. Since the presence of glucocorticoid receptors is a prerequisite for glucocorticoid action, we have investigated the presence and cellular distribution of glucocorticoid receptors within the rat submaxillary gland. Binding experiments using [3H]dexamethasone revealed the presence of high affinity binding sites in rat submaxillary tissue homogenates. Most of these sites were specifically competed by dexamethasone, corticosterone, and a pure glucocorticoid agonist RU 28362. Neither testosterone nor dihydrotestosterone competed for glucocorticoid binding. The cellular distribution of glucocorticoid receptors within the submaxillary gland was investigated by immunocytochemistry, using two highly specific glucocorticoid receptor antibodies. The receptor was localized in the GCT cells, but not in the acinar cells of rat and mouse submaxillary tissue sections. In GCT cells, the glucocorticoid receptor colocalized with several secretory polypeptides, including epidermal growth factor, nerve growth factor, alpha 2u-globulin, and atrial natriuretic factor

  18. Long-term safety, efficacy, and patient acceptability of teriparatide in the management of glucocorticoid-induced osteoporosis

    Directory of Open Access Journals (Sweden)

    Dore RK

    2013-05-01

    Full Text Available Robin K DoreDavid Geffen School of Medicine, University of California, Los Angeles, CA, USAAbstract: Glucocorticoids are commonly prescribed medications to treat multiple diseases across many medical specialties. One of the most common yet largely unappreciated side effect of glucocorticoid use is increased risk of fracture. Many different therapies are indicated to prevent and treat this condition; many guidelines exist that suggest appropriate use of both glucocorticoids and the medications approved to prevent this common side effect of glucocorticoid therapy. Nevertheless, 30%–50% of patients on long-term glucocorticoid therapy sustain a fracture. Teriparatide, recombinant human parathyroid hormone (1–34, is a daily self-injectable therapy for 24 months approved for use in patients taking long-term glucocorticoids. Teriparatide has been shown to increase bone mineral density and reduce vertebral fracture risk in glucocorticoid-treated patients. Glucocorticoids have many adverse effects on bone that teriparatide has been shown to prevent or negate. Given the fact that preventive therapy for glucocorticoid-induced osteoporosis is often not prescribed, one wonders whether a daily self-injectable therapy for this condition would be prescribed by physicians and accepted by patients. This article reviews the epidemiology, pathophysiology, treatment, guidelines, and persistence data (when available for patients with glucocorticoid-induced osteoporosis treated with teriparatide.Keywords: glucocorticoid-induced osteoporosis, teriparatide, anabolic, PTH, parathyroid hormone

  19. The distorting effect of varying diets on fecal glucocorticoid measurements as indicators of stress

    DEFF Research Database (Denmark)

    Kalliokoski, Otto; Teilmann, A. Charlotte; Abelson, Klas S. P.

    2015-01-01

    The physiological stress response is frequently gauged in animals, non-invasively, through measuring glucocorticoids in excreta. A concern with this method is, however, the unknown effect of variations in diets on the measurements. With an energy dense diet, leading to reduced defecation, will low...... concentrations of glucocorticoids be artificially inflated? Can this effect be overcome by measuring the total output of glucocorticoids in excreta? In a controlled laboratory setting we explored the effect in mice. When standard mouse chow – high in dietary fiber – was replaced with a 17% more energy-dense diet...

  20. The Ups and Downs of Glucocorticoid Signaling | Center for Cancer Research

    Science.gov (United States)

    Glucocorticoids are steroids that react to stress by regulating inflammation and controlling metabolism. Because of their anti-inflammatory and immunosuppressive properties, corticosteroids are among the most frequently prescribed drugs. Glucocorticoids are often used to treat arthritis and autoimmune diseases and are also given in combination with other drugs to treat cancers—such as leukemias and lymphomas—or to alleviate side effects from chemotherapy and radiation. In humans, a glucocorticoid called cortisol is released from the adrenal gland approximately every hour to send signals to cells throughout the body. This pulsed release of hormone is called ultradian secretion.  

  1. Influence of chronic x-ray exposure on adrenal glucocorticoid function and adrenocorticocyte membrane potential

    International Nuclear Information System (INIS)

    Gorban', Je.M.; Topol'nikova, N.V.

    1998-01-01

    The peculiarities of adrenal glucocorticoid function and membrane potential (MP) of zona fasciculata adrenocorticocyte (ACC) in rats after chronic x-ray exposure was studied. The changes of adrenal glucocorticoid function caused by chronic x-ray exposure within a relatively small period of irradiation (1.5 months) are obscure and manifest themselves only at physiological load. With the prolongation of the period (8 and 15 months), more considerable inhibition of the adrenal glucocorticoid function and disturbances in the membrane mechanisms of ACC MP level regulation are revealed

  2. OSTEOPENIA in cancellous bone of sheep induced by Glucocorticoid alone

    DEFF Research Database (Denmark)

    Ding, Ming; Cheng, L.; Bollen, Peter

    2008-01-01

    Introduction: There is a great need for suitable large animal models that closely resemble osteoporosis in humans, and that they have adequate bone size for bone prosthesis and biomaterial research. Previous investigations have shown that osteoporotic sheep model requires glucocorticoid (GC......) microarchitectural properties and mechanical properties of sheep cancellous bone after a 7 months steroid treatment; and thus to validate a large animal model for orthopaedic implant/biomaterial research. Materials and Methods: Eighteen female sheep were randomly allocated into 3 groups: group 1 (GC-1) received GC......, osteocalcin was significantly reduced after 7 months but a rebound phenomenon was observed 3 months after cessation of GC. In conclusion, this study has validated an osteopenia sheep model. Bone quality was significantly reduced following a 7 months GC-treatment and recovered after further 3 month observation...

  3. Glucocorticoid: A potential role in microgravity-induced bone loss

    Science.gov (United States)

    Yang, Jiancheng; Yang, Zhouqi; Li, Wenbin; Xue, Yanru; Xu, Huiyun; Li, Jingbao; Shang, Peng

    2017-11-01

    Exposure of animals and humans to conditions of microgravity, including actual spaceflight and simulated microgravity, results in numerous negative alterations to bone structure and mechanical properties. Although there are abundant researches on bone loss in microgravity, the explicit mechanism is not completely understood. At present, it is widely accepted that the absence of mechanical stimulus plays a predominant role in bone homeostasis disorders in conditions of weightlessness. However, aside from mechanical unloading, nonmechanical factors such as various hormones, cytokines, dietary nutrition, etc. are important as well in microgravity induced bone loss. The stress-induced increase in endogenous glucocorticoid (GC) levels is inevitable in microgravity environments. Moreover, it is well known that GCs have a detrimental effect to bone health at excess concentrations. Therefore, GC plays a potential role in microgravity-induced bone loss. This review summarizeds several studies and their prospective solutions to this hypothesis.

  4. Methodological considerations for measuring glucocorticoid metabolites in feathers

    Science.gov (United States)

    Berk, Sara A.; McGettrick, Julie R.; Hansen, Warren K.; Breuner, Creagh W.

    2016-01-01

    In recent years, researchers have begun to use corticosteroid metabolites in feathers (fCORT) as a metric of stress physiology in birds. However, there remain substantial questions about how to measure fCORT most accurately. Notably, small samples contain artificially high amounts of fCORT per millimetre of feather (the small sample artefact). Furthermore, it appears that fCORT is correlated with circulating plasma corticosterone only when levels are artificially elevated by the use of corticosterone implants. Here, we used several approaches to address current methodological issues with the measurement of fCORT. First, we verified that the small sample artefact exists across species and feather types. Second, we attempted to correct for this effect by increasing the amount of methanol relative to the amount of feather during extraction. We consistently detected more fCORT per millimetre or per milligram of feather in small samples than in large samples even when we adjusted methanol:feather concentrations. We also used high-performance liquid chromatography to identify hormone metabolites present in feathers and measured the reactivity of these metabolites against the most commonly used antibody for measuring fCORT. We verified that our antibody is mainly identifying corticosterone (CORT) in feathers, but other metabolites have significant cross-reactivity. Lastly, we measured faecal glucocorticoid metabolites in house sparrows and correlated these measurements with corticosteroid metabolites deposited in concurrently grown feathers; we found no correlation between faecal glucocorticoid metabolites and fCORT. We suggest that researchers should be cautious in their interpretation of fCORT in wild birds and should seek alternative validation methods to examine species-specific relationships between environmental challenges and fCORT. PMID:27335650

  5. Inflammation in Parkinson’s disease: Role of glucocorticoids

    Directory of Open Access Journals (Sweden)

    Maria Trinidad eHerrero

    2015-04-01

    Full Text Available Chronic inflammation is a major characteristic feature of Parkinson’s disease (PD. Studies in PDpatients show evidence of augmented levels of potent pro-inflammatory molecules e.g. TNF-α, iNOS,IL-1β whereas in experimental Parkinsonism it has been consistently demonstrated that dopaminergicneurons are particularly vulnerable to activated glia releasing these toxic factors. Recent geneticstudies point to the role of immune system in the etiology of PD, thus in combination withenvironmental factors, both peripheral and CNS-mediated immune responses could play importantroles in onset and progression of PD. Whereas microglia, astrocytes and infiltrating T cells are knownto mediate chronic inflammation, the roles of other immune-competent cells are less well understood.Inflammation is a tightly controlled process. One major effector system of regulation is HPA axis.Glucocorticoids released from adrenal glands upon stimulation of HPA axis, in response to either cellinjury or presence of pathogen, activate their receptor, GR. GR regulates inflammation both throughdirect transcriptional action on target genes and by indirectly inhibiting transcriptional activities oftranscriptional factors such as NF-kB, AP-1 or interferon regulatory factors. In PD patients, the HPAaxis is unbalanced and the cortisol levels are significantly increased, implying a deregulation of GRfunction in immune cells. In experimental Parkinsonism, the activation of microglial GR has a crucialeffect in diminishing microglial cell activation and reducing dopaminergic degeneration. Moreover,glucocorticoids are also known to regulate human brain vasculature as well as blood brain barrierpermeability, any dysfunction in their actions may influence infiltration of cytotoxic moleculesresulting in increased vulnerability of dopamine neurons in PD. Overall, deregulation ofGR actions is likely important in dopamine neuron degeneration throughestablishment of chronic inflammation.

  6. Efficacy and safety of canagliflozin when used in conjunction with incretin-mimetic therapy in patients with type 2 diabetes

    NARCIS (Netherlands)

    Fulcher, G.; Matthews, D. R.; Perkovic, V.; de Zeeuw, D.; Mahaffey, K. W.; Mathieu, C.; Woo, V.; Wysham, C.; Capuano, G.; Desai, M.; Shaw, W.; Vercruysse, F.; Meininger, G.; Neal, B.

    Aims: To assess the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes enrolled in the CANagliflozin cardioVascular Assessment Study (CANVAS) who were on an incretin mimetic [dipeptidyl peptidase-4 (DPP-4) inhibitor or

  7. L-Eye to Me: The Combined Role of Need for Cognition and Facial Trustworthiness in Mimetic Desires

    Science.gov (United States)

    Treinen, Evelyne; Corneille, Olivier; Luypaert, Gaylord

    2012-01-01

    Recent studies showed that stimuli are evaluated more favourably when they are perceived to capture others' attention, an effect coined "mimetic desire". The aim of the present research was to examine the combined role of Need for Cognition and target's facial trustworthiness in this effect. Participants saw movie excerpts of trustworthy and…

  8. Apolipoprotein A-1 mimetic peptide 4F promotes endothelial repairing and compromises reendothelialization impaired by oxidized HDL through SR-B1

    Directory of Open Access Journals (Sweden)

    Dan He

    2018-05-01

    Full Text Available Disruption of endothelial monolayer integrity is the primary instigating factor for many cardiovascular diseases. High density lipoprotein (HDL oxidized by heme enzyme myeloperoxidase (MPO is dysfunctional in promoting endothelial repair. Apolipoprotein A-1 mimetic 4F with its pleiotropic benefits has been proven effective in many in vivo models. In this study we investigated whether 4F promotes endothelial repair and restores the impaired function of oxidized HDL (Cl/NO2-HDL in promoting re-endothelialization. We demonstrate that 4F and Cl/NO2-HDL act on scavenger receptor type I (SR-B1 using human aorta endothelial cells (HAEC and SR-B1 (-/- mouse aortic endothelial cells. Wound healing, transwell migration, lamellipodia formation and single cell migration assay experiments show that 4F treatment is associated with a recovery of endothelial cell migration and associated with significantly increased endothelial nitric oxide synthase (eNOS activity, Akt phosphorylation and SR-B1 expression. 4F increases NO generation and diminishes oxidative stress. In vivo, 4F can stimulate cell proliferation and re-endothelialization in the carotid artery after treatment with Cl/NO2-HDL in a carotid artery electric injury model but fails to do so in SR-B1(-/- mice. These findings demonstrate that 4F promotes endothelial cell migration and has a potential therapeutic benefit against early endothelial injury in cardiovascular diseases.

  9. Apolipoprotein E-Mimetic Peptide COG1410 Promotes Autophagy by Phosphorylating GSK-3β in Early Brain Injury Following Experimental Subarachnoid Hemorrhage

    Directory of Open Access Journals (Sweden)

    Xinshen Li

    2018-03-01

    Full Text Available COG1410, a mimetic peptide derived from the apolipoprotein E (apoE receptor binding region, exerts positive effect on neurological deficits in early brain injury (EBI after experimental subarachnoid hemorrhage (SAH. Currently the neuroprotective effect of COG1410 includes inhibiting BBB disruption, reducing neuronal apoptosis, and neuroinflammation. However, the effect and mechanism of COG1410 to subcellular organelles disorder have not been fully investigated. As the main pathway for recycling long-lived proteins and damaged organelles, neuronal autophagy is activated in SAH and exhibits neuroprotective effects by reducing the insults of EBI. Pharmacologically elevated autophagy usually contributes to alleviated brain injury, while few of the agents achieved clinical transformation. In this study, we explored the activation of autophagy during EBI by measuring the Beclin-1 and LC3B-II protein levels. Administration of COG1410 notably elevated the autophagic markers expression in neurons, simultaneously reversed the neurological deficits. Furthermore, the up-regulated autophagy by COG1410 was further promoted by p-GSK-3β agonist, whereas decreased by p-GSK-3β inhibitor. Taken together, these data suggest that the COG1410 might be a promising therapeutic strategy for EBI via promoting autophagy in SAH.

  10. In silico-designed novel non-peptidic ABAD LD hot spot mimetics reverse Aβ-induced mitochondrial impairments in vitro.

    Science.gov (United States)

    Viswanath, Ambily Nath Indu; Kim, TaeHun; Jung, Seo Yun; Lim, Sang Min; Pae, Ae Nim

    2017-12-01

    Present work aimed to introduce non-peptidic ABAD loop D (L D ) hot spot mimetics as ABAD-Aβ inhibitors. A full-length atomistic model of ABAD-Aβ complex was built as a scaffold to launch the lead design and its topology later verified by cross-checking the computational mutagenesis results with that of in vitro data. Thereafter, the interactions of prime Aβ-binding L D residues-Tyr101, Thr108, and Thr110-were translated into specific pharmacophore features and this hypothesis subsequently used as a virtual screen query. ELISA-based screening of 20 hits identified two promising lead candidates, VC15 and VC19 with an IC 50 of 4.4 ± 0.3 and 9.6 ± 0.1 μm, respectively. They productively reversed Aβ-induced mitochondrial dysfunctions such as mitochondrial membrane potential loss (JC-1 assay), toxicity (MTT assay), and ATP reduction (ATP assay) in addition to increased cell viabilities. This is the first reporting of L D hot spot-centric in silico scheme to discover novel compounds with promising ABAD-Aβ inhibitory potential. These chemotypes are proposed for further structural optimization to derive novel Alzheimer's disease (AD) therapeutics. © 2017 John Wiley & Sons A/S.

  11. Fibronectin- and collagen-mimetic ligands regulate bone marrow stromal cell chondrogenesis in three-dimensional hydrogels

    Directory of Open Access Journals (Sweden)

    JT Connelly

    2011-09-01

    Full Text Available Modification of tissue engineering scaffolds with bioactive molecules is a potential strategy for modulating cell behavior and guiding tissue regeneration. While adhesion to RGD peptides has been shown to inhibit in vitro chondrogenesis, the effects of extracellular matrix (ECM-mimetic ligands with complex secondary and tertiary structures are unknown. This study aimed to determine whether collagen- and fibronectin-mimetic ligands would retain biologic functionality in three-dimensional (3D hydrogels, whether different ECM-mimetic ligands differentially influence in vitro chondrogenesis, and if effects of ligands on differentiation depend on soluble biochemical stimuli. A linear RGD peptide, a recombinant fibronectin fragment containing the seven to ten Type III repeats (FnIII7-10 and a triple helical, collagen mimetic peptide with the GFOGER motif were covalently coupled to agarose gels using the sulfo-SANPAH crosslinker, and bone marrow stromal cells (BMSCs were cultured within the 3D hydrogels. The ligands retained biologic functionality within the agarose gels and promoted density-dependent BMSC spreading. Interactions with all adhesive ligands inhibited stimulation by chondrogenic factors of collagen Type II and aggrecan mRNA levels and deposition of sulfated glycosaminoglycans. In medium containing fetal bovine serum, interactions with the GFOGER peptide enhanced mRNA expression of the osteogenic gene osteocalcin whereas FnIII7-10 inhibited osteocalcin expression. In conclusion, modification of agarose hydrogels with ECM-mimetic ligands can influence the differentiation of BMSCs in a manner that depends strongly on the presence and nature of soluble biochemical stimuli.

  12. Effects of an Aβ-antibody fragment on Aβ aggregation and astrocytic uptake are modulated by apolipoprotein E and J mimetic peptides.

    Directory of Open Access Journals (Sweden)

    Laia Montoliu-Gaya

    Full Text Available Aβ-Immunotherapy has long been studied in the treatment of Alzheimer's disease (AD, but not how other molecules involved in the disease can affect antibody performance. We previously designed an antibody fragment, scFv-h3D6, and showed that it precludes Aβ-induced cytotoxicity by withdrawing Aβ oligomers from the amyloid pathway towards a non-toxic, worm-like pathway. ScFv-h3D6 was effective at the behavioral, cellular, and molecular levels in the 3xTg-AD mouse model. Because scFv-h3D6 treatment restored apolipoprotein E (apoE and J (apoJ concentrations to non-pathological values, and Aβ internalization by glial cells was found to be decreased in the presence of these apolipoproteins, we now aimed to test the influence of scFv-h3D6 on Aβ aggregation and cellular uptake by primary human astrocytes in the presence of therapeutic apoE and apoJ mimetic peptides (MPs. Firstly, we demonstrated by CD and FTIR that the molecules used in this work were well folded. Next, interactions between apoE or apoJ-MP, scFv-h3D6 and Aβ were studied by CD. The conformational change induced by the interaction of Aβ with apoE-MP was much bigger than the induced with apoJ-MP, in line with the observed formation of protective worm-like fibrils by the scFv-h3D6/Aβ complex in the presence of apoJ-MP, but not of apoE-MP. ScFv-h3D6, apoJ-MP, and apoE-MP to a different extent reduced Aβ uptake by astrocytes, and apoE-MP partially interfered with the dramatic reduction by scFv-h3D6 while apoJ-MP had no effect on scFv-h3D6 action. As sustained Aβ uptake by astrocytes may impair their normal functions, and ultimately neuronal viability, this work shows another beneficence of scFv-h3D6 treatment, which is not further improved by the use of apoE or apoJ mimetic peptides.

  13. Decreased plasma cholesterol esterification and cholesteryl ester transfer in hypopituitary patients on glucocorticoid replacement therapy

    NARCIS (Netherlands)

    Beentjes, JAM; Van Tol, A; Sluiter, WJ; Dullaart, RPF

    Cardiovascular risk is increased in hypopituitary patients. No data are available with respect to the effect of glucocorticoid replacement therapy on high density lipoproteins (HDL) metabolism in such patients. Plasma lecithin:choresterol acyl transferase (LCAT), cholesteryl ester transfer protein

  14. Glucocorticoid and cytokine crosstalk: Feedback, feedforward, and co-regulatory interactions determine repression or resistance.

    Science.gov (United States)

    Newton, Robert; Shah, Suharsh; Altonsy, Mohammed O; Gerber, Antony N

    2017-04-28

    Inflammatory signals induce feedback and feedforward systems that provide temporal control. Although glucocorticoids can repress inflammatory gene expression, glucocorticoid receptor recruitment increases expression of negative feedback and feedforward regulators, including the phosphatase, DUSP1, the ubiquitin-modifying enzyme, TNFAIP3, or the mRNA-destabilizing protein, ZFP36. Moreover, glucocorticoid receptor cooperativity with factors, including nuclear factor-κB (NF-κB), may enhance regulator expression to promote repression. Conversely, MAPKs, which are inhibited by glucocorticoids, provide feedforward control to limit expression of the transcription factor IRF1, and the chemokine, CXCL10. We propose that modulation of feedback and feedforward control can determine repression or resistance of inflammatory gene expression toglucocorticoid. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  15. The effects of glucocorticoid on microarchitecture, collagen, mineral and mechanical properties of sheep femur cortical bone

    DEFF Research Database (Denmark)

    Ding, Ming; Danielsen, Carl C; Overgaard, Søren

    2010-01-01

    The effects of glucocorticoid on microarchitecture, collagen, mineral and mechanical properties of sheep femur cortical bone – Validation of large animal model for tissue engineering and biomaterial research Ming Ding,1* Carl Christian Danielsen,2 Søren Overgaard1 1Orthopaedic Research Laboratory......, Department of Orthopaedics and Traumatology, Odense University Hospital, Institute of Clinical Research, University of Southern Denmark, Odense C, Denmark 2Department of Connective Tissue Biology, Institute of Anatomy, University of Aarhus, Aarhus C, Denmark Osteopenia in sheep has been successfully induced...... by glucocorticoid treatment and the changes in properties of cancellous bone were comparable with those observed in humans after long-term glucocorticoid treatment. However, the influence on cortical bone has not been thoroughly elucidated. This study aimed to investigate the influence of glucocorticoid on sheep...

  16. Regulation of hippocampal neurogenesis by systemic factors including stress, glucocorticoids, sleep, and inflammation

    NARCIS (Netherlands)

    Lucassen, P.J.; Oomen, C.; van Dam, A.-M.; Czéh, B.; Gage, F.H.; Kempermann, G.; Song, H.

    2008-01-01

    This review summarizes and discusses the regulation of adult neurogenesis and hippocampal cellular plasticity by systemic factors. We focus on the role of stress, glucocorticoids, and related factors such as sleep deprivation and inflammation.

  17. Stress, glucocorticoids and memory: implications for treating fear-related disorders.

    Science.gov (United States)

    de Quervain, Dominique; Schwabe, Lars; Roozendaal, Benno

    2017-01-01

    Glucocorticoid stress hormones are crucially involved in modulating mnemonic processing of emotionally arousing experiences. They enhance the consolidation of new memories, including those that extinguish older memories, but impair the retrieval of information stored in long-term memory. As strong aversive memories lie at the core of several fear-related disorders, including post-traumatic stress disorder and phobias, the memory-modulating properties of glucocorticoids have recently become of considerable translational interest. Clinical trials have provided the first evidence that glucocorticoid-based pharmacotherapies aimed at attenuating aversive memories might be helpful in the treatment of fear-related disorders. Here, we review important advances in the understanding of how glucocorticoids mediate stress effects on memory processes, and discuss the translational potential of these new conceptual insights.

  18. Memory consolidation in human sleep depends on inhibition of glucocorticoid release.

    Science.gov (United States)

    Plihal, W; Born, J

    1999-09-09

    Early sleep dominated by slow-wave sleep has been found to be particularly relevant for declarative memory formation via hippocampo-neocortical networks. Concurrently, early nocturnal sleep is characterized by an inhibition of glucocorticoid release from the adrenals. Here, we show in healthy humans that this inhibition serves to support declarative memory consolidation during sleep. Elevating plasma glucocorticoid concentration during early sleep by administration of cortisol impaired consolidation of paired associate words, but not of non-declarative memory of visuomotor skills. Since glucocorticoid concentration was enhanced only during retention sleep, but not during acquisition or retrieval, a specific effect on the consolidation process is indicated. Blocking mineralocorticoid receptors by canrenoate did not affect memory, suggesting inactivation of glucocorticoid receptors to be the essential prerequisite for memory consolidation during early sleep.

  19. The different roles of glucocorticoids in the hippocampus and hypothalamus in chronic stress-induced HPA axis hyperactivity.

    Directory of Open Access Journals (Sweden)

    Li-Juan Zhu

    Full Text Available Hypothalamus-pituitary-adrenal (HPA hyperactivity is observed in many patients suffering from depression and the mechanism underling the dysfunction of HPA axis is not well understood. Chronic stress has a causal relationship with the hyperactivity of HPA axis. Stress induces the over-synthesis of glucocorticoids, which will arrive at all the body containing the brain. It is still complicated whether glucocorticoids account for chronic stress-induced HPA axis hyperactivity and in which part of the brain the glucocorticoids account for chronic stress-induced HPA axis hyperactivity. Here, we demonstrated that glucocorticoids were indispensable and sufficient for chronic stress-induced hyperactivity of HPA axis. Although acute glucocorticoids elevation in the hippocampus and hypothalamus exerted a negative regulation of HPA axis, we found that chronic glucocorticoids elevation in the hippocampus but not in the hypothalamus accounted for chronic stress-induced hyperactivity of HPA axis. Chronic glucocorticoids exposure in the hypothalamus still exerted a negative regulation of HPA axis activity. More importantly, we found mineralocorticoid receptor (MR - neuronal nitric oxide synthesis enzyme (nNOS - nitric oxide (NO pathway mediated the different roles of glucocorticoids in the hippocampus and hypothalamus in regulating HPA axis activity. This study suggests that the glucocorticoids in the hippocampus play an important role in the development of HPA axis hyperactivity and the glucocorticoids in the hypothalamus can't induce hyperactivity of HPA axis, revealing new insights into understanding the mechanism of depression.

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

    Science.gov (United States)

    Petersen, Irene; Nazareth, Irwin

    2012-01-01

    Objective To investigate whether there is an increased risk of cardiovascular events in people who exhibit iatrogenic Cushing’s syndrome during treatment with glucocorticoids. Design Cohort study. Setting 424 UK general practices contributing to The Health Improvement Network database. Participants People prescribed systemic glucocorticoids and with a diagnosis of iatrogenic Cushing’s syndrome (n=547) and two comparison groups: those prescribed glucocorticoids and with no diagnosis of iatrogenic Cushing’s syndrome (n=3231) and those not prescribed systemic glucocorticoids (n=3282). Main outcome measures Incidence of cardiovascular events within a year after diagnosis of iatrogenic Cushing’s syndrome or after a randomly selected date, and association between iatrogenic Cushing’s syndrome and risk of cardiovascular events. Results 417 cardiovascular events occurred in 341 patients. Taking into account only the first event by patient (coronary heart disease n=177, heart failure n=101, ischaemic stroke n=63), the incidence rates of cardiovascular events per 100 person years at risk were 15.1 (95% confidence interval 11.8 to 18.4) in those prescribed glucocorticoids and with a diagnosis of iatrogenic Cushing’s syndrome, 6.4 (5.5 to 7.3) in those prescribed glucocorticoids without a diagnosis of iatrogenic Cushing’s syndrome, and 4.1 (3.4 to 4.8) in those not prescribed glucocorticoids. In multivariate analyses adjusted for sex, age, intensity of glucocorticoid use, underlying disease, smoking status, and use of aspirin, diabetes drugs, antihypertensive drugs, lipid lowering drugs, or oral anticoagulant drugs, the relation between iatrogenic Cushing’s syndrome and cardiovascular events was strong (adjusted hazard ratios 2.27 (95% confidence interval 1.48 to 3.47) for coronary heart disease, 3.77 (2.41 to 5.90) for heart failure, and 2.23 (0.96 to 5.17) for ischaemic cerebrovascular events). The adjusted hazard ratio for any cardiovascular event was 4

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

    Science.gov (United States)

    Fardet, Laurence; Petersen, Irene; Nazareth, Irwin

    2012-07-30

    To investigate whether there is an increased risk of cardiovascular events in people who exhibit iatrogenic Cushing's syndrome during treatment with glucocorticoids. Cohort study. 424 UK general practices contributing to The Health Improvement Network database. People prescribed systemic glucocorticoids and with a diagnosis of iatrogenic Cushing's syndrome (n = 547) and two comparison groups: those prescribed glucocorticoids and with no diagnosis of iatrogenic Cushing's syndrome (n = 3231) and those not prescribed systemic glucocorticoids (n = 3282). Incidence of cardiovascular events within a year after diagnosis of iatrogenic Cushing's syndrome or after a randomly selected date, and association between iatrogenic Cushing's syndrome and risk of cardiovascular events. 417 cardiovascular events occurred in 341 patients. Taking into account only the first event by patient (coronary heart disease n = 177, heart failure n = 101, ischaemic stroke n = 63), the incidence rates of cardiovascular events per 100 person years at risk were 15.1 (95% confidence interval 11.8 to 18.4) in those prescribed glucocorticoids and with a diagnosis of iatrogenic Cushing's syndrome, 6.4 (5.5 to 7.3) in those prescribed glucocorticoids without a diagnosis of iatrogenic Cushing's syndrome, and 4.1 (3.4 to 4.8) in those not prescribed glucocorticoids. In multivariate analyses adjusted for sex, age, intensity of glucocorticoid use, underlying disease, smoking status, and use of aspirin, diabetes drugs, antihypertensive drugs, lipid lowering drugs, or oral anticoagulant drugs, the relation between iatrogenic Cushing's syndrome and cardiovascular events was strong (adjusted hazard ratios 2.27 (95% confidence interval 1.48 to 3.47) for coronary heart disease, 3.77 (2.41 to 5.90) for heart failure, and 2.23 (0.96 to 5.17) for ischaemic cerebrovascular events). The adjusted hazard ratio for any cardiovascular event was 4.16 (2.98 to 5.82) when the group prescribed glucocorticoids and with

  2. Cellular and biochemical actions of adrenal glucocorticoid hormones on rat thymic lymphocytes.

    OpenAIRE

    Young, D A; Voris, B P; Nicholson, M L

    1981-01-01

    The molecular, biochemical, and cellular effects of adrenal glucocorticoid hormones on thymic lymphocytes are reviewed, with emphasis on their relationship to the growth suppressive and lethal actions that occur in lymphoid tissues when glucocorticoids are administered to the whole animal. The data support the hypothesis that the hormonal inhibition of growth and development is a consequence of its ability to suppress cellular energy production, causing the cells to behave as though they were...

  3. Safety aspects of preoperative high-dose glucocorticoid in primary total knee replacement

    DEFF Research Database (Denmark)

    Jørgensen, C C; Pitter, F T; Kehlet, H

    2017-01-01

    Background: Preoperative single high-dose glucocorticoid may have early outcome benefits in total hip arthroplasty (THA) and knee arthroplasty (TKA), but long-term safety aspects have not been evaluated. Methods: From October 2013, the departments reporting to the prospective Lundbeck Foundation....... Conclusions: In this detailed prospective cohort study, preoperative high-dose glucocorticoid administration was not associated with LOS >4 days, readmissions or infectious complications in TKA patients without contraindications....

  4. Synovial DKK1 expression is regulated by local glucocorticoid metabolism in inflammatory arthritis

    OpenAIRE

    Hardy, Rowan; Juarez, Maria; Naylor, Amy; Tu, Jinwen; Rabbitt, Elizabeth H; Filer, Andrew; Stewart, Paul M; Buckley, Christopher D; Raza, Karim; Cooper, Mark S

    2012-01-01

    Introduction: Inflammatory arthritis is associated with increased bone resorption and suppressed bone formation. The Wnt antagonist dickkopf-1 (DKK1) is secreted by synovial fibroblasts in response to inflammation and this protein has been proposed to be a master regulator of bone remodelling in inflammatory arthritis. Local glucocorticoid production is also significantly increased during joint inflammation. Therefore, we investigated how locally derived glucocorticoids and inflammatory cytok...

  5. Glucocorticoids have state-dependent stimulant effects on the mesencephalic dopaminergic transmission.

    OpenAIRE

    Piazza, P V; Rougé-Pont, F; Deroche, V; Maccari, S; Simon, H; Le Moal, M

    1996-01-01

    An increase in the activity of mesencephalic dopaminergic neurons has been implicated in the appearance of pathological behaviors such as psychosis and drug abuse. Several observations suggest that glucocorticoids might contribute to such an increase in dopaminergic activity. The present experiments therefore analyzed the effects of corticosterone, the major glucocorticoid in the rat, both on dopamine release in the nucleus accumbens of freely moving animals by means of microdialysis, and on ...

  6. Glucocorticoid effects on object recognition memory require training-associated emotional arousal

    OpenAIRE

    Okuda, Shoki; Roozendaal, Benno; McGaugh, James L.

    2004-01-01

    Considerable evidence implicates glucocorticoid hormones in the regulation of memory consolidation and memory retrieval. The present experiments investigated whether the influence of these hormones on memory depends on the level of emotional arousal induced by the training experience. We investigated this issue in male Sprague–Dawley rats by examining the effects of immediate posttraining systemic injections of the glucocorticoid corticosterone on object recognition memory under two condition...

  7. Preadmission glucocorticoid use and anastomotic leakage after colon and rectal cancer resections: a Danish cohort study

    Science.gov (United States)

    Ostenfeld, Eva Bjerre; Erichsen, Rune; Baron, John A; Thorlacius-Ussing, Ole; Iversen, Lene Hjerrild; Riis, Anders H; Sørensen, Henrik Toft

    2015-01-01

    Objective To examine whether preadmission glucocorticoid use increases the risk of anastomotic leakage after colon and rectal cancer resections. Design A population-based cohort study. Setting Denmark (2001–2011). Participants We identified patients who had undergone a primary anastomosis after a colorectal cancer resection by linking medical registries. Participants who filled their most recent glucocorticoid prescription ≤90, 91–365 and >365 days before their surgery date were categorised as current, recent and former users, respectively. Main outcome measures We calculated 30-day absolute risk of anastomotic leakage and computed ORs using logistic regression models with adjustment for potential confounders. Results Of the 18 190 patients with colon cancer, anastomotic leakage occurred in 1184 (6.5%). Glucocorticoid use overall was not associated with an increased risk of leakage (6.4% vs 6.9% among never-users; OR 1.05; 95% CI 0.89 to 1.23). Categories of oral, inhaled or intestinal-acting glucocorticoids did not greatly affect risk of leakage. Anastomotic leakage occurred in 695 (13.2%) of 5284 patients with rectal cancer. Glucocorticoid use overall slightly increased risk of leakage (14.6% vs 12.8% among never-users; OR 1.36, 95% CI 1.08 to 1.72). Results did not differ significantly within glucocorticoid categories. Conclusions Preadmission glucocorticoids modestly increased the risk of anastomotic leakage mainly after rectal cancer resection. However, absolute risk differences were small and the clinical impact of glucocorticoid use may therefore be limited. PMID:26408282

  8. Endocannabinoids in the rat basolateral amygdala enhance memory consolidation and enable glucocorticoid modulation of memory

    OpenAIRE

    Campolongo, Patrizia; Roozendaal, Benno; Trezza, Viviana; Hauer, Daniela; Schelling, Gustav; McGaugh, James L.; Cuomo, Vincenzo

    2009-01-01

    Extensive evidence indicates that the basolateral complex of the amygdala (BLA) modulates the consolidation of memories for emotionally arousing experiences, an effect that involves the activation of the glucocorticoid system. Because the BLA expresses high densities of cannabinoid CB1 receptors, the present experiments investigated whether the endocannabinoid system in the BLA influences memory consolidation and whether glucocorticoids interact with this system. The CB1 receptor agonist WIN5...

  9. 11beta-hydroxysteroid dehydrogenase type 1 regulates glucocorticoid-induced insulin resistance in skeletal muscle.

    LENUS (Irish Health Repository)

    Morgan, Stuart A

    2009-11-01

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

  10. Do the interactions between glucocorticoids and sex hormones regulate the development of the Metabolic Syndrome?

    Directory of Open Access Journals (Sweden)

    Marià eAlemany

    2012-02-01

    Full Text Available The metabolic syndrome is basically a maturity-onset disease. Typically, its manifestations begin to flourish years after the initial dietary or environmental aggression began. Since most hormonal, metabolic or defense responses are practically immediate, the procrastinated response don't seem justified. Only in childhood, the damages of the metabolic syndrome appear with minimal delay. Sex affects the incidence of the metabolic syndrome, but this is more an effect of timing than absolute gender differences, females holding better than males up to menopause, when the differences between sexes tend to disappear. The metabolic syndrome is related to an immune response, countered by a permanent increase in glucocorticoids, which keep the immune system at bay but also induce insulin resistance, alter the lipid metabolism, favor fat deposition, mobilize protein and decrease androgen synthesis. Androgens limit the operation of glucocorticoids, which is also partly blocked by estrogens, since they decrease inflammation (which enhances glucocorticoid release. These facts suggest that the appearance of the metabolic syndrome symptoms depends on the strength (i.e. levels of androgens and estrogens. The predominance of glucocorticoids and the full manifestation of the syndrome in men are favored by decreased androgen activity. Low androgens can be found in infancy, maturity, advanced age, or because of their inhibition by glucocorticoids (inflammation, stress, medical treatment. Estrogens decrease inflammation and reduce the glucocorticoid response. Low estrogen (infancy, menopause again allow the predominance of glucocorticoids and the manifestation of the metabolic syndrome. It is postulated that the equilibrium between sex hormones and glucocorticoids may be a critical element in the timing of the manifestation of metabolic syndrome-related pathologies.

  11. Peripheral CLOCK regulates target-tissue glucocorticoid receptor transcriptional activity in a circadian fashion in man.

    Directory of Open Access Journals (Sweden)

    Evangelia Charmandari

    Full Text Available Circulating cortisol fluctuates diurnally under the control of the "master" circadian CLOCK, while the peripheral "slave" counterpart of the latter regulates the transcriptional activity of the glucocorticoid receptor (GR at local glucocorticoid target tissues through acetylation. In this manuscript, we studied the effect of CLOCK-mediated GR acetylation on the sensitivity of peripheral tissues to glucocorticoids in humans.We examined GR acetylation and mRNA expression of GR, CLOCK-related and glucocorticoid-responsive genes in peripheral blood mononuclear cells (PBMCs obtained at 8 am and 8 pm from 10 healthy subjects, as well as in PBMCs obtained in the morning and cultured for 24 hours with exposure to 3-hour hydrocortisone pulses every 6 hours. We used EBV-transformed lymphocytes (EBVLs as non-synchronized controls.GR acetylation was higher in the morning than in the evening in PBMCs, mirroring the fluctuations of circulating cortisol in reverse phase. All known glucocorticoid-responsive genes tested responded as expected to hydrocortisone in non-synchronized EBVLs, however, some of these genes did not show the expected diurnal mRNA fluctuations in PBMCs in vivo. Instead, their mRNA oscillated in a Clock- and a GR acetylation-dependent fashion in naturally synchronized PBMCs cultured ex vivo in the absence of the endogenous glucocorticoid, suggesting that circulating cortisol might prevent circadian GR acetylation-dependent effects in some glucocorticoid-responsive genes in vivo.Peripheral CLOCK-mediated circadian acetylation of the human GR may function as a target-tissue, gene-specific counter regulatory mechanism to the actions of diurnally fluctuating cortisol, effectively decreasing tissue sensitivity to glucocorticoids in the morning and increasing it at night.

  12. Peripheral CLOCK Regulates Target-Tissue Glucocorticoid Receptor Transcriptional Activity in a Circadian Fashion in Man

    Science.gov (United States)

    Charmandari, Evangelia; Chrousos, George P.; Lambrou, George I.; Pavlaki, Aikaterini; Koide, Hisashi; Ng, Sinnie Sin Man; Kino, Tomoshige

    2011-01-01

    Context and Objective Circulating cortisol fluctuates diurnally under the control of the “master” circadian CLOCK, while the peripheral “slave” counterpart of the latter regulates the transcriptional activity of the glucocorticoid receptor (GR) at local glucocorticoid target tissues through acetylation. In this manuscript, we studied the effect of CLOCK-mediated GR acetylation on the sensitivity of peripheral tissues to glucocorticoids in humans. Design and Participants We examined GR acetylation and mRNA expression of GR, CLOCK-related and glucocorticoid-responsive genes in peripheral blood mononuclear cells (PBMCs) obtained at 8 am and 8 pm from 10 healthy subjects, as well as in PBMCs obtained in the morning and cultured for 24 hours with exposure to 3-hour hydrocortisone pulses every 6 hours. We used EBV-transformed lymphocytes (EBVLs) as non-synchronized controls. Results GR acetylation was higher in the morning than in the evening in PBMCs, mirroring the fluctuations of circulating cortisol in reverse phase. All known glucocorticoid-responsive genes tested responded as expected to hydrocortisone in non-synchronized EBVLs, however, some of these genes did not show the expected diurnal mRNA fluctuations in PBMCs in vivo. Instead, their mRNA oscillated in a Clock- and a GR acetylation-dependent fashion in naturally synchronized PBMCs cultured ex vivo in the absence of the endogenous glucocorticoid, suggesting that circulating cortisol might prevent circadian GR acetylation-dependent effects in some glucocorticoid-responsive genes in vivo. Conclusions Peripheral CLOCK-mediated circadian acetylation of the human GR may function as a target-tissue, gene-specific counter regulatory mechanism to the actions of diurnally fluctuating cortisol, effectively decreasing tissue sensitivity to glucocorticoids in the morning and increasing it at night. PMID:21980503

  13. Advances in the design and higher-order assembly of collagen mimetic peptides for regenerative medicine.

    Science.gov (United States)

    Strauss, Kevin; Chmielewski, Jean

    2017-08-01

    Regenerative medicine makes use of cell-supporting biomaterials to replace lost or damaged tissue. Collagen holds great potential in this regard caused by its biocompatibility and structural versatility. While natural collagen has shown promise for regenerative medicine, collagen mimetic peptides (CMPs) have emerged that allow far higher degrees of customization and ease of preparation. A wide range of two and three-dimensional assemblies have been generated from CMPs, many of which accommodate cellular adhesion and encapsulation, through careful sequence design and the exploitation of electrostatic and hydrophobic forces. But the methodology that has generated the greatest plethora of viable biomaterials is metal-promoted assembly of CMP triple helices-a rapid process that occurs under physiological conditions. Architectures generated in this manner promote cell growth, enable directed attachment of bioactive cargo, and produce living tissue. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Synthetic, structural mimetics of the β-hairpin flap of HIV-1 protease inhibit enzyme function.

    Science.gov (United States)

    Chauhan, Jay; Chen, Shen-En; Fenstermacher, Katherine J; Naser-Tavakolian, Aurash; Reingewertz, Tali; Salmo, Rosene; Lee, Christian; Williams, Emori; Raje, Mithun; Sundberg, Eric; DeStefano, Jeffrey J; Freire, Ernesto; Fletcher, Steven

    2015-11-01

    Small-molecule mimetics of the β-hairpin flap of HIV-1 protease (HIV-1 PR) were designed based on a 1,4-benzodiazepine scaffold as a strategy to interfere with the flap-flap protein-protein interaction, which functions as a gated mechanism to control access to the active site. Michaelis-Menten kinetics suggested our small-molecules are competitive inhibitors, which indicates the mode of inhibition is through binding the active site or sterically blocking access to the active site and preventing flap closure, as designed. More generally, a new bioactive scaffold for HIV-1PR inhibition has been discovered, with the most potent compound inhibiting the protease with a modest K(i) of 11 μM. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-11-15

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

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

    International Nuclear Information System (INIS)

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

    2013-01-01

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

  17. Effects of a single glucocorticoid injection on propylene glycol-treated cows with clinical ketosis.

    Science.gov (United States)

    van der Drift, Saskia G A; Houweling, Martin; Bouman, Marina; Koets, Ad P; Tielens, Aloysius G M; Nielen, Mirjam; Jorritsma, Ruurd

    2015-05-01

    This study investigated the metabolic effects of glucocorticoids when administered to propylene glycol-treated cows with clinical ketosis. Clinical ketosis was defined by depressed feed intake and milk production, and a maximal score for acetoacetate in urine. All cows received 250 mL oral propylene glycol twice daily for 3 days and were randomly assigned to a single intramuscular injection with sterile isotonic saline solution (n = 14) or dexamethasone-21-isonicotinate (n = 17). Metabolic blood variables were monitored for 6 days and adipose tissue variables for 3 days. β-Hydroxybutyrate (BHBA) concentrations in blood decreased in all cows during treatment, but were lower in glucocorticoid-treated cows. Cows treated with glucocorticoids had higher plasma glucose and insulin concentrations, whereas concentrations of non-esterified fatty acids, 3-methylhistidine and growth hormone were unaffected. mRNA expression of hormone-sensitive lipase, BHBA receptor and peroxisome proliferator-activated receptor type γ in adipose tissue was not affected. This shows that lipolytic effects do not appear to be important in ketotic cows when glucocorticoids are combined with PG. Plasma 3-methyl histidine concentrations were similar in both groups, suggesting that glucocorticoids did not increase muscle breakdown and that the greater rise in plasma glucose in glucocorticoid-treated cows may not be due to increased supply of glucogenic amino acids from muscle. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. Activated Glucocorticoid Receptor Interacts with the INHAT Component Set/TAF-Iβ and Releases it from a Glucocorticoid-responsive Gene Promoter, Relieving Repression: Implications for the Pathogenesis of Glucocorticoid Resistance in Acute Undifferentiated Leukemia with Set-Can Translocation

    Science.gov (United States)

    Ichijo, Takamasa; Chrousos, George P.; Kino, Tomoshige

    2008-01-01

    SUMMARY Set/template-activating factor (TAF)-Iβ, part of the Set-Can oncogene product found in acute undifferentiated leukemia, is a component of the inhibitor of acetyltransferases (INHAT) complex. Set/TAF-Iβ interacted with the DNA-binding domain of the glucocorticoid receptor (GR) in yeast two-hybrid screening, and repressed GR-induced transcriptional activity of a chromatin-integrated glucocorticoid-responsive and a natural promoter. Set/TAF-Iβ was co-precipitated with glucocorticoid response elements (GREs) of these promoters in the absence of dexamethasone, while addition of the hormone caused dissociation of Set/TAF-Iβ from and attraction of the p160-type coactivator GRIP1 to the promoter GREs. Set-Can fusion protein, on the other hand, did not interact with GR, was constitutively co-precipitated with GREs and suppressed GRIP1-induced enhancement of GR transcriptional activity and histone acetylation. Thus, Set/TAF-Iβ acts as a ligand-activated GR-responsive transcriptional repressor, while Set-Can does not retain physiologic responsiveness to ligand-bound GR, possibly contributing to the poor responsiveness of Set-Can-harboring leukemic cells to glucocorticoids. PMID:18096310

  19. Activated glucocorticoid receptor interacts with the INHAT component Set/TAF-Ibeta and releases it from a glucocorticoid-responsive gene promoter, relieving repression: implications for the pathogenesis of glucocorticoid resistance in acute undifferentiated leukemia with Set-Can translocation.

    Science.gov (United States)

    Ichijo, Takamasa; Chrousos, George P; Kino, Tomoshige

    2008-02-13

    Set/template-activating factor (TAF)-Ibeta, part of the Set-Can oncogene product found in acute undifferentiated leukemia, is a component of the inhibitor of acetyltransferases (INHAT) complex. Set/TAF-Ibeta interacted with the DNA-binding domain of the glucocorticoid receptor (GR) in yeast two-hybrid screening, and repressed GR-induced transcriptional activity of a chromatin-integrated glucocorticoid-responsive and a natural promoter. Set/TAF-Ibeta was co-precipitated with glucocorticoid response elements (GREs) of these promoters in the absence of dexamethasone, while addition of the hormone caused dissociation of Set/TAF-Ibeta from and attraction of the p160-type coactivator GRIP1 to the promoter GREs. Set-Can fusion protein, on the other hand, did not interact with GR, was constitutively co-precipitated with GREs and suppressed GRIP1-induced enhancement of GR transcriptional activity and histone acetylation. Thus, Set/TAF-Ibeta acts as a ligand-activated GR-responsive transcriptional repressor, while Set-Can does not retain physiologic responsiveness to ligand-bound GR, possibly contributing to the poor responsiveness of Set-Can-harboring leukemic cells to glucocorticoids.

  20. In Situ Enzymatically Generated Photoswitchable Oxidase Mimetics and Their Application for Colorimetric Detection of Glucose Oxidase.

    Science.gov (United States)

    Cao, Gen-Xia; Wu, Xiu-Ming; Dong, Yu-Ming; Li, Zai-Jun; Wang, Guang-Li

    2016-07-09

    In this study, a simple and amplified colorimetric assay is developed for the detection of the enzymatic activity of glucose oxidase (GOx) based on in situ formation of a photoswitchable oxidase mimetic of PO₄(3-)-capped CdS quantum dots (QDs). GOx catalyzes the oxidation of 1-thio-β-d-glucose to give 1-thio-β-d-gluconic acid which spontaneously hydrolyzes to β-d-gluconic acid and H₂S; the generated H₂S instantly reacts with Cd(2+) in the presence of Na₃PO₄ to give PO₄(3-)-stabilized CdS QDs in situ. Under visible-light (λ ≥ 400 nm) stimulation, the PO₄(3-)-capped CdS QDs are a new style of oxidase mimic derived by producing some active species, such as h⁺, (•)OH, O₂(•-) and a little H₂O₂, which can oxidize the typical substrate (3,3,5,5-tetramethylbenzydine (TMB)) with a color change. Based on the GOx-triggered growth of the oxidase mimetics of PO₄(3-)-capped CdS QDs in situ, we developed a simple and amplified colorimetric assay to probe the enzymatic activity of GOx. The proposed method allowed the detection of the enzymatic activity of GOx over the range from 25 μg/L to 50 mg/L with a low detection limit of 6.6 μg/L. We believe the PO₄(3-)-capped CdS QDs generated in situ with photo-stimulated enzyme-mimicking activity may find wide potential applications in biosensors.

  1. Early life trauma, depression and the glucocorticoid receptor gene--an epigenetic perspective.

    Science.gov (United States)

    Smart, C; Strathdee, G; Watson, S; Murgatroyd, C; McAllister-Williams, R H

    2015-12-01

    Hopes to identify genetic susceptibility loci accounting for the heritability seen in unipolar depression have not been fully realized. Family history remains the 'gold standard' for both risk stratification and prognosis in complex phenotypes such as depression. Meanwhile, the physiological mechanisms underlying life-event triggers for depression remain opaque. Epigenetics, comprising heritable changes in gene expression other than alterations of the nucleotide sequence, may offer a way to deepen our understanding of the aetiology and pathophysiology of unipolar depression and optimize treatments. A heuristic target for exploring the relevance of epigenetic changes in unipolar depression is the hypothalamic-pituitary-adrenal (HPA) axis. The glucocorticoid receptor (GR) gene (NR3C1) has been found to be susceptible to epigenetic modification, specifically DNA methylation, in the context of environmental stress such as early life trauma, which is an established risk for depression later in life. In this paper we discuss the progress that has been made by studies that have investigated the relationship between depression, early trauma, the HPA axis and the NR3C1 gene. Difficulties with the design of these studies are also explored. Future efforts will need to comprehensively address epigenetic natural histories at the population, tissue, cell and gene levels. The complex interactions between the epigenome, genome and environment, as well as ongoing nosological difficulties, also pose significant challenges. The work that has been done so far is nevertheless encouraging and suggests potential mechanistic and biomarker roles for differential DNA methylation patterns in NR3C1 as well as novel therapeutic targets.

  2. Eosinophil Resistance to Glucocorticoid-Induced Apoptosis is Mediated by the Transcription Factor NFIL3

    Science.gov (United States)

    Pazdrak, Konrad; Moon, Young; Straub, Christof; Stafford, Susan; Kurosky, Alexander

    2016-01-01

    The mainstay of asthma therapy, glucocorticoids (GCs) exert their therapeutic effects through the inhibition of inflammatory signaling and induction of eosinophil apoptosis. However, laboratory and clinical observations of GC-resistant asthma suggest that GCs' effects on eosinophil viability may depend on the state of eosinophil activation. In the present study we demonstrate that eosinophils stimulated with IL-5 show impaired prop-aptoptotic response to GCs. We sought to determine the contribution of GC-mediated transactivating (TA) and transrepressing (TR) pathways in modulation of activated eosinophils' response to GC by comparing their response to the selective GC receptor (GR) agonist Compound A (CpdA) devoid of TA activity to that upon treatment with Dexamethasone (Dex). IL-5-activated eosinophils showed contrasting responses to CpdA and Dex, as IL-5-treated eosinophils showed no increase in apoptosis compared to cells treated with Dex alone, while CpdA elicited an apoptotic response regardless of IL-5 stimulation. Proteomic analysis revealed that both Nuclear Factor IL-3 (NFIL3) and Map Kinase Phosphatase 1 (MKP1) were inducible by IL-5 and enhanced by Dex; however, CpdA had no effect on NFIL3 and MKP1 expression. We found that inhibiting NFIL3 with specific siRNA or by blocking the IL-5-inducible Pim-1 kinase abrogated the protective effect of IL-5 on Dex-induced apoptosis, indicating crosstalk between IL-5 anti-apoptotic pathways and GR-mediated TA signaling occurring via the NFIL3 molecule. Collectively, these results indicate that 1) GCs' TA pathway may support eosinophil viability in IL-5-stimulated cells through synergistic upregulation of NFIL3; and 2) functional inhibition of IL-5 signaling (anti-Pim1) or the use of selective GR agonists that don't upregulate NFIL3 may be effective strategies for the restoring pro-apoptotic effect of GCs on IL-5-activated eosinophils. PMID:26880402

  3. Emerging Role of Corticosteroid Binding Globulin in Glucocorticoid-driven Metabolic Disorders

    Directory of Open Access Journals (Sweden)

    Marie-Pierre Moisan

    2016-12-01

    Full Text Available Glucocorticoid hormones (GCs are critical for survival since they ensure energy supply necessary to the body in an ever challenging environment. GCs are known to act on appetite, glucose metabolism, fatty acid metabolism and storage. However, in order to be beneficial to the body, GC levels should be maintained in an optimal window of concentrations. Not surprisingly, conditions of GC excess or deficiency, e.g. Cushing’s syndrome or Addison’s disease are associated with severe alterations of energy metabolism. Corticosteroid Binding Globulin (CBG, through its high specific affinity for GCs, plays a critical role in regulating plasma GC levels. Genetic studies in various species including humans have revealed that CBG is the major factor influencing inter-individual genetic variability of plasma GC levels, both in basal and stress conditions. Some, but not all of these genetic studies have also provided data linking CBG levels to body composition. The examination of CBG-deficient mice submitted to hyperlipidic diets unveiled specific roles for CBG in lipid storage and metabolism. The importance of CBG is even more striking when animals are submitted to high-fat diet combined to chronic stress, mimicking our occidental lifestyle. An influence of CBG on appetite has not been reported but remains to be more finely analyzed. Overall, a role of CBG in GC-driven metabolic disorders is emerging in recent studies. Although subtle, the influence of CBG in these diseases could open the way to new therapeutic interventions since CBG is easily accessible in the blood.

  4. Microarray-based screening of differentially expressed genes in glucocorticoid-induced avascular necrosis

    Science.gov (United States)

    Huang, Gangyong; Wei, Yibing; Zhao, Guanglei; Xia, Jun; Wang, Siqun; Wu, Jianguo; Chen, Feiyan; Chen, Jie; Shi, Jingshen

    2017-01-01

    The underlying mechanisms of glucocorticoid (GC)-induced avascular necrosis of the femoral head (ANFH) have yet to be fully understood, in particular the mechanisms associated with the change of gene expression pattern. The present study aimed to identify key genes with a differential expression pattern in GC-induced ANFH. E-MEXP-2751 microarray data were downloaded from the ArrayExpress database. Differentially expressed genes (DEGs) were identified in 5 femoral head samples of steroid-induced ANFH rats compared with 5 placebo-treated rat samples. Gene Ontology (GO) and pathway enrichment analyses were performed upon these DEGs. A total 93 DEGs (46 upregulated and 47 downregulated genes) were identified in GC-induced ANFH samples. These DEGs were enriched in different GO terms and pathways, including chondrocyte differentiation and detection of chemical stimuli. The enrichment map revealed that skeletal system development was interconnected with several other GO terms by gene overlap. The literature mined network analysis revealed that 5 upregulated genes were associated with femoral necrosis, including parathyroid hormone receptor 1 (PTHR1), vitamin D (1,25-Dihydroxyvitamin D3) receptor (VDR), collagen, type II, α1, proprotein convertase subtilisin/kexin type 6 and zinc finger protein 354C (ZFP354C). In addition, ZFP354C and VDR were identified to transcription factors. Furthermore, PTHR1 was revealed to interact with VDR, and α-2-macroglobulin (A2M) interacted with fibronectin 1 (FN1) in the PPI network. PTHR1 may be involved in GC-induced ANFH via interacting with VDR. A2M may also be involved in the development of GC-induced ANFH through interacting with FN1. An improved understanding of the molecular mechanisms underlying GC-induced ANFH may provide novel targets for diagnostics and therapeutic treatment. PMID:28393228

  5. Chronic stress accelerates ligature-induced periodontitis by suppressing glucocorticoid receptor-α signaling.

    Science.gov (United States)

    Lu, Huaixiu; Xu, Minguang; Wang, Feng; Liu, Shisen; Gu, Jing; Lin, Songshan; Zhao, Lisheng

    2016-03-25

    Periodontitis is a common chronic inflammatory disease. Recent studies have shown that chronic stress (CS) might modulate periodontal disease, but there are few models of CS-induced periodontitis, and the underlying mechanisms are unclear. The present study established a rat model of periodontitis associated with CS induced by nylon thread ligatures. The severity of periodontitis was evaluated in this model by radiographic and pathological examination. The inflammatory reaction indicated by the elevated serum levels of interleukin (IL)-1β, IL-6 and IL-8 was assessed by enzyme-linked immunosorbent assay. Toll-like receptor-4 (TLR4) and glucocorticoid receptor-α (GR-α) expressions were detected by reverse transcriptase-PCR and western blotting. Open-field tests and serum corticosterone were used to evaluate CS. The results showed that CS induced behavioral changes and increased corticosterone levels of the animals with periodontitis. CS stimulation markedly increased alveolar bone loss, periodontal pocket depth and the number of plaques. It also enhanced the inflammatory reaction. These results suggest that CS accelerated the ligature-induced pathological changes associated with periodontitis. Further analysis of the mechanisms involved showed that GR-α expression was significantly downregulated in periodontal tissues of the animals undergoing CS. Blocking GR-α signaling in lipopolysaccharide and corticosteroid-treated human periodontal ligament fibroblast cells in vitro significantly upregulated the expression of p-Akt (protein kinase B) and TLR4, promoted nuclear factor-κB activity and increased levels of IL-1β, IL-6 and IL-8. This research suggests that CS might accelerate the pathological progression of periodontitis by a GR-α signaling-mediated inflammatory response and that this may be a potential therapeutic target for the treatment of periodontal disease, particularly in patients with CS.

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

    Directory of Open Access Journals (Sweden)

    Chen Chun-Hung

    2011-08-01

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

  7. Glucocorticoid treatment and impaired mood, memory and metabolism in people with diabetes: the Edinburgh Type 2 Diabetes Study

    Science.gov (United States)

    Reynolds, Rebecca M; Labad, Javier; Sears, Alison V; Williamson, Rachel M; Strachan, Mark W J; Deary, Ian J; Lowe, Gordon D O; Price, Jackie F; Walker, Brian R

    2012-01-01

    Objective Both type 2 diabetes and glucocorticoid therapy are highly prevalent. Although people with type 2 diabetes may be more susceptible to adverse effects of glucocorticoids, and it is recommended that glucocorticoid therapy is avoided for fear of worsening glycaemic control, the extent to which this advice is followed and the consequences when glucocorticoids are prescribed are poorly documented. The aim was to assess the characteristics of people with type 2 diabetes prescribed glucocorticoids in a real-world setting and to quantify resulting adverse effects. Design Cross-sectional cohort study. Methods Cardiometabolic variables, body fat distribution, cognitive function and mood were studied in the 1066 participants of the Edinburgh Type 2 Diabetes Study, of whom 162 (15%) were taking systemic, topical or inhaled glucocorticoids. Results Glucocorticoid therapy was more common in women and in smokers but was not avoided in patients with diabetic complications or cardiovascular risk factors. People taking glucocorticoids were more centrally obese with slightly higher HbA1c and total serum cholesterol but were no more likely to have hepatic steatosis or hypertension. Glucocorticoid treatment was associated with substantially lower mood and greater anxiety. Women taking glucocorticoid therapy were twice as likely to report depressive symptoms compared with those not taking treatment. Glucocorticoid therapy was also associated with poorer cognitive function among those with subclinical atherosclerosis, as indicated by low ankle–brachial pressure index. Conclusions Glucocorticoids are prescribed commonly for people with type 2 diabetes despite being associated with adverse indices of glycaemic control, cardiovascular risk factors, mood and cognitive function. PMID:22408122

  8. Age-related synthesis of glucocorticoids in thymocytes

    International Nuclear Information System (INIS)

    Qiao Shengjun; Chen Liying; Okret, Sam; Jondal, Mikael

    2008-01-01

    Glucocorticoids (GCs) are primarily synthesized in the adrenal glands but an ectopic production has also been reported in the brain, the gastrointestinal tract and in thymic epithelial cells (TEC). Here we show that thymocytes express genes encoding for all enzymes required for de novo GC synthesis and produce the hormone as demonstrated by both a GC specific reporter assay and a corticosterone specific ELISA assay. Interestingly, GC synthesis is detectable in cells from young mice (4 weeks) and thereafter increases during aging (14-22 weeks) together with an increased gene expression of the rate-limiting enzymes StAR and CYP11A1. Hormone production occurred at a thymocyte differentiation stage characterized by being double positive for the CD4 and CD8 surface markers but was found to be unrelated to CD69 expression, a marker for thymocytes undergoing positive selection. No GC synthesis was found in resting or anti-CD3 activated CD4 and CD8 positive T cells isolated from the spleen. Thymocyte-derived GC had an anti-proliferative effect on a GR-transfected cell line and induced apoptosis in thymocytes. The age- and differentiation stage-related GC synthesis in thymocytes may play a role in the involution process that the thymus gland undergoes

  9. Combined Effects of Glucocorticoid and Noradrenergic Activity on Loss Aversion.

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    Margittai, Zsofia; Nave, Gideon; Van Wingerden, Marijn; Schnitzler, Alfons; Schwabe, Lars; Kalenscher, Tobias

    2018-01-01

    Loss aversion is a well-known behavioral regularity in financial decision making, describing humans' tendency to overweigh losses compared to gains of the same amount. Recent research indicates that stress and associated hormonal changes affect loss aversion, yet the underlying neuroendocrine mechanisms are still poorly understood. Here, we investigated the causal influence of two major stress neuromodulators, cortisol and noradrenaline, on loss aversion during financial decision making. In a double-blind, placebo-controlled between-subject design, we orally administered either the α2-adrenergic antagonist yohimbine (increasing noradrenergic stimulation), hydrocortisone, both substances, or a placebo to healthy young men. We tested the treatments' influence on a financial decision-making task measuring loss aversion and risk attitude. We found that both drugs combined, relative to either drug by itself, reduced loss aversion in the absence of an effect on risk attitude or choice consistency. Our data suggest that concurrent glucocorticoid and noradrenergic activity prompts an alignment of reward- with loss-sensitivity, and thus diminishes loss aversion. Our results have implications for the understanding of the susceptibility to biases in decision making.

  10. Glucocorticoids and Type 2 Diabetes: From Physiology to Pathology

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    Guido Di Dalmazi

    2012-01-01

    Full Text Available Type 2 diabetes mellitus is the result of interaction between genetic and environmental factors, leading to heterogeneous and progressive pancreatic β-cell dysfunction. Overweight and obesity are major contributors to the development of insulin resistance and impaired glucose tolerance. The inability of β cells to secrete enough insulin produces type 2 diabetes. Abnormalities in other hormones such as reduced secretion of the incretin glucagon-like peptide 1 (GLP-1, hyperglucagonemia, and raised concentrations of other counterregulatory hormones also contribute to insulin resistance, reduced insulin secretion, and hyperglycaemia in type 2 diabetes. Clinical-overt and experimental cortisol excess is associated with profound metabolic disturbances of intermediate metabolism resulting in abdominal obesity, insulin resistance, and low HDL-cholesterol levels, which can lead to diabetes. It was therefore suggested that subtle abnormalities in cortisol secretion and action are one of the missing links between insulin resistance and other features of the metabolic syndrome. The aim of this paper is to address the role of glucocorticoids on glucose homeostasis and to explain the relationship between hypercortisolism and type 2 diabetes.

  11. Osteoporosis prophylaxis in patients receiving chronic glucocorticoid therapy

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    Ali, Mir Sadat; AlElq, Abdulmohsen H.; AlShafei, Badar A.; AbuJubarac, Mohammed A.; AlTurki, Haifa A.

    2009-01-01

    Glucocorticoid-induced osteoporosis (GIOP) is the most common form of secondary osteoporosis, yet few patients receive proper measures to prevent its development. We retrospectively searched prescription records to determine if patients receiving oral prednisolone were receiving prophylaxis or treatment for osteopenia and osteoporosis. Patients who were prescribed greater or equal to 7.5 milligrams of prednisolone for 6 months or longer during a 6- month period were identified through the prescription monitoring system. Demographic and clinical data were extracted from the patient records, and dual energy x-ray absorptiometry (DEXA) scans were retrieved, when available. Use of oral calcium, vitamin D and anti-resorptives was recorded. One hundred males and 65 females were receiving oral prednisolone for a mean (SD) duration of 40.4 (29.9) months in males and 41.2 (36.4) months in females. Twenty-one females (12.7%) and 5 (3%) males had bone mineral density measured by DEXA. Of those, 10 (47.6%) females and 3 (50%) males were osteoporotic and 11(52.4%) females and 2 (40%) males were osteopenic. Calcium and vitamin D were prescribed to the majority of patients (60% to 80%), but none were prescribed antiresorptive/anabolic therapy. Patients in this study were neither investigated properly nor treated according to the minimum recommendations for the management of GIOP. Physician awareness about the prevention and treatment of GIOP should be a priority for the local health care system. (author)

  12. Genetic, functional and molecular features of glucocorticoid receptor binding.

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    Francesca Luca

    Full Text Available Glucocorticoids (GCs are key mediators of stress response and are widely used as pharmacological agents to treat immune diseases, such as asthma and inflammatory bowel disease, and certain types of cancer. GCs act mainly by activating the GC receptor (GR, which interacts with other transcription factors to regulate gene expression. Here, we combined different functional genomics approaches to gain molecular insights into the mechanisms of action of GC. By profiling the transcriptional response to GC over time in 4 Yoruba (YRI and 4 Tuscans (TSI lymphoblastoid cell lines (LCLs, we suggest that the transcriptional response to GC is variable not only in time, but also in direction (positive or negative depending on the presence of specific interacting transcription factors. Accordingly, when we performed ChIP-seq for GR and NF-κB in two YRI LCLs treated with GC or with vehicle control, we observed that features of GR binding sites differ for up- and down-regulated genes. Finally, we show that eQTLs that affect expression patterns only in the presence of GC are 1.9-fold more likely to occur in GR binding sites, compared to eQTLs that affect expression only in its absence. Our results indicate that genetic variation at GR and interacting transcription factors binding sites influences variability in gene expression, and attest to the power of combining different functional genomic approaches.

  13. Reduced glucocorticoid receptor expression predicts bladder tumor recurrence and progression.

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    Ishiguro, Hitoshi; Kawahara, Takashi; Zheng, Yichun; Netto, George J; Miyamoto, Hiroshi

    2014-08-01

    To assess the levels of glucocorticoid receptor (GR) expression in bladder tumors because the status and its prognostic value remain largely unknown. We immunohistochemically stained for GR in bladder tumor and matched non-neoplastic bladder tissue specimens. Overall, GR was positive in 129 (87%) of 149 urothelial tumors, which was significantly (P=.026) lower than in non-neoplastic urothelium (90 [96%] of 94). Forty-two (79%) of 53 low-grade tumors vs 45 (47%) of 96 high-grade carcinomas (Pcancer-specific survival of MI tumors (P=.067). Multivariate analysis identified low GR expression as a strong predictor for recurrence of NMI tumors (P=.034). GR expression was downregulated in bladder tumors compared with nonneoplastic bladder tumors and in high-grade/MI tumors compared with low-grade/NMI tumors. Decreased expression of GR, as an independent prognosticator, predicted recurrence of NMI tumors. These results support experimental evidence suggesting an inhibitory role of GR signals in bladder cancer outgrowth. Copyright© by the American Society for Clinical Pathology.

  14. Interaction of glucocorticoids and progesterone derivatives with human serum albumin.

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    Abboud, Rola; Akil, Mohammad; Charcosset, Catherine; Greige-Gerges, Hélène

    2017-10-01

    Glucocorticoids (GCs) and progesterone derivatives (PGDs) are steroid hormones with well-known biological activities. Their interaction with human serum albumin (HSA) may control their distribution. Their binding to albumin is poorly studied in literature. This paper deals with the interaction of a series of GCs (cortisol, cortisone, prednisolone, prednisone, 6-methylprednisolone and 9-fluorocortisol acetate) and PGDs (progesterone, hydroxylated PGDs, methylated PGDs and dydrogesterone) with HSA solution (pH 7.4) at molar ratios steroid to HSA varying from 0 to 10. Similar titrations were conducted using Trp aqueous solution. Fluorescence titration method and Fourier transform infrared spectroscopy (FTIR) are used. PGDs (except dydrogesterone), cortisone and 9-fluorocortisol acetate affected weakly the fluorescence of Trp in buffer solution while they decreased in a dose-dependent manner that of HSA. Their binding constants to HSA were then calculated. Moreover, displacement experiment was performed using bilirubin as a site marker. The binding constant of bilirubin to albumin was determined in the absence and presence of a steroid at a molar ratio steroid to HSA of 1. The results indicate that the steroids bind to HSA at site I in a pocket different from that of bilirubin. Furthermore, the peak positions of amide I and amide II bands of HSA were shifted in the presence of progesterone, dydrogesterone and GCs. Also a variation was observed in amide I region indicating the formation of hydrogen bonding between albumin and steroids. Copyright © 2017 Elsevier B.V. All rights reserved.

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

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

  16. Inhibition of glycogen synthase kinase-3β attenuates glucocorticoid-induced suppression of myogenic differentiation in vitro.

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    Zhenyu Ma

    Full Text Available Glucocorticoids are the only therapy that has been demonstrated to alter the progress of Duchenne muscular dystrophy (DMD, the most common muscular dystrophy in children. However, glucocorticoids disturb skeletal muscle metabolism and hamper myogenesis and muscle regeneration. The mechanisms involved in the glucocorticoid-mediated suppression of myogenic differentiation are not fully understood. Glycogen synthase kinase-3β (GSK-3β is considered to play a central role as a negative regulator in myogenic differentiation. Here, we showed that glucocorticoid treatment during the first 48 h in differentiation medium decreased the level of phosphorylated Ser9-GSK-3β, an inactive form of GSK-3β, suggesting that glucocorticoids affect GSK-3β activity. We then investigated whether GSK-3β inhibition could regulate glucocorticoid-mediated suppression of myogenic differentiation in vitro. Two methods were employed to inhibit GSK-3β: pharmacological inhibition with LiCl and GSK-3β gene knockdown. We found that both methods resulted in enhanced myotube formation and increased levels of muscle regulatory factors and muscle-specific protein expression. Importantly, GSK-3β inhibition attenuated glucocorticoid-induced suppression of myogenic differentiation. Collectively, these data suggest the involvement of GSK-3β in the glucocorticoid-mediated impairment of myogenic differentiation. Therefore, the inhibition of GSK-3β may be a strategy for preventing glucocorticoid-induced muscle degeneration.

  17. Ex vivo stimulation of whole blood as a means to determine glucocorticoid sensitivity

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    Burnsides C

    2012-08-01

    Full Text Available Christopher Burnsides,1,* Jacqueline Corry,1,* Jacob Alexander,1 Catherine Balint,1 David Cosmar,1 Gary Phillips,2 Jeanette I Webster Marketon1,31Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Internal Medicine, 2Center for Biostatistics, 3Institute for Behavioral Medicine Research, Wexner Medical Center at The Ohio State University, Columbus, OH, USA*JC and CB have equally contributed to this workPurpose: Glucocorticoids are commonly prescribed to treat a number of diseases including the majority of inflammatory diseases. Despite considerable interpersonal variability in response to glucocorticoids, an insensitivity rate of about 30%, and the risk of adverse side effects of glucocorticoid therapy, currently no assay is performed to determine sensitivity.Patients and methods: Here we propose a whole blood ex vivo stimulation assay to interrogate known glucocorticoid receptor (GR up- and downregulated genes to indicate glucocorticoid sensitivity. We have chosen to employ real-time PCR in order to provide a relatively fast and inexpensive assay.Results: We show that the GR-regulated genes, GILZ and FKBP51, are upregulated in whole blood by treatment with dexamethasone and that LPS-induction of cytokines (IL-6 and TNFα are repressed by dexamethasone in a dose responsive manner. There is considerable interpersonal variability in the maximum induction of these genes but little variation in the EC50 and IC50 concentrations. The regulation of the GR-induced genes differs throughout the day whereas the suppression of LPS-induced cytokines is not as sensitive to time of day.Conclusion: In all, this assay would provide a method to determine glucocorticoid receptor responsiveness in whole blood.Keywords: glucocorticoid responsiveness, gene regulation, nuclear receptor, GILZ, FKBP51, cytokines

  18. Effects of chronic mild stress on behavioral and neurobiological parameters - Role of glucocorticoid.

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    Chen, Jiao; Wang, Zhen-zhen; Zuo, Wei; Zhang, Shuai; Chu, Shi-feng; Chen, Nai-hong

    2016-02-01

    Major depression is thought to originate from maladaptation to adverse events, particularly when impairments occur in mood-related brain regions. Hypothalamus-pituitary-adrenal (HPA) axis is one of the major systems involved in physiological stress response. HPA axis dysfunction and high glucocorticoid concentrations play an important role in the pathogenesis of depression. In addition, astrocytic disability and dysfunction of neurotrophin brain-derived neurotrophin factor (BDNF) greatly influence the development of depression and anxiety disorders. Therefore, we investigated whether depressive-like and anxiety-like behaviors manifest in the absence of glucocorticoid production and circulation in adrenalectomized (ADX) rats after chronic mild stress (CMS) exposure and its potential molecular mechanisms. The results demonstrate that glucocorticoid-controlled rats showed anxiety-like behaviors but not depression-like behaviors after CMS. Molecular and cellular changes included the decreased BDNF in the hippocampus, astrocytic dysfunction with connexin43 (cx43) decreasing and abnormality in gap junction in prefrontal cortex (PFC). Interestingly, we did not find any changes in glucocorticoid receptor (GR) or its chaperone protein FK506 binding protein 51 (FKBP5) expression in the hippocampus or PFC in ADX rats subjected to CMS. In conclusion, the production and circulation of glucocorticoids are one of the contributing factors in the development of depression-like behaviors in response to CMS. In contrast, the effects of CMS on anxiety-like behaviors are independent of the presence of circulating glucocorticoids. Meanwhile, stress decreased GR expression and enhanced FKBP5 expression via higher glucocorticoid exposure. Gap junction dysfunction and changes in BDNF may be associated with anxiety-like behaviors. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. The next step for stress research in primates: To identify relationships between glucocorticoid secretion and fitness.

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    Beehner, Jacinta C; Bergman, Thore J

    2017-05-01

    Glucocorticoids are hormones that mediate the energetic demands that accompany environmental challenges. It is therefore not surprising that these metabolic hormones have come to dominate endocrine research on the health and fitness of wild populations. Yet, several problems have been identified in the vertebrate research that also apply to the non-human primate research. First, glucocorticoids should not be used as a proxy for fitness (unless a link has previously been established between glucocorticoids and fitness for a particular population). Second, stress research in behavioral ecology has been overly focused on "chronic stress" despite little evidence that chronic stress hampers fitness in wild animals. Third, research effort has been disproportionately focused on the causes of glucocorticoid variation rather than the fitness consequences. With these problems in mind, we have three objectives for this review. We describe the conceptual framework behind the "stress concept", emphasizing that high glucocorticoids do not necessarily indicate a stress response, and that a stress response does not necessarily indicate an animal is in poor health. Then, we conduct a comprehensive review of all studies on "stress" in wild primates, including any study that examined environmental factors, the stress response, and/or fitness (or proxies for fitness). Remarkably, not a single primate study establishes a connection between all three. Finally, we provide several recommendations for future research in the field of primate behavioral endocrinology, primarily the need to move beyond identifying the factors that cause glucocorticoid secretion to additionally focus on the relationship between glucocorticoids and fitness. We believe that this is an important next step for research on stress physiology in primates. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Scaling mimesis: Morphometric and ecomorphological similarities in three sympatric plant-mimetic fish of the family Carangidae (Teleostei).

    Science.gov (United States)

    Queiroz, Alexya Cunha de; Vallinoto, Marcelo; Sakai, Yoichi; Giarrizzo, Tommaso; Barros, Breno

    2018-01-01

    The mimetic juveniles of a number of carangid fish species resemble plant parts floating near the water surface, such as leaves, seeds and other plant debris. The present study is the first to verify the morphological similarities and ecomorphological relationships between three carangids (Oligoplites saurus, Oligoplites palometa and Trachinotus falcatus) and their associated plant models. Behavioral observations were conducted in the estuary of Curuçá River, in northeastern Pará (Brazil) between August 2015 and July 2016. Individual fishes and associated floating objects (models) were sampled for comparative analysis using both geometric and morphometric approaches. While the mimetic fish and their models retain their own distinct, intrinsic morphological features, a high degree of morphological similarity was found between each fish species and its model. The morphometric analyses revealed a general tendency of isometric development in all three fish species, probably related to their pelagic habitats, during all ontogenetic stages.

  1. The arbitrary order mimetic finite difference method for a diffusion equation with a non-symmetric diffusion tensor

    Science.gov (United States)

    Gyrya, V.; Lipnikov, K.

    2017-11-01

    We present the arbitrary order mimetic finite difference (MFD) discretization for the diffusion equation with non-symmetric tensorial diffusion coefficient in a mixed formulation on general polygonal meshes. The diffusion tensor is assumed to be positive definite. The asymmetry of the diffusion tensor requires changes to the standard MFD construction. We present new approach for the construction that guarantees positive definiteness of the non-symmetric mass matrix in the space of discrete velocities. The numerically observed convergence rate for the scalar quantity matches the predicted one in the case of the lowest order mimetic scheme. For higher orders schemes, we observed super-convergence by one order for the scalar variable which is consistent with the previously published result for a symmetric diffusion tensor. The new scheme was also tested on a time-dependent problem modeling the Hall effect in the resistive magnetohydrodynamics.

  2. Bioinspired Hydroxyapatite/Poly(methyl methacrylate) Composite with a Nacre-Mimetic Architecture by a Bidirectional Freezing Method.

    Science.gov (United States)

    Bai, Hao; Walsh, Flynn; Gludovatz, Bernd; Delattre, Benjamin; Huang, Caili; Chen, Yuan; Tomsia, Antoni P; Ritchie, Robert O

    2016-01-06

    Using a bidirectional freezing technique, combined with uniaxial pressing and in situ polymerization, "nacre-mimetic" hydroxyapatite/poly(methyl methacrylate) (PMMA) composites are developed by processing large-scale aligned lamellar ceramic scaffolds. Structural and mechanical characterization shows "brick-and-mortar" structures, akin to nacre, with interesting combinations of strength, stiffness, and work of fracture, which provide a pathway to making strong and tough lightweight materials. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Effect of the Nerve Growth Factor Mimetic GK-2 on Brain Structural and Functional State in the Early Postresuscitation Period

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    M. Sh. Avrushchenko

    2012-01-01

    Full Text Available Objective: to evaluate the efficacy of the nerve growth factor mimetic GK-2 used to improve the structural and functional state of the brain in the early postresuscitation period. Material and methods. Cardiac arrest was induced in mature male albino rats for 12 minutes, followed by resuscitation. The neurological state of the resuscitated animals was assessed by a scoring scale. On postresuscitation day 7, the density and composition of neuronal populations of Purkinje cells in the lateral cerebellar region and pyramidal neurons in the hippocampal CA1 sector were determined by a differential morphometric analysis. The results were statistically processed using the ANOVA method. Results. The use of GK-2 was found to accelerate neurological recovery in the resuscitated animals. On day 7 after 12-minute cardiac arrest, the resuscitated animals showed neuronal dystrophic changes and death in the neuronal populations highly susceptible to ischemia. It was shown that the systemic administration of the nerve growth factor mimetic GK-2 contributed to a reduction in the magnitude and depth of postresuscitation changes in the cerebellar Purkinje cells and prevented dystrophic changes in the pyramidal cells of the hippocampal CA1 sector. The findings suggest that GK-2 has a neuroprotective effect in the recovery period after total body ischemia. Conclusion. The results of this study indicate the efficiency of the systemic administration of the nerve growth factor mimetic GK-2 in improving the brain structural and functional state in the early postresuscitation period. This determines perspectives for the use of GK-2 to prevent and correct posthypoxic encephalopathies. Key words: the nerve growth factor mimetic GK-2, postresuscitation period, neuronal dystrophic changes and death, neurological status.

  4. Neutrophils are not less sensitive than other blood leukocytes to the genomic effects of glucocorticoids.

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    Gaelle Hirsch

    Full Text Available Neutrophils are generally considered less responsive to glucocorticoids compared to other inflammatory cells. The reported increase in human neutrophil survival mediated by these drugs partly supports this assertion. However, it was recently shown that dexamethasone exerts potent anti-inflammatory effects in equine peripheral blood neutrophils. Few comparative studies of glucocorticoid effects in neutrophils and other leukocytes have been reported and a relative insensitivity of neutrophils to these drugs could not be ruled out.We assessed glucocorticoid-responsiveness in equine and human peripheral blood neutrophils and neutrophil-depleted leukocytes.Blood neutrophils and neutrophil-depleted leukocytes were isolated from 6 healthy horses and 4 human healthy subjects. Cells were incubated for 5 h with or without LPS (100 ng/mL alone or combined with hydrocortisone, prednisolone or dexamethasone (10(-8 M and 10(-6 M. IL-1β, TNF-α, IL-8, glutamine synthetase and GR-α mRNA expression was quantified by qPCR. Equine neutrophils were also incubated for 20 h with or without the three glucocorticoids and cell survival was assessed by flow cytometry and light microscopy on cytospin preparations.We found that glucocorticoids down-regulated LPS-induced pro-inflammatory mRNA expression in both cell populations and species. These drugs also significantly increased glutamine synthetase gene expression in both equine cell populations. The magnitude of glucocorticoid response between cell populations was generally similar in both species. We also showed that dexamethasone had a comparable inhibitory effect on pro-inflammatory gene expression in both human and equine neutrophils. As reported in other species, glucocorticoids significantly increase the survival in equine neutrophils.Glucocorticoids exert genomic effects of similar magnitude on neutrophils and on other blood leukocytes. We speculate that the poor response to glucocorticoids observed in some

  5. Neutrophils Are Not Less Sensitive Than Other Blood Leukocytes to the Genomic Effects of Glucocorticoids

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    Hirsch, Gaelle; Lavoie-Lamoureux, Anouk; Beauchamp, Guy; Lavoie, Jean-Pierre

    2012-01-01

    Background Neutrophils are generally considered less responsive to glucocorticoids compared to other inflammatory cells. The reported increase in human neutrophil survival mediated by these drugs partly supports this assertion. However, it was recently shown that dexamethasone exerts potent anti-inflammatory effects in equine peripheral blood neutrophils. Few comparative studies of glucocorticoid effects in neutrophils and other leukocytes have been reported and a relative insensitivity of neutrophils to these drugs could not be ruled out. Objective We assessed glucocorticoid-responsiveness in equine and human peripheral blood neutrophils and neutrophil-depleted leukocytes. Methods Blood neutrophils and neutrophil-depleted leukocytes were isolated from 6 healthy horses and 4 human healthy subjects. Cells were incubated for 5 h with or without LPS (100 ng/mL) alone or combined with hydrocortisone, prednisolone or dexamethasone (10−8 M and 10−6 M). IL-1β, TNF-α, IL-8, glutamine synthetase and GR-α mRNA expression was quantified by qPCR. Equine neutrophils were also incubated for 20 h with or without the three glucocorticoids and cell survival was assessed by flow cytometry and light microscopy on cytospin preparations. Results We found that glucocorticoids down-regulated LPS-induced pro-inflammatory mRNA expression in both cell populations and species. These drugs also significantly increased glutamine synthetase gene expression in both equine cell populations. The magnitude of glucocorticoid response between cell populations was generally similar in both species. We also showed that dexamethasone had a comparable inhibitory effect on pro-inflammatory gene expression in both human and equine neutrophils. As reported in other species, glucocorticoids significantly increase the survival in equine neutrophils. Conclusions Glucocorticoids exert genomic effects of similar magnitude on neutrophils and on other blood leukocytes. We speculate that the poor response to

  6. Interventions Targeting Glucocorticoid-Krüppel-like Factor 15-Branched-Chain Amino Acid Signaling Improve Disease Phenotypes in Spinal Muscular Atrophy Mice

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    Lisa M. Walter

    2018-05-01

    Full Text Available The circadian glucocorticoid-Krüppel-like factor 15-branched-chain amino acid (GC-KLF15-BCAA signaling pathway is a key regulatory axis in muscle, whose imbalance has wide-reaching effects on metabolic homeostasis. Spinal muscular atrophy (SMA is a neuromuscular disorder also characterized by intrinsic muscle pathologies, metabolic abnormalities and disrupted sleep patterns, which can influence or be influenced by circadian regulatory networks that control behavioral and metabolic rhythms. We therefore set out to investigate the contribution of the GC-KLF15-BCAA pathway in SMA pathophysiology of Taiwanese Smn−/−;SMN2 and Smn2B/− mouse models. We thus uncover substantial dysregulation of GC-KLF15-BCAA diurnal rhythmicity in serum, skeletal muscle and metabolic tissues of SMA mice. Importantly, modulating the components of the GC-KLF15-BCAA pathway via pharmacological (prednisolone, genetic (muscle-specific Klf15 overexpression and dietary (BCAA supplementation interventions significantly improves disease phenotypes in SMA mice. Our study highlights the GC-KLF15-BCAA pathway as a contributor to SMA pathogenesis and provides several treatment avenues to alleviate peripheral manifestations of the disease. The therapeutic potential of targeting metabolic perturbations by diet and commercially available drugs could have a broader implementation across other neuromuscular and metabolic disorders characterized by altered GC-KLF15-BCAA signaling. Keywords: Spinal muscular atrophy, KLF15, Glucocorticoids, Branched-chain amino acids, Metabolism, Therapy

  7. Human Lactoferricin Is Partially Folded in Aqueous Solution and Is Better Stabilized in a Membrane Mimetic Solvent

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    Hunter, Howard N.; Demcoe, A. Ross; Jenssen, Håvard; Gutteberg, Tore J.; Vogel, Hans J.

    2005-01-01

    Lactoferricins are highly basic bioactive peptides that are released in the stomach through proteolytic cleavage of various lactoferrin proteins. Here we have determined the solution structure of human lactoferricin (LfcinH) by conventional two-dimensional nuclear magnetic resonance methods in both aqueous solution and a membrane mimetic solvent. Unlike the 25-residue bovine lactoferricin (LfcinB), which adopts a somewhat distorted antiparallel β sheet, the longer LfcinH peptide shows a helical content from Gln14 to Lys29 in the membrane mimetic solvent but a nonexistent β-sheet character in either the N- or C-terminal regions of the peptide. The helical characteristic of the LfcinH peptide resembles the conformation that this region adopts in the crystal structure of the intact protein. The LfcinH structure determined in aqueous solution displays a nascent helix in the form of a coiled conformation in the region from Gln14 to Lys29. Numerous hydrophobic interactions create the basis for the better-defined overall structure observed in the membrane mimetic solvent. The 49-residue LfcinH peptide isolated for these studies was found to be slightly longer than previously reported peptide preparations and was found to have an intact peptide bond between residues Ala11 and Val12. The distinct solution structures of LfcinH and LfcinB represent a novel difference in the physical properties of these two peptides, which contributes to their unique physiological activities. PMID:16048952

  8. Tetra(p-tolyl)borate-functionalized solvent polymeric membrane: a facile and sensitive sensing platform for peroxidase and peroxidase mimetics.

    Science.gov (United States)

    Wang, Xuewei; Qin, Wei

    2013-07-22

    The determination of peroxidase activities is the basis for enzyme-labeled bioaffinity assays, peroxidase-mimicking DNAzymes- and nanoparticles-based assays, and characterization of the catalytic functions of peroxidase mimetics. Here, a facile, sensitive, and cost-effective solvent polymeric membrane-based peroxidase detection platform is described that utilizes reaction intermediates with different pKa values from those of substrates and final products. Several key but long-debated intermediates in the peroxidative oxidation of o-phenylenediamine (o-PD) have been identified and their charge states have been estimated. By using a solvent polymeric membrane functionalized by an appropriate substituted tetraphenylborate as a receptor, those cationic intermediates could be transferred into the membrane from the aqueous phase to induce a large cationic potential response. Thus, the potentiometric indication of the o-PD oxidation catalyzed by peroxidase or its mimetics can be fulfilled. Horseradish peroxidase has been detected with a detection limit at least two orders of magnitude lower than those obtained by spectrophotometric techniques and traditional membrane-based methods. As an example of peroxidase mimetics, G-quadruplex DNAzymes were probed by the intermediate-sensitive membrane and a label-free thrombin detection protocol was developed based on the catalytic activity of the thrombin-binding G-quadruplex aptamer. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Assessment of faecal glucocorticoid metabolite excretion in captive female fishing cats (Prionailurus viverinus) in Thailand.

    Science.gov (United States)

    Khonmee, Jaruwan; Vorawattanatham, Narathip; Pinyopummin, Anuchai; Thitaram, Chatchote; Somgird, Chaleamchat; Punyapornwithaya, Veerasak; Brown, Janine L

    2016-01-01

    There is little information on the endocrinology of fishing cats (Prionailurus viverinus), an endangered species in Southeast Asia, especially that pertaining to adrenal function. This study characterized faecal glucocorticoid metabolites in female fishing cats housed at Chiang Mai Night Safari to investigate seasonal and age relationships in hormone patterns. Faecal samples were collected 3 days/week for 1 year from seven females ranging in age from 4.5 to 9.6 years. A corticosterone enzyme immunoassay was validated for fishing cats by showing increases (∼60%) in faecal glucocorticoid immunoactivity above pre-treatment baseline levels within 1-2 days after an adrenocorticotrophic hormone injection. Faecal glucocorticoid metabolite concentrations were not related to age (P > 0.05), but there was a seasonal effect, with concentrations being higher (P fishing cats, and we found that glucocorticoid metabolite production was influenced by seasonal factors, but not by age. We conclude that weather patterns should be taken into consideration in future studies of glucocorticoid activity in this endangered species, especially those studies aimed at improving captive management to create self-sustaining and healthy populations.

  10. Influence of postnatal glucocorticoids on hippocampal-dependent learning varies with elevation patterns and administration methods.

    Science.gov (United States)

    Claflin, Dragana I; Schmidt, Kevin D; Vallandingham, Zachary D; Kraszpulski, Michal; Hennessy, Michael B

    2017-09-01

    Recent interest in the lasting effects of early-life stress has expanded to include effects on cognitive performance. An increase in circulating glucocorticoids is induced by stress exposure and glucocorticoid effects on the hippocampus likely underlie many of the cognitive consequences. Here we review studies showing that corticosterone administered to young rats at the conclusion of the stress-hyporesponsiveness period affects later performance in hippocampally-mediated trace eyeblink conditioning. The nature and even direction of these effects varies with the elevation patterns (level, duration, temporal fluctuation) achieved by different administration methods. We present new time course data indicating that constant glucocorticoid elevations generally corresponded with hippocampus-mediated learning deficits, whereas acute, cyclical elevations corresponded with improved initial acquisition. Sensitivity was greater for males than for females. Further, changes in hippocampal neurogenesis paralleled some but not all effects. The findings demonstrate that specific patterns of glucocorticoid elevation produced by different drug administration procedures can have markedly different, sex-specific consequences on basic cognitive performance and underlying hippocampal physiology. Implications of these findings for glucocorticoid medications prescribed in childhood are discussed. Copyright © 2017 Elsevier Inc. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Natalie G. Burford

    2017-10-01

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

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

    Science.gov (United States)

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

    2017-10-16

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

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

    Science.gov (United States)

    Atsak, Piray; Hauer, Daniela; Campolongo, Patrizia; Schelling, Gustav; McGaugh, James L.; Roozendaal, Benno

    2012-01-01

    There is extensive evidence that glucocorticoid hormones impair the retrieval of memory of emotionally arousing experiences. Although it is known that glucocorticoid effects on memory retrieval impairment depend on rapid interactions with arousal-induced noradrenergic activity, the exact mechanism underlying this presumably nongenomically mediated glucocorticoid action remains to be elucidated. Here, we show that the hippocampal endocannabinoid system, a rapidly activated retrograde messenger system, is involved in mediating glucocorticoid effects on retrieval of contextual fear memory. Systemic administration of corticosterone (0.3–3 mg/kg) to male Sprague–Dawley rats 1 h before retention testing impaired the retrieval of contextual fear memory without impairing the retrieval of auditory fear memory or directly affecting the expression of freezing behavior. Importantly, a blockade of hippocampal CB1 receptors with AM251 prevented the impairing effect of corticosterone on retrieval of contextual fear memory, whereas the same impairing dose of corticosterone increased hippocampal levels of the endocannabinoid 2-arachidonoylglycerol. We also found that antagonism of hippocampal β-adrenoceptor activity with local infusions of propranolol blocked the memory retrieval impairment induced by the CB receptor agonist WIN55,212–2. Thus, these findings strongly suggest that the endocannabinoid system plays an intermediary role in regulating rapid glucocorticoid effects on noradrenergic activity in impairing memory retrieval of emotionally arousing experiences. PMID:22331883

  14. Paired hormone response elements predict caveolin-1 as a glucocorticoid target gene.

    Directory of Open Access Journals (Sweden)

    Marinus F van Batenburg

    2010-01-01

    Full Text Available Glucocorticoids act in part via glucocorticoid receptor binding to hormone response elements (HREs, but their direct target genes in vivo are still largely unknown. We developed the criterion that genomic occurrence of paired HREs at an inter-HRE distance less than 200 bp predicts hormone responsiveness, based on synergy of multiple HREs, and HRE information from known target genes. This criterion predicts a substantial number of novel responsive genes, when applied to genomic regions 10 kb upstream of genes. Multiple-tissue in situ hybridization showed that mRNA expression of 6 out of 10 selected genes was induced in a tissue-specific manner in mice treated with a single dose of corticosterone, with the spleen being the most responsive organ. Caveolin-1 was strongly responsive in several organs, and the HRE pair in its upstream region showed increased occupancy by glucocorticoid receptor in response to corticosterone. Our approach allowed for discovery of novel tissue specific glucocorticoid target genes, which may exemplify responses underlying the permissive actions of glucocorticoids.

  15. The tobacco smoke component acrolein induces glucocorticoid resistant gene expression via inhibition of histone deacetylase.

    Science.gov (United States)

    Randall, Matthew J; Haenen, Guido R M M; Bouwman, Freek G; van der Vliet, Albert; Bast, Aalt

    2016-01-05

    Chronic obstructive pulmonary disease (COPD) is the leading cause of cigarette smoke-related death worldwide. Acrolein, a crucial reactive electrophile found in cigarette smoke mimics many of the toxic effects of cigarette smoke-exposure in the lung. In macrophages, cigarette smoke is known to hinder histone deacetylases (HDACs), glucocorticoid-regulated enzymes that play an important role in the pathogenesis of glucocorticoid resistant inflammation, a common feature of COPD. Thus, we hypothesize that acrolein plays a role in COPD-associated glucocorticoid resistance. To examine the role of acrolein on glucocorticoid resistance, U937 monocytes, differentiated with PMA to macrophage-like cells were treated with acrolein for 0.5h followed by stimulation with hydrocortisone for 8h, or treated simultaneously with LPS and hydrocortisone for 8h without acrolein. GSH and nuclear HDAC activity were measured, or gene expression was analyzed by qPCR. Acrolein-mediated TNFα gene expression was not suppressed by hydrocortisone whereas LPS-induced TNFα expression was suppressed. Acrolein also significantly inhibited nuclear HDAC activity in macrophage-like cells. Incubation of recombinant HDAC2 with acrolein led to the formation of an HDAC2-acrolein adduct identified by mass spectrometry. Therefore, these results suggest that acrolein-induced inflammatory gene expression is resistant to suppression by the endogenous glucocorticoid, hydrocortisone. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  16. SDF-1 improves wound healing ability of glucocorticoid-treated adipose tissue-derived mesenchymal stem cells.

    Science.gov (United States)

    Kato, Toshiki; Khanh, Vuong Cat; Sato, Kazutoshi; Takeuchi, Kosuke; Carolina, Erica; Yamashita, Toshiharu; Sugaya, Hisashi; Yoshioka, Tomokazu; Mishima, Hajime; Ohneda, Osamu

    2017-11-18

    Glucocorticoids cause the delayed wound healing by suppressing inflammation that is required for wound healing process. Adipose tissue-derived mesenchymal stem cells (AT-MSCs) play an important role for wound healing by their cytokine productions including stromal derived factor 1 (SDF-1). However, it has not been clear how glucocorticoids affect the wound healing ability of AT-MSCs. In this study, we found that glucocorticoid downregulated SDF-1 expression in AT-MSCs. In addition, glucocorticoid-treated AT-MSCs induced less migration of inflammatory cells and impaired wound healing capacity compared with glucocorticoid-untreated AT-MSCs. Of note, prostaglandin E2 (PGE2) synthesis-related gene expression was downregulated by glucocorticoid and PGE2 treatment rescued not only SDF-1 expression in the presence of glucocorticoid but also their wound healing capacity in vivo. Furthermore, we found SDF-1-overexpressed AT-MSCs restored wound healing capacity even after treatment of glucocorticoid. Consistent with the results obtained from glucocorticoid-treated AT-MSCs, we found that AT-MSCs isolated from steroidal osteonecrosis donors (sAT-MSCs) who received chronic glucocorticoid therapy showed less SDF-1 expression and impaired wound healing capacity compared with traumatic osteonecrosis donor-derived AT-MSCs (nAT-MSCs). Moreover, the SDF-1 level was also reduced in plasma derived from steroidal osteonecrosis donors compared with traumatic osteonecrosis donors. These results provide the evidence that concomitant application of AT-MSCs with glucocorticoid shows impaired biological modulatory effects that induce impaired wound healing. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Using superoxide dismutase/catalase mimetics to manipulate the redox environment of neural precursor cells

    International Nuclear Information System (INIS)

    Limoli, C. L.; Giedzinski, E.; Baure, J.; Doctrow, S. R.; Rola, R.; Fike, J. R.

    2006-01-01

    Past work has shown that neural precursor cells are predisposed to redox sensitive changes, and that oxidative stress plays a critical role in the acute and persistent changes that occur within the irradiated CNS. Irradiation leads to a marked rise in reactive oxygen species (ROS) that correlates with oxidative endpoints in vivo and reductions in neuro-genesis. To better understand the impact of oxidative stress on neural precursor cells, and to determine if radiation-induced oxidative damage and precursor cell loss after irradiation could be reduced, a series of antioxidant compounds (EUK-134, EUK-163, EUK-172, EUK-189) were tested, three of which possess both superoxide dismutase (SOD) and catalase activities and one (EUK-163) whose only significant activity is SOD. Our results show that these SOD/catalase mimetics apparently increase the oxidation of a ROS-sensitive fluorescent indicator dye, particularly after short (12 h) treatments, but that longer treatments (24 h) decrease oxidation attributable to radiation-induced ROS. Similarly, other studies found that cells incubated with CuZnSOD showed some increase in intracellular ROS levels. Subsequent data suggested that the dye-oxidising capabilities of the EUK compounds were linked to differences in their catalase activity and, most likely, their ability to catalyse per-oxidative pathways. In unirradiated mice, the EUK-134 analogue induced some decrease of proliferating precursor cells and immature neurons 48 h after radiation, an effect that may be attributable to cytotoxicity and/or inhibition of precursor proliferation. In irradiated mice, a single injection of EUK-134 was not found to be an effective radioprotector at acute times (48 h). The present results support continued development of our in vitro model as a tool for predicting certain in vivo responses, and suggest that in some biological systems the capability to scavenge superoxide but produce excess H 2 O 2 , as is known for CuZnSOD, may be

  18. Juvenile obesity enhances emotional memory and amygdala plasticity through glucocorticoids.

    Science.gov (United States)

    Boitard, Chloé; Maroun, Mouna; Tantot, Frédéric; Cavaroc, Amandine; Sauvant, Julie; Marchand, Alain; Layé, Sophie; Capuron, Lucile; Darnaudery, Muriel; Castanon, Nathalie; Coutureau, Etienne; Vouimba, Rose-Marie; Ferreira, Guillaume

    2015-03-04

    In addition to metabolic and cardiovascular disorders, obesity is associated with adverse cognitive and emotional outcomes. Its growing prevalence during adolescence is particularly alarming since recent evidence indicates that obesity can affect hippocampal function during this developmental period. Adolescence is a decisive period for maturation of the amygdala and the hypothalamic-pituitary-adrenal (HPA) stress axis, both required for lifelong cognitive and emotional processing. However, little data are available on the impact of obesity during adolescence on amygdala function. Herein, we therefore evaluate in rats whether juvenile high-fat diet (HFD)-induced obesity alters amygdala-dependent emotional memory and whether it depends on HPA axis deregulation. Exposure to HFD from weaning to adulthood, i.e., covering adolescence, enhances long-term emotional memories as assessed by odor-malaise and tone-shock associations. Juvenile HFD also enhances emotion-induced neuronal activation of the basolateral complex of the amygdala (BLA), which correlates with protracted plasma corticosterone release. HFD exposure restricted to adulthood does not modify all these parameters, indicating adolescence is a vulnerable period to the effects of HFD-induced obesity. Finally, exaggerated emotional memory and BLA synaptic plasticity after juvenile HFD are alleviated by a glucocorticoid receptor antagonist. Altogether, our results demonstrate that juvenile HFD alters HPA axis reactivity leading to an enhancement of amygdala-dependent synaptic and memory processes. Adolescence represents a period of increased susceptibility to the effects of diet-induced obesity on amygdala function. Copyright © 2015 the authors 0270-6474/15/354092-12$15.00/0.

  19. Glucocorticoid programming of the fetal male hippocampal epigenome.

    Science.gov (United States)

    Crudo, Ariann; Suderman, Matthew; Moisiadis, Vasilis G; Petropoulos, Sophie; Kostaki, Alisa; Hallett, Michael; Szyf, Moshe; Matthews, Stephen G

    2013-03-01

    The late-gestation surge in fetal plasma cortisol is critical for maturation of fetal organ systems. As a result, synthetic glucocorticoids (sGCs) are administered to pregnant women at risk of delivering preterm. However, animal studies have shown that fetal exposure to sGC results in increased risk of behavioral, endocrine, and metabolic abnormalities in offspring. Here, we test the hypothesis that prenatal GC exposure resulting from the fetal cortisol surge or after sGC exposure results in promoter-specific epigenetic changes in the hippocampus. Fetal guinea pig hippocampi were collected before (gestational day [GD52]) and after (GD65) the fetal plasma cortisol surge (Term∼GD67) and 24 hours after (GD52) and 14 days after (GD65) two repeat courses of maternal sGC (betamethasone) treatment (n = 3-4/gp). We identified extensive genome-wide alterations in promoter methylation in late fetal development (coincident with the fetal cortisol surge), whereby the majority of the affected promoters exhibited hypomethylation. Fetuses exposed to sGC in late gestation exhibited substantial differences in DNA methylation and histone h3 lysine 9 (H3K9) acetylation in specific gene promoters; 24 hours after the sGC treatment, the majority of genes affected were hypomethylated or hyperacetylated. However, 14 days after sGC exposure these differences did not persist, whereas other promoters became hypermethylated or hyperacetylated. These data support the hypothesis that the fetal GC surge is responsible, in part, for significant variations in genome-wide promoter methylation and that prenatal sGC treatment profoundly changes the epigenetic landscape, affecting both DNA methylation and H3K9 acetylation. This is important given the widespread use of sGC in the management of women in preterm labor.

  20. Glucocorticoid receptor haplotypes conferring increased sensitivity (BclI and N363S) are associated with faster progression of multiple sclerosis

    DEFF Research Database (Denmark)

    Melief, Jeroen; Koper, Jan W; Endert, Erik

    2016-01-01

    As high cortisol levels are implicated in suppressed disease activity of multiple sclerosis (MS), glucocorticoid receptor (GR) polymorphisms that affect glucocorticoid (GC) sensitivity may impact on this by changing local immunomodulation or regulation of the hypothalamus-pituitary-adrenal (HPA...

  1. Role of Exercise Therapy in Prevention of Decline in Aging Muscle Function: Glucocorticoid Myopathy and Unloading

    Directory of Open Access Journals (Sweden)

    Teet Seene

    2012-01-01

    Full Text Available Changes in skeletal muscle quantity and quality lead to disability in the aging population. Physiological changes in aging skeletal muscle are associated with a decline in mass, strength, and inability to maintain balance. Glucocorticoids, which are in wide exploitation in various clinical scenarios, lead to the loss of the myofibrillar apparatus, changes in the extracellular matrix, and a decrease in muscle strength and motor activity, particularly in the elderly. Exercise therapy has shown to be a useful tool for the prevention of different diseases, including glucocorticoid myopathy and muscle unloading in the elderly. The purpose of the paper is to discuss the possibilities of using exercise therapy in the prevention of glucocorticoid caused myopathy and unloading in the elderly and to describe relationships between the muscle contractile apparatus and the extracellular matrix in different types of aging muscles.

  2. Competitive inhibition of [3H]dexamethasone binding to mammary glucocorticoid receptor by leupeptin

    International Nuclear Information System (INIS)

    Hsieh, L.C.C.; Su, C.; Markland, F.S. Jr.

    1987-01-01

    The inhibitory effect of leupeptin on [ 3 H]dexamethasone binding to the glucocorticoid receptor from lactating goat mammary cytosol has been studied. Leupeptin (10 mM) caused a significant (about 35%) inhibition of [ 3 H]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 [ 3 H]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)

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

    Science.gov (United States)

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

    2016-09-01

    Cholestatic liver disease is characterized by a disruption of bile flow, bile acid toxicity, liver injury, and hypercholesterolemia. Relatively high secretion of glucocorticoids by the adrenals has been observed under cholestatic conditions. Here we investigated a contribution of the rise in endogenous glucocorticoids to initial stage cholestasis pathology. Adrenalectomized or sham-operated control C57BL/6 mice were given an oral dose of alpha-naphthylisothiocyanate to induce cholestasis. Adrenalectomy effectively lowered plasma corticosterone levels (18±5ng/ml vs 472±58ng/ml; Phypercholesterolemia. In conclusion, we have shown that endogenous glucocorticoids exacerbate the liver injury and hypercholesterolemia associated with acute cholestasis in mice. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Environmental Enrichment Effect on Fecal Glucocorticoid Metabolites and Captive Maned Wolf (Chrysocyon brachyurus) Behavior.

    Science.gov (United States)

    Coelho, Carlyle Mendes; de Azevedo, Cristiano Schetini; Guimarães, Marcelo Alcino de Barros Vaz; Young, Robert John

    2016-01-01

    Environmental enrichment is a technique that may reduce the stress of nonhuman animals in captivity. Stress may interfere with normal behavioral expression and affect cognitive decision making. Noninvasive hormonal studies can provide important information about the stress statuses of animals. This study evaluated the effectiveness of different environmental enrichment treatments in the diminution of fecal glucocorticoid metabolites (stress indicators) of three captive maned wolves (Chrysocyon brachyurus). Correlations of the fecal glucocorticoid metabolite levels with expressed behaviors were also determined. Results showed that environmental enrichment reduced fecal glucocorticoid metabolite levels. Furthermore, interspecific and foraging enrichment items were most effective in reducing stress in two of the three wolves. No definite pattern was found between behavioral and physiological responses to stress. In conclusion, these behavioral and physiological data showed that maned wolves responded positively from an animal well being perspective to the enrichment items presented.

  5. Learned Avoidance in the Male Syrian Hamster: Investigating the Outcome of a Glucocorticoid Antagonist on Reconsolidation

    Directory of Open Access Journals (Sweden)

    Erik Haugsnes

    2015-02-01

    Full Text Available In this experiment, we used our Conflict Alleyway Apparatus and a glucocorticoid antagonist, mifepristone, to investigate the role of glucocorticoids in the reconsolidation of learned avoidance in defeated male Syrian hamsters. Subjects were tested for memory deficits 48 hours and 96 hours after the drug/vehicle was administered. It were hypothesized that mifepristone administration would produce memory deficits when the defeat memory had been reactivated, and that this deficit would be present 48 hours and 96 hours after the administration. Prolonged deficits that are dependent upon memory reactivation would suggest that glucocorticoids play a role in reconsolidation of learned avoidance. Our results indicated a strong evidence for learned avoidance after defeat; however, we did not find any significant drug effect.

  6. The Role and Mechanisms of Action of Glucocorticoid Involvement in Memory Storage

    Science.gov (United States)

    Sandi, Carmen

    1998-01-01

    Adrenal steroid hormones modulate learning and memory processes by interacting with specific glucocorticoid receptors at different brain areas. In this article, certain components of the physiological response to stress elicited by learning situations are proposed to form an integral aspect of the neurobiological mechanism underlying memory formation. By reviewing the work carried out in different learning models in chicks (passive avoidance learning) and rats (spatial orientation in the Morris water maze and contextual fear conditioning), a role for brain corticosterone action through the glucocorticoid receptor type on the mechanisms of memory consolidation is hypothesized. Evidence is also presented to relate post-training corticosterone levels to the strength of memory storage. Finally, the possible molecular mechanisms that might mediate the influences of glucocorticoids in synaptic plasticity subserving long-term memory formation are considered, mainly by focusing on studies implicating a steroid action through (i) glutamatergic transmission and (ii) cell adhesion molecules. PMID:9920681

  7. Diretrizes para prevenção e tratamento da osteoporose induzida por glicocorticoide Guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis

    Directory of Open Access Journals (Sweden)

    Rosa Maria Rodrigues Pereira

    2012-08-01

    Full Text Available Os glicocorticoides (GC são prescritos por praticamente todas as especialidades médicas, e cerca de 0,5% da população geral do Reino Unido utiliza esses medicamentos. Com o aumento da sobrevida dos pacientes com doenças reumatológicas, a morbidade secundária ao uso dessa medicação representa um aspecto importante que deve ser considerado no manejo de nossos pacientes. As incidências de fraturas vertebrais e não vertebrais são elevadas, variando de 30%-50% em pessoas que usam GC por mais de três meses. Assim, a osteoporose e as fraturas por fragilidade devem ser prevenidas e tratadas em todos os pacientes que iniciarão ou que já estejam em uso desses esteroides. Diversas recomendações elaboradas por várias sociedades internacionais têm sido descritas na literatura, porém não há consenso entre elas. Recentemente, o Americam College of Rheumatology publicou novas recomendações, porém elas são fundamentadas na FRAX (WHO Fracture Risk Assessment Tool para analisar o risco de cada indivíduo e, dessa maneira, não podem ser completamente utilizadas pela população brasileira. Dessa forma, a Comissão de Osteoporose e Doenças Osteometabólicas da Sociedade Brasileira de Reumatologia, em conjunto com a Associação Médica Brasileira e a Associação Brasileira de Medicina Física e Reabilitação, implementou as diretrizes brasileiras de osteoporose induzida por glicocorticoide (OPIG, baseando-se na melhor evidência científica disponível e/ou experiência de experts. DESCRIÇÃO DO MÉTODO DE COLETA DE EVIDÊNCIA: A revisão bibliográfica de artigos científicos desta diretriz foi realizada na base de dados MEDLINE. A busca de evidência partiu de cenários clínicos reais, e utilizou as seguintes palavras-chave (MeSH terms: Osteoporosis, Osteoporosis/chemically induced*= (Glucocorticoids= Adrenal Cortex Hormones, Steroids, Glucocorticoids, Glucocorticoids/administration and dosage, Glucocorticoids/therapeutic use

  8. DMPD: Glucocorticoids and the innate immune system: crosstalk with the toll-likereceptor signaling network. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17576036 Glucocorticoids and the innate immune system: crosstalk with the toll-like...07 May 13. (.png) (.svg) (.html) (.csml) Show Glucocorticoids and the innate immune system: crosstalk with t...nd the innate immune system: crosstalk with the toll-likereceptor signaling network. Authors Chinenov Y, Rog

  9. A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined with Enzalutamide in Castrate-Resistant Prostate Cancer

    Science.gov (United States)

    2017-12-01

    Receptor Antagonist Mifepristone Combined with Enzalutamide in Castrate-Resistant Prostate Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER... receptor (AR) targeted therapies, prostate cancer adapts. One way it adapts is by upregulating another hormone receptor , the glucocorticoid receptor (GR...trial. 15. SUBJECT TERMS Castration resistant prostate cancer (CRPC); Androgen Receptor (AR); Glucocorticoid receptor (GR); Enzalutamide;

  10. How does stress affect human being—a molecular dynamic simulation study on cortisol and its glucocorticoid receptor

    Directory of Open Access Journals (Sweden)

    Dan Zhang

    2017-03-01

    Full Text Available Stress can be either positive or negative to human beings. Under stressful conditions, the mental and physical conditions of human can be affected. There exists certain relation between stress and illness. The cortisol and other glucocorticoids bind to the same receptor, which is called glucocorticoid receptor. Some evidences indicated that cortisol molecule binding to its glucocorticoid receptor was necessary for the stress response. Up to now, the structure–function relationships between cortisol molecule and its glucocorticoid receptor have not been deliberated from the atomic-level. In order to get a detailed understanding of the structure–function relationships between the cortisol molecule and glucocorticoids receptor, we have carried out molecular dynamic (MD simulations on glucocorticoid receptor (Apo system and cortisol with its glucocorticoid receptor complex (HCY system. On the basis of molecular dynamic simulations, a couple of key residues were identified, which were crucial for the binding of cortisol molecule. The results of binding free energy calculations are in good agreement with the experiment data. Our research gives clear insights from atomic-level into the structural–functional aspects of cortisol molecule and its glucocorticoid receptor, and also provides valuable information for the design of drug which can treat stress related illnesses.

  11. Divergent effects of endogenous and exogenous glucocorticoid-induced leucine zipper in animal models of inflammation and arthritis

    NARCIS (Netherlands)

    Ngo, Devi; Beaulieu, Elaine; Gu, Ran; Leaney, Alexandra; Santos, Leilani; Fan, Huapeng; Yang, Yuanhang; Kao, Wenping; Xu, Jiake; Escriou, Virginie; Loiler, Scott; Vervoordeldonk, Margriet J.; Morand, Eric F.

    2013-01-01

    Glucocorticoid-induced leucine zipper (GILZ) has effects on inflammatory pathways that suggest it to be a key inhibitory regulator of the immune system, and its expression is exquisitely sensitive to induction by glucocorticoids. We undertook this study to test our hypothesis that GILZ deficiency

  12. Glucocorticoid cell reception in mice of different strains with natural killer cell activity depressed during immobilization stress

    International Nuclear Information System (INIS)

    Lyashko, V.N.; Sukhikh, G.T.

    1987-01-01

    The authors study differences in stress-induced depression of natural killer cell activity in mice of different inbred lines, depending on parameters of glucocorticoid binding with glucorticoid receptors of spleen cells and on the hormonal status of the animals. In determining the parameters of glucocorticoid binding on intact splenocytes, aliquots of a suspension of washed splenocytes were incubated with tritium-labeled dexamethasone

  13. Mimetic finite difference method for the stokes problem on polygonal meshes

    Energy Technology Data Exchange (ETDEWEB)

    Lipnikov, K [Los Alamos National Laboratory; Beirao Da Veiga, L [DIPARTIMENTO DI MATE; Gyrya, V [PENNSYLVANIA STATE UNIV; Manzini, G [ISTIUTO DI MATEMATICA

    2009-01-01

    Various approaches to extend the finite element methods to non-traditional elements (pyramids, polyhedra, etc.) have been developed over the last decade. Building of basis functions for such elements is a challenging task and may require extensive geometry analysis. The mimetic finite difference (MFD) method has many similarities with low-order finite element methods. Both methods try to preserve fundamental properties of physical and mathematical models. The essential difference is that the MFD method uses only the surface representation of discrete unknowns to build stiffness and mass matrices. Since no extension inside the mesh element is required, practical implementation of the MFD method is simple for polygonal meshes that may include degenerate and non-convex elements. In this article, we develop a MFD method for the Stokes problem on arbitrary polygonal meshes. The method is constructed for tensor coefficients, which will allow to apply it to the linear elasticity problem. The numerical experiments show the second-order convergence for the velocity variable and the first-order for the pressure.

  14. In Vitro Mimetic Models for the Bone-Cartilage Interface Regeneration.

    Science.gov (United States)

    Bicho, Diana; Pina, Sandra; Oliveira, J Miguel; Reis, Rui L

    2018-01-01

    In embryonic development, pure cartilage structures are in the basis of bone-cartilage interfaces. Despite this fact, the mature bone and cartilage structures can vary greatly in composition and function. Nevertheless, they collaborate in the osteochondral region to create a smooth transition zone that supports the movements and forces resulting from the daily activities. In this sense, all the hierarchical organization is involved in the maintenance and reestablishment of the equilibrium in case of damage. Therefore, this interface has attracted a great deal of interest in order to understand the mechanisms of regeneration or disease progression in osteoarthritis. With that purpose, in vitro tissue models (either static or dynamic) have been studied. Static in vitro tissue models include monocultures, co-cultures, 3D cultures, and ex vivo cultures, mostly cultivated in flat surfaces, while dynamic models involve the use of bioreactors and microfluidic systems. The latter have emerged as alternatives to study the cellular interactions in a more authentic manner over some disadvantages of the static models. The current alternatives of in vitro mimetic models for bone-cartilage interface regeneration are overviewed and discussed herein.

  15. Synthetic mimetics of the endogenous gastrointestinal nanomineral: Silent constructs that trap macromolecules for intracellular delivery.

    Science.gov (United States)

    Pele, Laetitia C; Haas, Carolin T; Hewitt, Rachel E; Robertson, Jack; Skepper, Jeremy; Brown, Andy; Hernandez-Garrido, Juan Carlos; Midgley, Paul A; Faria, Nuno; Chappell, Helen; Powell, Jonathan J

    2017-02-01

    Amorphous magnesium-substituted calcium phosphate (AMCP) nanoparticles (75-150nm) form constitutively in large numbers in the mammalian gut. Collective evidence indicates that they trap and deliver luminal macromolecules to mucosal antigen presenting cells (APCs) and facilitate gut immune homeostasis. Here, we report on a synthetic mimetic of the endogenous AMCP and show that it has marked capacity to trap macromolecules during formation. Macromolecular capture into AMCP involved incorporation as shown by STEM tomography of the synthetic AMCP particle with 5nm ultra-fine iron (III) oxohydroxide. In vitro, organic cargo-loaded synthetic AMCP was taken up by APCs and tracked to lysosomal compartments. The AMCP itself did not regulate any gene, or modify any gene regulation by its cargo, based upon whole genome transcriptomic analyses. We conclude that synthetic AMCP can efficiently trap macromolecules and deliver them to APCs in a silent fashion, and may thus represent a new platform for antigen delivery. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  16. Microwave-assisted synthesis of triple-helical, collagen-mimetic lipopeptides

    Science.gov (United States)

    Banerjee, Jayati; Hanson, Andrea J; Muhonen, Wallace W; Shabb, John B; Mallik, Sanku

    2018-01-01

    Collagen-mimetic peptides and lipopeptides are widely used as substrates for matrix degrading enzymes, as new biomaterials for tissue engineering, as drug delivery systems and so on. However, the preparation and subsequent purification of these peptides and their fatty-acid conjugates are really challenging. Herein, we report a rapid microwave-assisted, solid-phase synthetic protocol to prepare the fatty-acid conjugated, triple-helical peptides containing the cleavage site for the enzyme matrix metalloproteinase-9 (MMP-9). We employed a PEG-based resin as the solid support and the amino acids were protected with Fmoc- and tert-butyl groups. The amino acids were coupled at 50 °C (25 W of microwave power) for 5 min. The deprotection reactions were carried out at 75 °C (35 W of microwave power) for 3 min. Using this protocol, a peptide containing 23 amino acids was synthesized and then conjugated to stearic acid in 14 h. PMID:20057380

  17. Discrete conservation properties for shallow water flows using mixed mimetic spectral elements

    Science.gov (United States)

    Lee, D.; Palha, A.; Gerritsma, M.

    2018-03-01

    A mixed mimetic spectral element method is applied to solve the rotating shallow water equations. The mixed method uses the recently developed spectral element histopolation functions, which exactly satisfy the fundamental theorem of calculus with respect to the standard Lagrange basis functions in one dimension. These are used to construct tensor product solution spaces which satisfy the generalized Stokes theorem, as well as the annihilation of the gradient operator by the curl and the curl by the divergence. This allows for the exact conservation of first order moments (mass, vorticity), as well as higher moments (energy, potential enstrophy), subject to the truncation error of the time stepping scheme. The continuity equation is solved in the strong form, such that mass conservation holds point wise, while the momentum equation is solved in the weak form such that vorticity is globally conserved. While mass, vorticity and energy conservation hold for any quadrature rule, potential enstrophy conservation is dependent on exact spatial integration. The method possesses a weak form statement of geostrophic balance due to the compatible nature of the solution spaces and arbitrarily high order spatial error convergence.

  18. Data assimilation method for fractured reservoirs using mimetic finite differences and ensemble Kalman filter

    KAUST Repository

    Ping, Jing

    2017-05-19

    Optimal management of subsurface processes requires the characterization of the uncertainty in reservoir description and reservoir performance prediction. For fractured reservoirs, the location and orientation of fractures are crucial for predicting production characteristics. With the help of accurate and comprehensive knowledge of fracture distributions, early water/CO 2 breakthrough can be prevented and sweep efficiency can be improved. However, since the rock property fields are highly non-Gaussian in this case, it is a challenge to estimate fracture distributions by conventional history matching approaches. In this work, a method that combines vector-based level-set parameterization technique and ensemble Kalman filter (EnKF) for estimating fracture distributions is presented. Performing the necessary forward modeling is particularly challenging. In addition to the large number of forward models needed, each model is used for sampling of randomly located fractures. Conventional mesh generation for such systems would be time consuming if possible at all. For these reasons, we rely on a novel polyhedral mesh method using the mimetic finite difference (MFD) method. A discrete fracture model is adopted that maintains the full geometry of the fracture network. By using a cut-cell paradigm, a computational mesh for the matrix can be generated quickly and reliably. In this research, we apply this workflow on 2D two-phase fractured reservoirs. The combination of MFD approach, level-set parameterization, and EnKF provides an effective solution to address the challenges in the history matching problem of highly non-Gaussian fractured reservoirs.

  19. M402, a novel heparan sulfate mimetic, targets multiple pathways implicated in tumor progression and metastasis.

    Directory of Open Access Journals (Sweden)

    He Zhou

    Full Text Available Heparan sulfate proteoglycans (HSPGs play a key role in shaping the tumor microenvironment by presenting growth factors, cytokines, and other soluble factors that are critical for host cell recruitment and activation, as well as promoting tumor progression, metastasis, and survival. M402 is a rationally engineered, non-cytotoxic heparan sulfate (HS mimetic, designed to inhibit multiple factors implicated in tumor-host cell interactions, including VEGF, FGF2, SDF-1α, P-selectin, and heparanase. A single s.c. dose of M402 effectively inhibited seeding of B16F10 murine melanoma cells to the lung in an experimental metastasis model. Fluorescent-labeled M402 demonstrated selective accumulation in the primary tumor. Immunohistological analyses of the primary tumor revealed a decrease in microvessel density in M402 treated animals, suggesting anti-angiogenesis to be one of the mechanisms involved in-vivo. M402 treatment also normalized circulating levels of myeloid derived suppressor cells in tumor bearing mice. Chronic administration of M402, alone or in combination with cisplatin or docetaxel, inhibited spontaneous metastasis and prolonged survival in an orthotopic 4T1 murine mammary carcinoma model. These data demonstrate that modulating HSPG biology represents a novel approach to target multiple factors involved in tumor progression and metastasis.

  20. Carbohydrate Mimetic Peptides Augment Carbohydrate-Reactive Immune Responses in the Absence of Immune Pathology

    Energy Technology Data Exchange (ETDEWEB)

    Hennings, Leah; Artaud, Cecile; Jousheghany, Fariba; Monzavi-Karbassi, Behjatolah; Pashov, Anastas; Kieber-Emmons, Thomas, E-mail: tke@uams.edu [Winthrop P. Rockefeller Cancer Institute and Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States)

    2011-11-11

    Among the most challenging of clinical targets for cancer immunotherapy are Tumor Associated Carbohydrate Antigens (TACAs). To augment immune responses to TACA we are developing carbohydrate mimetic peptides (CMPs) that are sufficiently potent to activate broad-spectrum anti-tumor reactivity. However, the activation of immune responses against terminal mono- and disaccharide constituents of TACA raises concerns regarding the balance between “tumor destruction” and “tissue damage”, as mono- and disaccharides are also expressed on normal tissue. To support the development of CMPs for clinical trial testing, we demonstrate in preclinical safety assessment studies in mice that vaccination with CMPs can enhance responses to TACAs without mediating tissue damage to normal cells expressing TACA. BALB/c mice were immunized with CMPs that mimic TACAs reactive with Griffonia simplicifolia lectin 1 (GS-I), and tissue reactivity of serum antibodies were compared with the tissue staining profile of GS-I. Tissues from CMP immunized mice were analyzed using hematoxylin and eosin stain, and Luxol-fast blue staining for myelination. Western blots of membranes from murine mammary 4T1 cells, syngeneic with BALB/c mice, were also compared using GS-I, immunized serum antibodies, and naive serum antibodies. CMP immunization enhanced glycan reactivities with no evidence of pathological autoimmunity in any immunized mice demonstrating that tissue damage is not an inevitable consequence of TACA reactive responses.

  1. Carbohydrate Mimetic Peptides Augment Carbohydrate-Reactive Immune Responses in the Absence of Immune Pathology

    International Nuclear Information System (INIS)

    Hennings, Leah; Artaud, Cecile; Jousheghany, Fariba; Monzavi-Karbassi, Behjatolah; Pashov, Anastas; Kieber-Emmons, Thomas

    2011-01-01

    Among the most challenging of clinical targets for cancer immunotherapy are Tumor Associated Carbohydrate Antigens (TACAs). To augment immune responses to TACA we are developing carbohydrate mimetic peptides (CMPs) that are sufficiently potent to activate broad-spectrum anti-tumor reactivity. However, the activation of immune responses against terminal mono- and disaccharide constituents of TACA raises concerns regarding the balance between “tumor destruction” and “tissue damage”, as mono- and disaccharides are also expressed on normal tissue. To support the development of CMPs for clinical trial testing, we demonstrate in preclinical safety assessment studies in mice that vaccination with CMPs can enhance responses to TACAs without mediating tissue damage to normal cells expressing TACA. BALB/c mice were immunized with CMPs that mimic TACAs reactive with Griffonia simplicifolia lectin 1 (GS-I), and tissue reactivity of serum antibodies were compared with the tissue staining profile of GS-I. Tissues from CMP immunized mice were analyzed using hematoxylin and eosin stain, and Luxol-fast blue staining for myelination. Western blots of membranes from murine mammary 4T1 cells, syngeneic with BALB/c mice, were also compared using GS-I, immunized serum antibodies, and naive serum antibodies. CMP immunization enhanced glycan reactivities with no evidence of pathological autoimmunity in any immunized mice demonstrating that tissue damage is not an inevitable consequence of TACA reactive responses

  2. Wing scale ultrastructure underlying convergent and divergent iridescent colours in mimetic Heliconius butterflies.

    Science.gov (United States)

    Parnell, Andrew J; Bradford, James E; Curran, Emma V; Washington, Adam L; Adams, Gracie; Brien, Melanie N; Burg, Stephanie L; Morochz, Carlos; Fairclough, J Patrick A; Vukusic, Pete; Martin, Simon J; Doak, Scott; Nadeau, Nicola J

    2018-04-01

    Iridescence is an optical phenomenon whereby colour changes with the illumination and viewing angle. It can be produced by thin film interference or diffraction. Iridescent optical structures are fairly common in nature, but relatively little is known about their production or evolution. Here we describe the structures responsible for producing blue-green iridescent colour in Heliconius butterflies. Overall the wing scale structures of iridescent and non-iridescent Heliconius species are very similar, both having longitudinal ridges joined by cross-ribs. However, iridescent scales have ridges composed of layered lamellae, which act as multilayer reflectors. Differences in brightness between species can be explained by the extent of overlap of the lamellae and their curvature as well as the density of ridges on the scale. Heliconius are well known for their Müllerian mimicry. We find that iridescent structural colour is not closely matched between co-mimetic species. Differences appear less pronounced in models of Heliconius vision than models of avian vision, suggesting that they are not driven by selection to avoid heterospecific courtship by co-mimics. Ridge profiles appear to evolve relatively slowly, being similar between closely related taxa, while ridge density evolves faster and is similar between distantly related co-mimics. © 2018 The Authors.

  3. Design and facile synthesis of neoglycolipids as lactosylceramide mimetics and their transformation into glycoliposomes.

    Science.gov (United States)

    Harada, Yoichiro; Murata, Takeomi; Totani, Kazuhide; Kajimoto, Tetsuya; Masum, Shah Md; Tamba, Yukihiro; Yamazaki, Masahito; Usui, Taichi

    2005-01-01

    Neoglycolipids composed of disaccharide glycoside and phospholipid were designed and prepared as mimetics of lactosylceramide. The lactosyl- and N-acetyllactosaminyl-phospholipids (Lac-DPPA and LacNAc-DPPA) were enzymatically synthesized from lactose and LacNAc respectively by cellulase-mediated condensation with 1,6-hexanediol, followed by conjugation of the resulting glycosides and dipalmitoylphosphatidyl choline (DPPC) mediated by Streptomyces phospholipase D. Alternatively, allyl beta-lactoside was ozonolyzed to give an aldehyde, which was condensed with dipalmytoyl phosphatidyl ethanolamine to afford a second type of glycolipid (Lac-DPPE). NMR spectroscopy indicated that the neoglycolipids behave differently in different solvent systems. X-ray diffraction clearly showed that multilamellar vesicles (MLVs) of Lac-DPPE and Lac-DPPA-MLV are in the bilayer gel phase at 20 degrees C, whereas those of Lac-DPPE-MLV were in the lamellar liquid-crystalline phase at 50 degrees C. Differential scanning calorimetry showed that Lac-DPPE-MLV had complex thermotropic behavior depending on the incubation conditions. After a long incubation at 10 degrees C, endothermic transitions are observed at 39.6, 42.3 degrees C, and 42.9 degrees C. These neoglycolipids have the ability to trap calcein, a chelating derivative of fluorescein, in MLVs and showed specific binding to lectin in plate assays using fluorescently labeled compounds.

  4. HDL mimetic peptide CER-522 treatment regresses left ventricular diastolic dysfunction in cholesterol-fed rabbits.

    Science.gov (United States)

    Merlet, Nolwenn; Busseuil, David; Mihalache-Avram, Teodora; Mecteau, Melanie; Shi, Yanfen; Nachar, Walid; Brand, Genevieve; Brodeur, Mathieu R; Charpentier, Daniel; Rhainds, David; Sy, Gavin; Schwendeman, Anna; Lalwani, Narendra; Dasseux, Jean-Louis; Rhéaume, Eric; Tardif, Jean-Claude

    2016-07-15

    High-density lipoprotein (HDL) infusions induce rapid improvement of experimental atherosclerosis in rabbits but their effect on ventricular function remains unknown. We aimed to evaluate the effects of the HDL mimetic peptide CER-522 on left ventricular diastolic dysfunction (LVDD). Rabbits were fed with a cholesterol- and vitamin D2-enriched diet until mild aortic valve stenosis and hypercholesterolemia-induced LV hypertrophy and LVDD developed. Animals then received saline or 10 or 30mg/kg CER-522 infusions 6 times over 2weeks. We performed serial echocardiograms and LV histology to evaluate the effects of CER-522 therapy on LVDD. LVDD was reduced by CER-522 as shown by multiple parameters including early filling mitral deceleration time, deceleration rate, Em/Am ratio, E/Em ratio, pulmonary venous velocities, and LVDD score. These findings were associated with reduced macrophages (RAM-11 positive cells) in the pericoronary area and LV, and decreased levels of apoptotic cardiomyocytes in CER-522-treated rabbits. CER-522 treatment also resulted in decreased atheromatous plaques and internal elastic lamina area in coronary arteries. CER-522 improves LVDD in rabbits, with reductions of LV macrophage accumulation, cardiomyocyte apoptosis, coronary atherosclerosis and remodelling. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  5. Improving pancreatic islet in vitro functionality and transplantation efficiency by using heparin mimetic peptide nanofiber gels.

    Science.gov (United States)

    Uzunalli, Gozde; Tumtas, Yasin; Delibasi, Tuncay; Yasa, Oncay; Mercan, Sercan; Guler, Mustafa O; Tekinay, Ayse B

    2015-08-01

    Pancreatic islet transplantation is a promising treatment for type 1 diabetes. However, viability and functionality of the islets after transplantation are limited due to loss of integrity and destruction of blood vessel networks. Thus, it is important to provide a proper mechanically and biologically supportive environment for enhancing both in vitro islet culture and transplantation efficiency. Here, we demonstrate that heparin mimetic peptide amphiphile (HM-PA) nanofibrous network is a promising platform for these purposes. The islets cultured with peptide nanofiber gel containing growth factors exhibited a similar glucose stimulation index as that of the freshly isolated islets even after 7 days. After transplantation of islets to STZ-induced diabetic rats, 28 day-long monitoring displayed that islets that were transplanted in HM-PA nanofiber gels maintained better blood glucose levels at normal levels compared to the only islet transplantation group. In addition, intraperitoneal glucose tolerance test revealed that animals that were transplanted with islets within peptide gels showed a similar pattern with the healthy control group. Histological assessment showed that islets transplanted within peptide nanofiber gels demonstrated better islet integrity due to increased blood vessel density. This work demonstrates that using the HM-PA nanofiber gel platform enhances the islets function and islet transplantation efficiency both in vitro and in vivo. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  6. Cell-free expressed bacteriorhodopsin in different soluble membrane mimetics: biophysical properties and NMR accessibility.

    Science.gov (United States)

    Etzkorn, Manuel; Raschle, Thomas; Hagn, Franz; Gelev, Vladimir; Rice, Amanda J; Walz, Thomas; Wagner, Gerhard

    2013-03-05

    Selecting a suitable membrane-mimicking environment is of fundamental importance for the investigation of membrane proteins. Nonconventional surfactants, such as amphipathic polymers (amphipols) and lipid bilayer nanodiscs, have been introduced as promising environments that may overcome intrinsic disadvantages of detergent micelle systems. However, structural insights into the effects of different environments on the embedded protein are limited. Here, we present a comparative study of the heptahelical membrane protein bacteriorhodopsin in detergent micelles, amphipols, and nanodiscs. Our results confirm that nonconventional environments can increase stability of functional bacteriorhodopsin, and demonstrate that well-folded heptahelical membrane proteins are, in principle, accessible by solution-NMR methods in amphipols and phospholipid nanodiscs. Our data distinguish regions of bacteriorhodopsin that mediate membrane/solvent contacts in the tested environments, whereas the protein's functional inner core remains almost unperturbed. The presented data allow comparing the investigated membrane mimetics in terms of NMR spectral quality and thermal stability required for structural studies. Copyright © 2013 Elsevier Ltd. All rights reserved.

  7. Extreme Mechanical Behavior of Nacre-Mimetic Graphene-Oxide and Silk Nanocomposites.

    Science.gov (United States)

    Xie, Wanting; Tadepalli, Sirimuvva; Park, Sang Hyun; Kazemi-Moridani, Amir; Jiang, Qisheng; Singamaneni, Srikanth; Lee, Jae-Hwang

    2018-02-14

    Biological materials have the ability to withstand extreme mechanical forces due to their unique multilevel hierarchical structure. Here, we fabricated a nacre-mimetic nanocomposite comprised of silk fibroin and graphene oxide that exhibits hybridized dynamic responses arising from alternating high-contrast mechanical properties of the components at the nanoscale. Dynamic mechanical behavior of these nanocomposites is assessed through a microscale ballistic characterization using a 7.6 μm diameter silica sphere moving at a speed of approximately 400 m/s. The volume fraction of graphene oxide in these composites is systematically varied from 0 to 32 vol % to quantify the dynamic effects correlating with the structural morphologies of the graphene oxide flakes. Specific penetration energy of the films rapidly increases as the distribution of graphene oxide flakes evolves from noninteracting, isolated sheets to a partially overlapping continuous sheet. The specific penetration energy of the nanocomposite at the highest graphene oxide content tested here is found to be significantly higher than that of Kevlar fabrics and close to that of pure multilayer graphene. This study evidently demonstrates that the morphologies of nanoscale constituents and their interactions are critical to realize scalable high-performance nanocomposites using typical nanomaterial constituents having finite dimensions.

  8. Impact of peptide clustering on unbinding forces in the context of fusion mimetics

    International Nuclear Information System (INIS)

    Pähler, Gesa; Lorenz, Bärbel; Janshoff, Andreas

    2013-01-01

    Highlights: ► Coiled-coil peptides as SNARE mimetics for membrane fusion. ► Interaction forces assessed by colloidal probe microscopy. ► Lateral organization of lipopeptides visualized by atomic force microscopy. -- Abstract: Coiled-coil zipping and unzipping is a pivotal process in SNARE-regulated membrane fusion. In this study we examine this process mediated by a minimal model for coiled-coil formation employing force spectroscopy in the context of membrane-coated surfaces and probes. The interaction forces of several hundred pN are surprisingly low considering the proposed amount of molecular bonds in the contact zone. However, by means of high-resolution imaging employing atomic force microscopy and studying the lateral mobility of lipids and peptides as a function of coiled-coil formation, we are able to supply a detailed view on processes occurring on the membrane surfaces during force measurements. The interaction forces determined here are not only dependent on the peptide concentration on the surface, but also on the regional organization of lateral peptide clusters found prior to coiled-coil formation

  9. Effects of the potential lithium-mimetic, ebselen, on impulsivity and emotional processing.

    Science.gov (United States)

    Masaki, Charles; Sharpley, Ann L; Cooper, Charlotte M; Godlewska, Beata R; Singh, Nisha; Vasudevan, Sridhar R; Harmer, Catherine J; Churchill, Grant C; Sharp, Trevor; Rogers, Robert D; Cowen, Philip J

    2016-07-01

    Lithium remains the most effective treatment for bipolar disorder and also has important effects to lower suicidal behaviour, a property that may be linked to its ability to diminish impulsive, aggressive behaviour. The antioxidant drug, ebselen, has been proposed as a possible lithium-mimetic based on its ability in animals to inhibit inositol monophosphatase (IMPase), an action which it shares with lithium. The aim of the study was to determine whether treatment with ebselen altered emotional processing and diminished measures of risk-taking behaviour. We studied 20 healthy participants who were tested on two occasions receiving either ebselen (3600 mg over 24 h) or identical placebo in a double-blind, randomized, cross-over design. Three hours after the final dose of ebselen/placebo, participants completed the Cambridge Gambling Task (CGT) and a task that required the detection of emotional facial expressions (facial emotion recognition task (FERT)). On the CGT, relative to placebo, ebselen reduced delay aversion while on the FERT, it increased the recognition of positive vs negative facial expressions. The study suggests that at the dosage used, ebselen can decrease impulsivity and produce a positive bias in emotional processing. These findings have implications for the possible use of ebselen in the disorders characterized by impulsive behaviour and dysphoric mood.

  10. Glutathione-mimetic D609 alleviates memory deficits and reduces amyloid-β deposition in an AβPP/PS1 transgenic mouse model.

    Science.gov (United States)

    Yang, Hui; Xie, ZhaoHong; Wei, LiFei; Ding, Mao; Wang, Ping; Bi, JianZhong

    2018-04-18

    Excessive extracellular deposition of amyloid-β-peptide (Aβ) in the brain is a pathological hallmark of Alzheimer's disease (AD). Oxidative stress is associated with the onset and progression of AD and contributes to Aβ generation. Tricyclodecan-9-yl-xanthogenate (D609) is a glutathione (GSH)-mimetic compound. Although the antioxidant properties of D609 have been well-studied, its potential therapeutic significance on AD remains unclear. In the present study, we used a mouse model of AD to investigate the effects and the mechanism of action of D609 on AD. We found that D609 treatment significantly improved the spatial learning and alleviated the memory decline in the mice harboring amyloid precursor protein (APP) and presenilin-1 (PS1) double mutations (AβPP/PS1 mice). D609 treatment also increased GSH level, GSH and oxidative glutathione ratio, and superoxide dismutase activity, whereas decreased malondialdehyde and protein carbonyl levels, suggesting that D609 alleviated oxidative stress in AβPP/PS1 mice. In addition, D609 reduced β-secretase 1 level and decreased amyloidogenic processing of AβPP, consequently reducing Aβ deposition in the mice. Thus, our findings suggest that D609 might produce beneficial effects on the prevention and treatment of AD.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/.

  11. Ex vivo investigation of ocular tissue distribution following intravitreal administration of connexin43 mimetic peptide using the microdialysis technique and LC-MS/MS.

    Science.gov (United States)

    Bisht, Rohit; Mandal, Abhirup; Rupenthal, Ilva D; Mitra, Ashim K

    2016-12-01

    This study aimed to develop and evaluate an ex vivo eye model for intravitreal drug sampling and tissue distribution of connexin43 mimetic peptide (Cx43MP) following intravitreal injection using the microdialysis technique and LC-MS/MS. An LC-MS/MS method was developed, validated, and applied for quantification of Cx43MP in ocular tissues. Microdialysis probes were calibrated for in vitro recovery studies. Bovine eyes were fixed in a customized eye holder and after intravitreal injection of Cx43MP, microdialysis probes were implanted in the vitreous body. Vitreous samples were collected at particular time intervals over 24 h. Moreover, 24 and 48 h after intravitreal injection ocular tissues were collected, processed, and analyzed for Cx43MP concentrations using LC-MS/MS. The LC-MS/MS method showed good linearity (r 2  = 0.9991). The mean percent recovery for lower (LQC), medium (MQC), and higher quality control (HQC) (0.244, 3.906, and 125 μg/mL) was found to be 83.83, 84.92, and 94.52, respectively, with accuracy ranges between 96 and 99 % and limits of detection (LOD) and quantification (LOQ) of 0.122 and 0.412 μg/mL. The in vitro recovery of the probes was found to be over 80 %. As per microdialysis sample analysis, the Cx43MP concentration was found to increase slowly in the vitreous body up to 16 h and thereafter declined. After 48 h, the Cx43MP concentration was higher in vitreous, cornea, and retina compared to lens, iris, and aqueous humor. This ex vivo model may therefore be a useful tool to investigate intravitreal kinetics and ocular disposition of therapeutic molecules after intravitreal injection.

  12. PG545, a heparan sulfate mimetic, reduces heparanase expression in vivo, blocks spontaneous metastases and enhances overall survival in the 4T1 breast carcinoma model.

    Directory of Open Access Journals (Sweden)

    Edward Hammond

    Full Text Available PG545 is a clinically relevant heparan sulfate (HS mimetic which, in addition to possessing anti-angiogenic properties, also acts as a heparanase inhibitor which may differentiate its mechanism(s of action from approved angiogenesis inhibitors. The degradation of HS by heparanase has been strongly implicated in cell dissemination and the metastatic process. Thus, the anti-metastatic activity of PG545 has been linked to the enzymatic function of heparanase - the only endoglycosidase known to cleave HS, an important component of the extracellular matrix (ECM which represents a potential avenue for therapeutic intervention for certain metastatic cancer indications. Recent concerns raised about the paucity of overall survival as an endpoint in mouse models of clinically relevant metastasis led us to examine the effect of PG545 on the progression of both primary tumor growth and the spontaneously metastasizing disease in the 4T1 syngeneic breast carcinoma model in a non-surgical and surgical (mastectomy setting. PG545 significantly inhibited primary tumor growth but importantly also inhibited lung metastasis in treated mice, an effect not observed with the tyrosine kinase inhibitor sorafenib. Importantly, PG545 significantly enhanced overall survival compared to vehicle control and the sorafenib group, suggesting PG545's inhibitory effect on heparanase is indeed a critical attribute to induce anti-metastatic activity. In addition to blocking a common angiogenic signalling pathway in tumor cells, the expression of heparanase in the primary tumor and lung was also significantly reduced by PG545 treatment. These results support the ongoing development of PG545 and highlight the potential utility in metastatic disease settings.

  13. Glucocorticoid Regulation of Food-Choice Behavior in Humans: Evidence from Cushing's Syndrome.

    Science.gov (United States)

    Moeller, Scott J; Couto, Lizette; Cohen, Vanessa; Lalazar, Yelena; Makotkine, Iouri; Williams, Nia; Yehuda, Rachel; Goldstein, Rita Z; Geer, Eliza B

    2016-01-01

    The mechanisms by which glucocorticoids regulate food intake and resulting body mass in humans are not well-understood. One potential mechanism could involve modulation of reward processing, but human stress models examining effects of glucocorticoids on behavior contain important confounds. Here, we studied individuals with Cushing's syndrome, a rare endocrine disorder characterized by chronic excess endogenous glucocorticoids. Twenty-three patients with Cushing's syndrome (13 with active disease; 10 with disease in remission) and 15 controls with a comparably high body mass index (BMI) completed two simulated food-choice tasks (one with "explicit" task contingencies and one with "probabilistic" task contingencies), during which they indicated their objective preference for viewing high calorie food images vs. standardized pleasant, unpleasant, and neutral images. All participants also completed measures of food craving, and approximately half of the participants provided 24-h urine samples for assessment of cortisol and cortisone concentrations. Results showed that on the explicit task (but not the probabilistic task), participants with active Cushing's syndrome made fewer food-related choices than participants with Cushing's syndrome in remission, who in turn made fewer food-related choices than overweight controls. Corroborating this group effect, higher urine cortisone was negatively correlated with food-related choice in the subsample of all participants for whom these data were available. On the probabilistic task, despite a lack of group differences, higher food-related choice correlated with higher state and trait food craving in active Cushing's patients. Taken together, relative to overweight controls, Cushing's patients, particularly those with active disease, displayed a reduced vigor of responding for food rewards that was presumably attributable to glucocorticoid abnormalities. Beyond Cushing's, these results may have relevance for elucidating

  14. The obesity-associated transcription factor ETV5 modulates circulating glucocorticoids

    Science.gov (United States)

    Gutierrez-Aguilar, Ruth; Thompson, Abigail; Marchand, Nathalie; Dumont, Patrick; Woods, Stephen C.; de Launoit, Yvan; Seeley, Randy J.; Ulrich-Lai, Yvonne M.

    2015-01-01

    The transcription factor E-twenty-six version 5 (ETV5) has been linked with obesity in genome-wide association studies. Moreover, ETV5-deficient mice (knockout; KO) have reduced body weight, lower fat mass, and are resistant to diet-induced obesity, directly linking ETV5 to the regulation of energy balance and metabolism. ETV5 is expressed in hypothalamic brain regions that regulate both metabolism and HPA axis activity, suggesting that ETV5 may also modulate HPA axis function. In order to test this possibility, plasma corticosterone levels were measured in ETV5 KO and wildtype (WT) mice before (pre-stress) and after (post-stress) a mild stressor (intraperitoneal injection). ETV5 deficiency increased both pre- and post-stress plasma corticosterone, suggesting that loss of ETV5 elevated glucocorticoid tone. Consistent with this idea, ETV5 KO mice have reduced thymus weight, suggestive of increased glucocorticoid-induced thymic involution. ETV5 deficiency also decreased the mRNA expression of glucocorticoid receptor (GR), mineralocorticoid receptor (MR), and vasopressin receptor 1A in the hypothalamus, without altering vasopressin, corticotropin-releasing hormone, or oxytocin mRNA expression. In order to test whether reduced MR and GR expression affected glucocorticoid negative feedback, a dexamethasone suppression test was performed. Dexamethasone reduced plasma corticosterone in both ETV5 KO and WT mice, suggesting that glucocorticoid negative feedback was unaltered by ETV5 deficiency. In summary, these data suggest that the obesity-associated transcription factor ETV5 normally acts to diminish circulating glucocorticoids. This might occur directly via ETV5 actions on HPA-regulatory brain circuitry, and/or indirectly via ETV5-induced alterations in metabolic factors that then influence the HPA axis. PMID:25813907

  15. Assessment of faecal glucocorticoid metabolite excretion in captive female fishing cats (Prionailurus viverinus) in Thailand

    Science.gov (United States)

    Khonmee, Jaruwan; Vorawattanatham, Narathip; Pinyopummin, Anuchai; Thitaram, Chatchote; Somgird, Chaleamchat; Punyapornwithaya, Veerasak; Brown, Janine L.

    2016-01-01

    There is little information on the endocrinology of fishing cats (Prionailurus viverinus), an endangered species in Southeast Asia, especially that pertaining to adrenal function. This study characterized faecal glucocorticoid metabolites in female fishing cats housed at Chiang Mai Night Safari to investigate seasonal and age relationships in hormone patterns. Faecal samples were collected 3 days/week for 1 year from seven females ranging in age from 4.5 to 9.6 years. A corticosterone enzyme immunoassay was validated for fishing cats by showing increases (∼60%) in faecal glucocorticoid immunoactivity above pre-treatment baseline levels within 1–2 days after an adrenocorticotrophic hormone injection. Faecal glucocorticoid metabolite concentrations were not related to age (P > 0.05), but there was a seasonal effect, with concentrations being higher (P < 0.05) during the winter (1.54 ± 0.04 µg/g) and rainy season (1.43 ± 0.04 µg/g) compared with the summer (1.22 ± 0.05 µg/g). Significant relationships were found between faecal glucocorticoids and rainfall (positive) and day length (negative), but not a temperature–humidity index. This is the first study to assess adrenal steroidogenic activity in female fishing cats, and we found that glucocorticoid metabolite production was influenced by seasonal factors, but not by age. We conclude that weather patterns should be taken into consideration in future studies of glucocorticoid activity in this endangered species, especially those studies aimed at improving captive management to create self-sustaining and healthy populations. PMID:27293767

  16. A zebrafish model of glucocorticoid resistance shows serotonergic modulation of the stress response

    Directory of Open Access Journals (Sweden)

    Brian eGriffiths

    2012-10-01

    Full Text Available One function of glucocorticoids is to restore homeostasis after an acute stress response by providing negative feedback to stress circuits in the brain. Loss of this negative feedback leads to elevated physiological stress and may contribute to depression, anxiety and post-traumatic stress disorder. We investigated the early, developmental effects of glucocorticoid signaling deficits on stress physiology and related behaviors using a mutant zebrafish, grs357, with non-functional glucocorticoid receptors. These mutants are morphologically inconspicuous and adult-viable. A previous study of adult grs357 mutants showed loss of glucocorticoid-mediated negative feedback and elevated physiological and behavioral stress markers. Already at five days post-fertilization, mutant larvae had elevated whole body cortisol, increased expression of pro-opiomelanocortin (POMC, the precursor of adrenocorticotropic hormone (ACTH, and failed to show normal suppression of stress markers after dexamethasone treatment. Mutant larvae had larger auditory-evoked startle responses compared to wildtype sibling controls (grwt, despite having lower spontaneous activity levels. Fluoxetine (Prozac treatment in mutants decreased startle responding and increased spontaneous activity, making them behaviorally similar to wildtype. This result mirrors known effects of selective serotonin reuptake inhibitors (SSRIs in modifying glucocorticoid signaling and alleviating stress disorders in human patients. Our results suggest that larval grs357 zebrafish can be used to study behavioral, physiological and molecular aspects of stress disorders. Most importantly, interactions between glucocorticoid and serotonin signaling appear to be highly conserved among vertebrates, suggesting deep homologies at the neural circuit level and opening up new avenues for research into psychiatric conditions.

  17. Peripheral mechanisms contributing to the glucocorticoid hypersensitivity in proopiomelanocortin null mice treated with corticosterone

    Science.gov (United States)

    Michailidou, Zoi; Coll, Anthony P; Kenyon, Christopher J; Morton, Nicholas M; O'Rahilly, Stephen; Seckl, Jonathan R; Chapman, Karen E

    2007-01-01

    Proopiomelanocortin (POMC) deficiency causes severe obesity through hyperphagia of hypothalamic origin. However, low glucocorticoid levels caused by adrenal insufficiency mitigate against insulin resistance, hyperphagia and fat accretion in Pomc−/− mice. Upon exogenous glucocorticoid replacement, corticosterone-supplemented (CORT) Pomc−/− mice show exaggerated responses, including excessive fat accumulation, hyperleptinaemia and insulin resistance. To investigate the peripheral mechanisms underlying this glucocorticoid hypersensitivity, we examined the expression levels of key determinants and targets of glucocorticoid action in adipose tissue and liver. Despite lower basal expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which generates active glucocorticoids within cells, CORT-mediated induction of 11β-HSD1 mRNA levels was more pronounced in adipose tissues of Pomc−/− mice. Similarly, CORT treatment increased lipoprotein lipase mRNA levels in all fat depots in Pomc−/− mice, consistent with exaggerated fat accumulation. Glucocorticoid receptor (GR) mRNA levels were selectively elevated in liver and retroperitoneal fat of Pomc−/− mice but were corrected by CORT in the latter depot. In liver, CORT increased phosphoenolpyruvate carboxykinase mRNA levels specifically in Pomc−/− mice, consistent with their insulin-resistant phenotype. Furthermore, CORT induced hypertension in Pomc−/− mice, independently of adipose or liver renin–angiotensin system activation. These data suggest that CORT-inducible 11β-HSD1 expression in fat contributes to the adverse cardiometabolic effects of CORT in POMC deficiency, whereas higher GR levels may be more important in liver. PMID:17592030

  18. Dexras1 mediates glucocorticoid-associated adipogenesis and diet-induced obesity

    Science.gov (United States)

    Cha, Jiyoung Y.; Kim, Hyo Jung; Yu, Jung Hwan; Xu, Jing; Kim, Daham; Paul, Bindu D.; Choi, Hyeonjin; Kim, Seyun; Lee, Yoo Jeong; Ho, Gary P.; Rao, Feng; Snyder, Solomon H.; Kim, Jae-woo

    2013-01-01

    Adipogenesis, the conversion of precursor cells into adipocytes, is associated with obesity and is mediated by glucocorticoids acting via hitherto poorly characterized mechanisms. Dexras1 is a small G protein of the Ras family discovered on the basis of its marked induction by the synthetic glucocorticoid dexamethasone. We show that Dexras1 mediates adipogenesis and diet-induced obesity. Adipogenic differentiation of 3T3-L1 cells is abolished with Dexras1 depletion, whereas overexpression of Dexras1 elicits adipogenesis. Adipogenesis is markedly reduced in mouse embryonic fibroblasts from Dexras1-deleted mice, whereas adiposity and diet-induced weight gain are diminished in the mutant mice. PMID:24297897

  19. Spectroscopic characterization of bone tissue of experimental animals after glucocorticoid treatment and recovery period

    Science.gov (United States)

    Mitić, Žarko J.; Najman, Stevo J.; Cakić, Milorad D.; Ajduković, Zorica R.; Ignjatović, Nenad L.; Nikolić, Ružica S.; Nikolić, Goran M.; Stojanović, Sanja T.; Vukelić, Marija Đ.; Trajanović, Miroslav D.

    2014-09-01

    The influence of glucocorticoids on the composition and mineral/organic content of the mandible in tested animals after recovery and healing phase was investigated in this work. The results of FTIR analysis demonstrated that bone tissue composition was changed after glucocorticoid treatment. The increase of calcium, magnesium, phosphorus content and mineral part of bones was statistically significant in recovery phase and in treatment phase that included calcitonin and thymus extract. Some changes also happened in the organic part of the matrix, as indicated by intensity changes for already present IR bands and the appearance of new IR bands in the region 3500-1300 cm-1.

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

    Directory of Open Access Journals (Sweden)

    Emily C. Dunford

    2016-12-01

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

  1. Glucocorticoides: paradigma de medicina traslacional. De lo molecular al uso clínico Glucocorticoids: examples of translational medicine; from molecular aspects to bedside

    Directory of Open Access Journals (Sweden)

    Héctor A. Serra

    2012-04-01

    Full Text Available Los glucocorticoides o corticosteroides son fármacos antiinflamatorios, antialérgicos e inmunosupresores derivados del cortisol o hidrocortisona, hormona producida por la corteza adrenal. Su uso terapéutico fuera de la endocrinología data de la observación hecha por el reumatólogo Philip Hench quien, suponiendo que los pacientes con artritis reumatoidea tenían un déficit adrenal, inyectó en algunos cortisona, molécula de reciente producción industrial. El resultado obtenido fue tan contundente que se toma como ejemplo de la medicina traslacional. En la actualidad, los glucocorticoides figuran entre las drogas más usadas y, paralelamente, más temidas. Así, el objetivo de esta revisión es señalar los aspectos destacados de su farmacología para su uso racional en la práctica clínica.Glucocorticoids are anti-inflammatory, immunosuppressant and anti-allergic drugs derived from hydrocortisone. Their widespread use was originated from Hench's observations in patients with rheumatoid arthritis. These drugs are examples of translational medicine and they can be envisaged as one of the most prescribed and feared drugs. The objective of this review is to highlight their pharmacological properties and thus, allow a more suitable prescription.

  2. Glucocorticoids facilitate the transcription from the human cytomegalovirus major immediate early promoter in glucocorticoid receptor- and nuclear factor-I-like protein-dependent manner

    International Nuclear Information System (INIS)

    Inoue-Toyoda, Maki; Kato, Kohsuke; Nagata, Kyosuke; Yoshikawa, Hiroyuki

    2015-01-01

    Human cytomegalovirus (HCMV) is a common and usually asymptomatic virus agent in healthy individuals. Initiation of HCMV productive infection depends on expression of the major immediate early (MIE) genes. The transcription of HCMV MIE genes is regulated by a diverse set of transcription factors. It was previously reported that productive HCMV infection is triggered probably by elevation of the plasma hydroxycorticoid level. However, it is poorly understood whether the transcription of MIE genes is directly regulated by glucocorticoid. Here, we found that the dexamethasone (DEX), a synthetic glucocorticoid, facilitates the transcription of HCMV MIE genes through the MIE promoter and enhancer in a glucocorticoid receptor (GR)-dependent manner. By competitive EMSA and reporter assays, we revealed that an NF-I like protein is involved in DEX-mediated transcriptional activation of the MIE promoter. Thus, this study supports a notion that the increased level of hydroxycorticoid in the third trimester of pregnancy reactivates HCMV virus production from the latent state. - Highlights: • DEX facilitates the transcription from the HCMV MIE promoter. • GR is involved in DEX-dependent transcription from the HCMV MIE promoter. • A 17 bp repeat is responsible for the HCMV MIE promoter activation by DEX. • An NF-I-like protein is involved in the HCMV MIE promoter activation by DEX

  3. Naturally occurring, tumor-specific, therapeutic proteins.

    Science.gov (United States)

    Argiris, Konstantinos; Panethymitaki, Chrysoula; Tavassoli, Mahvash

    2011-05-01

    The emerging approach to cancer treatment known as targeted therapies offers hope in improving the treatment of therapy-resistant cancers. Recent understanding of the molecular pathogenesis of cancer has led to the development of targeted novel drugs such as monoclonal antibodies, small molecule inhibitors, mimetics, antisense and small interference RNA-based strategies, among others. These compounds act on specific targets that are believed to contribute to the development and progression of cancers and resistance of tumors to conventional therapies. Delivered individually or combined with chemo- and/or radiotherapy, such novel drugs have produced significant responses in certain types of cancer. Among the most successful novel compounds are those which target tyrosine kinases (imatinib, trastuzumab, sinutinib, cetuximab). However, these compounds can cause severe side-effects as they inhibit pathways such as epidermal growth factor receptor (EGFR) or platelet-derived growth factor receptor, which are also important for normal functions in non-transformed cells. Recently, a number of proteins have been identified which show a remarkable tumor-specific cytotoxic activity. This toxicity is independent of tumor type or specific genetic changes such as p53, pRB or EGFR aberrations. These tumor-specific killer proteins are either derived from common human and animal viruses such as E1A, E4ORF4 and VP3 (apoptin) or of cellular origin, such as TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) and MDA-7 (melanoma differentiation associated-7). This review aims to present a current overview of a selection of these proteins with preferential toxicity among cancer cells and will provide an insight into the possible mechanism of action, tumor specificity and their potential as novel tumor-specific cancer therapeutics.

  4. An investigation of the mimetic enzyme activity of two-dimensional Pd-based nanostructures

    Science.gov (United States)

    Wei, Jingping; Chen, Xiaolan; Shi, Saige; Mo, Shiguang; Zheng, Nanfeng

    2015-11-01

    In this work, we investigated the mimetic enzyme activity of two-dimensional (2D) Pd-based nanostructures (e.g. Pd nanosheets, Pd@Au and Pd@Pt nanoplates) and found that they possess intrinsic peroxidase-, oxidase- and catalase-like activities. These nanostructures were able to activate hydrogen peroxide or dissolved oxygen for catalyzing the oxidation of organic substrates, and decompose hydrogen peroxide to generate oxygen. More systematic investigations revealed that the peroxidase-like activities of these Pd-based nanomaterials were highly structure- and composition-dependent. Among them, Pd@Pt nanoplates displayed the highest peroxidase-like activity. Based on these findings, Pd-based nanostructures were applied for the colorimetric detection of H2O2 and glucose, and also the electro-catalytic reduction of H2O2. This work offers a promising prospect for the application of 2D noble metal nanostructures in biocatalysis.In this work, we investigated the mimetic enzyme activity of two-dimensional (2D) Pd-based nanostructures (e.g. Pd nanosheets, Pd@Au and Pd@Pt nanoplates) and found that they possess intrinsic peroxidase-, oxidase- and catalase-like activities. These nanostructures were able to activate hydrogen peroxide or dissolved oxygen for catalyzing the oxidation of organic substrates, and decompose hydrogen peroxide to generate oxygen. More systematic investigations revealed that the peroxidase-like activities of these Pd-based nanomaterials were highly structure- and composition-dependent. Among them, Pd@Pt nanoplates displayed the highest peroxidase-like activity. Based on these findings, Pd-based nanostructures were applied for the colorimetric detection of H2O2 and glucose, and also the electro-catalytic reduction of H2O2. This work offers a promising prospect for the application of 2D noble metal nanostructures in biocatalysis. Electronic supplementary information (ESI) available: TEM images, EDX and dispersion stability of Pd-based nanomaterials

  5. Interaction of basal forebrain cholinergic neurons with the glucocorticoid system in stress regulation and cognitive impairment

    Directory of Open Access Journals (Sweden)

    Saswati ePaul

    2015-04-01

    Full Text Available A substantial number of studies on basal forebrain cholinergic neurons (BFCN have provided compelling evidence for their role in the etiology of stress, cognitive aging, Alzheimer’s disease (AD, and other neurodegenerative diseases. BFCN project to a broad range of cortical sites and limbic structures, including the hippocampus, and are involved in stress and cognition. In particular, the hippocampus, the primary target tissue of the glucocorticoid stress hormones, is associated with cognitive function in tandem with hypothalamic-pituitary-adrenal (HPA axis modulation. The present review summarizes glucocorticoid and HPA axis research to date in an effort to establish the manner in which stress affects the release of acetylcholine, glucocorticoids, and their receptor in the context of cognitive processes. We attempt to provide the molecular interactive link between the glucocorticoids and cholinergic system that contributes to BFCN degeneration in stress-induced acceleration of cognitive decline in aging and AD. We also discuss the importance of animal models in facilitating such studies for pharmacological use, which could help decipher disease states and propose leads for pharmacological intervention.

  6. Glucocorticoid-induced effects on the growth plate and the IGF system

    NARCIS (Netherlands)

    Smink, Jeske Johanna

    2003-01-01

    Glucocorticoids (GCs) are widely used as anti-inflammatory and immunosuppressive drugs. The use of these potent drugs, however, often results in side-effects, such as growth retardation in children. For already many years, this GC-induced growth retardation is suggested to involve impaired action of

  7. Effect of lipopolysaccharide and antidepressant drugs on glucocorticoid receptor-mediated gene transcription

    Czech Academy of Sciences Publication Activity Database

    Budziszewska, B.; Basta-Kaim, A.; Kubera, M.; Jaworska, L.; Leskiewicz, M.; Tetich, M.; Otczyk, M.; Zajícová, Alena; Holáň, Vladimír; Lasoń, W.

    2005-01-01

    Roč. 57, č. 4 (2005), s. 540-544 ISSN 1734-1140 Grant - others:State Committee for Scientific Research (KBN)(PL) 6P05A076 Institutional research plan: CEZ:AV0Z5052915 Keywords : glucocorticoid receptor * antidepressant drugs * interleukin-6 Subject RIV: EB - Genetics ; Molecular Biology

  8. Antisense to the glucocorticoid receptor in hippocampal dentate gyrus reduces immobility in forced swim test

    NARCIS (Netherlands)

    Korte, S.M.; de Kloet, E.R.; Buwalda, B; Bouman, S.D.; Bohus, B

    1996-01-01

    Immobility time of rats in the forced swim test was reduced after bilateral infusion of an 18-mer antisense phosphorothioate oligodeoxynucleotide targeted to the glucocorticoid receptor mRNA into the dentate gyrus of the hippocampus. Vehicle-, sense- and scrambled sequence-treated animals spent

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

    NARCIS (Netherlands)

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

    2012-01-01

    Glucocorticoids are known to enhance the consolidation of memory of emotionally arousing experiences by acting upon a network of interconnected brain regions. Although animal studies typically do not consider the insular cortex (IC) to be part of this network, the present findings indicate that the

  10. Endocannabinoids in the rat basolateral amygdala enhance memory consolidation and enable glucocorticoid modulation of memory

    NARCIS (Netherlands)

    Campolongo, Patrizia; Roozendaal, Benno; Trezza, Viviana; Hauer, Daniela; Schelling, Gustav; McGaugh, James L.; Cuomo, Vincenzo

    2009-01-01

    Extensive evidence indicates that the basolateral complex of the amygdala (BLA) modulates the consolidation of memories for emotionally arousing experiences, an effect that involves the activation of the glucocorticoid system. Because the BLA expresses high densities of cannabinoid CB1 receptors,

  11. The glucocorticoid receptor in the limbic system of the human brain

    NARCIS (Netherlands)

    Wang, Qian

    2016-01-01

    Glucocorticoid hormones (GCs) are important mediators of the stress response in mammals including humans. GCs are released from the adrenal in response to stress and affect numerous processes in the body and brain. Their levels are controlled via negative feedback exerted by GC binding to brain

  12. Identifying a Mechanism for Crosstalk Between the Estrogen and Glucocorticoid Receptors | Center for Cancer Research

    Science.gov (United States)

    Estrogen has long been known to play important roles in the development and progression of breast cancer. Its receptor (ER), a member of the steroid receptor family, binds to estrogen response elements (EREs) in DNA and regulates gene transcription. More recently, another steroid receptor family member, the glucocorticoid receptor (GR), has been implicated in breast cancer

  13. Localized demodicosis due to Demodex cati on the muzzle of two cats treated with inhalant glucocorticoids.

    Science.gov (United States)

    Bizikova, Petra

    2014-06-01

    Feline demodicosis due to Demodex cati is a rare skin disease often associated with concurrent disease and generalized immunosuppression. Local immunosuppression due to the application of topical immunomodulatory drugs, such as glucocorticoids and tacrolimus, or by tumour cells has been suggested as a potential trigger for development of localized demodicosis in humans and animals. The goal was to describe two cats with asthma that developed localized demodicosis on the muzzle as a result of chronic therapy with a glucocorticoid administered via dispensing inhaler mask. In both cats, the muzzle area exposed to the fluticasone-dispensing chamber exhibited patchy alopecia, mild erythema, crusting and scaling. Deep skin scraping revealed D. cati. Discontinuation or reduction of fluticasone and administration of milbemycin resulted in resolution of clinical signs within 2 months in both cats. A negative skin scrape was obtained after 7 months of milbemycin in one of the cats. Demodicosis should be considered as a possible differential diagnosis in cats with primary alopecia or other skin lesions on the face exposed to inhalant glucocorticoids. Minimization of contact between the inhalant glucocorticoid and the skin can be achieved by wiping residual powder from the face and by keeping the mask tightly pressed to the skin to avoid contact with the surrounding area. © 2014 ESVD and ACVD.

  14. Tumour necrosis factor-α inhibitors are glucocorticoid-sparing in rheumatoid arthritis

    DEFF Research Database (Denmark)

    Nilsson, Anna Christine; Christensen, Anne Friesgaard; Junker, Peter

    2011-01-01

    Rheumatoid arthritis (RA) is a chronic disease with autoimmune traits of unknown aetiology which primarily affects synovial joints. Glucocorticoids (GCs) are still widely used in RA treatment despite the expanding use of targeted and very efficient agents. The objective of this study was to assess...

  15. Transcriptional regulation of the tyrosine hydroxylase gene by glucocorticoid and cyclic AMP

    International Nuclear Information System (INIS)

    Lewis, E.J.; Harrington, C.A.; Chikaraishi, D.M.

    1987-01-01

    Glucocorticoid and cyclic AMP increase tyrosine hydroxylase (TH) activity and mRNA levels in pheochromocytoma cultures. The transcriptional activity of the TH gene, as measured by nuclear run-on assay, is also increased when cultures are treated with the synthetic glucocorticoid dexamethasone or agents that increase intracellular cyclic AMP, such as forskolin and 8-BrcAMP. Both inducers effect transcriptional changes within 10 min after treatment and are maximal after 30 min for forskolin and after 60 min for dexamethasone. The 5' flanking sequences of the TH gene were fused to the bacterial gene chloramphenicol acetyltransferase (CAT), and the hybrid gene was transfected into pheochromocytoma cultures and GH 4 pituitary cells. In both cell lines, a region of the TH gene containing bases -272 to +27 conferred induction of CAT by cyclic AMP, but not by glucocorticoid. The same results were found when a region of the TH gene containing -773 to + 27 was used. Thus, the sequences required for induction of TH by cyclic AMP are contained within 272 bases of 5' flanking sequence, but sequences sufficient for glucocorticoid regulation are not contained with 773 bases

  16. Topical glucocorticoid has no antinociceptive or anti-inflammatory effect in thermal injury

    DEFF Research Database (Denmark)

    Pedersen, J L; Møiniche, S; Kehlet, H

    1994-01-01

    We have studied the antinociceptive and anti-inflammatory effects of topical glucocorticoids in human thermal injury. The right and left legs of 12 healthy volunteers were allocated randomly to be treated with either 0.05% clobetasol propionate cream or placebo in a double-blind trial. Thermal...

  17. Concanavalin a increases beta-adrenergic and glucocorticoid receptors in porcine splenocytes

    International Nuclear Information System (INIS)

    Kelley, K.N.; Westly, H.J.

    1986-01-01

    We identified specific glucocorticoid and beta-adrenergic receptors on porcine splenocytes. There are 2000 to 4000 glucocorticoid receptors per cell with a K /SUB D/ of 2 to 4 nM and 1000 beta-adrenergic receptors with a K /SUB D/ of 0.3 to 0.6 nM. When splenocytes were incubated with concanavalin A (Con A), there was an approximate 2-fold increase in both gluococorticoid and beta-adrenergic receptors with no change in binding affinity. Incubation of splenocytes with cortisol as low as 40 nM (13 ng/ml) inhibited proliferation in response to Con A. This inhibitory effect of cortisol was not due to cytotoxic effects of glucocorticoids. At maximal physiologic concentrations (400 nM; 135 ng/ml), cortisol caused reductions in Con A activation of thymocytes and peripheral blood mononuclear cells. When eight wk old pigs were restrained, there was an increase in plasma cortisol, atrophy of thymus and reduction in skin test responses to phytohemagglutinin. On the basis of the data, we suggest that physiologic concentrations of stress asociated hormones affect functional activities of porcine lymphoid cells. Since activated splenocytes display increased numbers of receptors for these hormones, perhaps glucocorticoids or catecholamines normally function in vivo to suppress clonal expansion of antigen activated and autoreactive T lymphocytes

  18. Bile acids modulate glucocorticoid metabolism and the hypothalamic-pituitary-adrenal axis in obstructive jaundice

    DEFF Research Database (Denmark)

    McNeilly, Alison D; Macfarlane, David P; O'Flaherty, Emmett

    2010-01-01

    Suppression of the hypothalamic-pituitary-adrenal axis occurs in cirrhosis and cholestasis and is associated with increased concentrations of bile acids. We investigated whether this was mediated through bile acids acting to impair steroid clearance by inhibiting glucocorticoid metabolism by 5bet...

  19. Efficacy of Vitamin K2 for Glucocorticoid-induced Osteoporosis in Patients with Systemic Autoimmune Diseases.

    Science.gov (United States)

    Shikano, Kotaro; Kaneko, Kaichi; Kawazoe, Mai; Kaburaki, Makoto; Hasunuma, Tomoko; Kawai, Shinichi

    2016-01-01

    Objective Vitamin K2 (menatetrenone) is an effective treatment for patients with postmenopausal osteoporosis. We herein performed a subanalysis of patients with systemic autoimmune diseases undergoing glucocorticoid therapy in our previous prospective study. Methods Sixty patients were categorized into a group with vitamin K2 treatment (n=20, Group A) and a group without vitamin K2 treatment (n=40, Group B). All patients were treated with bisphosphonates. Results Serum levels of osteocalcin and undercarboxylated osteocalcin decreased significantly after the start of glucocorticoid therapy in both groups, while the serum osteocalcin level was significantly higher in Group A than Group B during the third (p=0.0250) and fourth weeks (p=0.0155). The serum level of the N-terminal peptide of type I procollagen, a bone formation marker, decreased during glucocorticoid therapy, but was significantly higher in Group A than Group B during the fourth week (p=0.0400). The bone mineral density and fracture rate showed no significant differences between the two groups. Conclusion Although vitamin K2 improves bone turnover markers in patients with osteoporosis on glucocorticoid therapy, it has no significant effect on the bone mineral density and fracture rate after 1.5 years of treatment.

  20. Early Life Stress Effects on the Glucocorticoid - BDNF interplay in the Hippocampus

    Directory of Open Access Journals (Sweden)

    Nikolaos P Daskalakis

    2015-11-01

    Full Text Available Early life stress (ELS is implicated in the etiology of multiple psychiatric disorders. Important biological effects of ELS are manifested in stress-susceptible regions of the hippocampus and are partially mediated by long-term effects on glucocorticoid and/or neurotrophin signaling pathways. Glucocorticoid (GC signaling mediates the regulation of the stress response to maintain homeostasis, while neurotrophin signaling plays a key role in neuronal outgrowth and is crucial for axonal guidance and synaptic integrity. The neurotrophin and glucocorticoid signaling pathways co-exist throughout the central nervous system (CNS, particularly in the hippocampus, which has high expression of glucocorticoid and mineralocorticoid receptors (GR and MR as well as brain-derived neurotrophic factor (BDNF and its receptor, tropomyosin-related kinase receptor B (TrkB. This review addresses the effects of ELS paradigms on GC- and BDNF- dependent mechanisms and their crosstalk in the hippocampus, including potential implications for the pathogenesis of common stress-related disorders.

  1. Effects of a single glucocorticoid injection on propylene glycol-treated cows with clinical ketosis

    NARCIS (Netherlands)

    van der Drift, Saskia G A; Houweling, Martin; Bouman, Marina; Koets, Ad P; Tielens, Aloysius G M; Nielen, Mirjam; Jorritsma, Ruurd

    2015-01-01

    This study investigated the metabolic effects of glucocorticoids when administered to propylene glycol-treated cows with clinical ketosis. Clinical ketosis was defined by depressed feed intake and milk production, and a maximal score for acetoacetate in urine. All cows received 250 mL oral propylene

  2. Determination of Glucocorticoids in UPLC-MS in Environmental Samples from an Occupational Setting

    Directory of Open Access Journals (Sweden)

    Enrico Oddone

    2015-01-01

    Full Text Available Occupational exposures to glucocorticoids are still a neglected issue in some work environments, including pharmaceutical plants. We developed an analytical method to quantify simultaneously 21 glucocorticoids using UPLC coupled with mass spectrometry to provide a basis to carry out environmental monitoring. Samples were taken from air, hand-washing tests, pad-tests and wipe-tests. This paper reports the contents of the analytical methodology, along with the results of this extensive environmental and personal monitoring of glucocorticoids. The method in UPLC-MS turned out to be suitable and effective for the aim of the study. Wipe-test and pad-test desorption was carried out using 50 mL syringes, a simple technique that saves time without adversely affecting analyte recovery. Results showed a widespread environmental pollution due to glucocorticoids. This is of particular concern. Evaluation of the dose absorbed by each worker and identification of a biomarker for occupational exposure will contribute to assessment and prevention of occupational exposure.

  3. Decreased ligand affinity rather than glucocorticoid receptor down-regulation in patients with endogenous Cushing's syndrome

    NARCIS (Netherlands)

    N.A.T.M. Huizenga (Nannette); W.W. de Herder (Wouter); J.W. Koper (Jan); P. de Lange (Pieter); A.O. Brinkmann (Albert); F.H. de Jong (Frank); S.W.J. Lamberts (Steven); A-J. van der Lely (Aart-Jan)

    2000-01-01

    textabstractOBJECTIVE: Glucocorticoids (GCs) serve a variety of important functions throughout the body. The synthesis and secretion of GCs are under the strict influence of the hypothalamo-pituitary-adrenal axis. The mechanisms of action of GCs are mediated by the

  4. Glucocorticoids Enhance Muscle Proteolysis through a Myostatin-Dependent Pathway at the Early Stage.

    Science.gov (United States)

    Wang, Ruxia; Jiao, Hongchao; Zhao, Jingpeng; Wang, Xiaojuan; Lin, Hai

    2016-01-01

    Myostatin, a member of the TGF-β superfamily of secreted proteins, is expressed primarily in skeletal muscle. It negatively regulates muscle mass and is associated with glucocorticoid-induced muscle atrophy. However, it remains unclear whether myostatin is involved in glucocorticoid-induced muscle protein turnover. The aim of the present study was to investigate the role of myostatin in protein metabolism during dexamethasone (DEX) treatment. Protein synthesis rates and the expression of the genes for myostatin, ubiquitin-proteasome atrogin-1, MuRF1, FoxO1/3a and mTOR/p70S6K were determined. The results show that DEX decreased (Pmyostatin. DEX increased (P0.05). The phosphorylation levels of mTOR and p70S6K were decreased by DEX treatment (Pmyostatin (P 0.05). In conclusion, the present study suggests that the myostatin signalling pathway is associated with glucocorticoid-induced muscle protein catabolism at the beginning of exposure. Myostatin is not a main pathway associated with the suppression of muscle protein synthesis by glucocorticoids.

  5. Glucocorticoid receptor number predicts increase in amygdala activity after severe stress

    NARCIS (Netherlands)

    Geuze, Elbert; van Wingen, Guido A.; van Zuiden, Mirjam; Rademaker, Arthur R.; Vermetten, Eric; Kavelaars, Annemieke; Fernández, Guillén; Heijnen, Cobi J.

    2012-01-01

    Introduction: Individuals who are exposed to a traumatic event are at increased risk of developing psychiatric disorders such as posttraumatic stress disorder (PTSD). Studies have shown that increased amygdala activity is frequently found in patients with PTSD. In addition, pre-trauma glucocorticoid

  6. LONGITUDINAL CHANGES IN GLUCOCORTICOID RECEPTOR 1F METHYLATION AND PSYCHOPATHOLOGY AFTER MILITARY DEPLOYMENT

    NARCIS (Netherlands)

    Schur, Remmelt; Boks, Marco; Rutten, Bart P. F.; Daskalakis, Nikolaos; de Nijs, Laurence; Joels, Marian; Kahn, Rene S.; Geuze, Elbert; Vermetten, Eric; Vinkers, Christiaan

    2017-01-01

    Background The glucocorticoid receptor (GR) 1F region is involved in transcription and expression of the GR protein and influences hypothalamic-pituitary-adrenal (HPA)-axis activity. Several studies have investigated GR-1F DNA methylation in the context of traumatic stress and psychiatric disorders,

  7. Longitudinal changes in glucocorticoid receptor exon 1F methylation and psychopathology after military deployment

    NARCIS (Netherlands)

    Schür, R R; Boks, M P; Rutten, Bart P. F.; Daskalakis, N.P.; de Nijs, Laurence; van Zuiden, M.; Kavelaars, A; Heijnen, C J; Joëls, M; Kahn, R S; Geuze, E; Vermetten, E; Vinkers, C H

    2017-01-01

    Several cross-sectional studies have demonstrated the relevance of DNA methylation of the glucocorticoid receptor exon 1F region (GR-1F) for trauma-related psychopathology. We conducted a longitudinal study to examine GR-1F methylation changes over time in relation to trauma exposure and the

  8. Electroconvulsive stimulations normalizes stress-induced changes in the glucocorticoid receptor and behaviour

    DEFF Research Database (Denmark)

    Hageman, Ida; Nielsen, Marianne; Wörtwein, Gitta

    2009-01-01

    Animal models of chronic stress, such as 21 days of 6h/daily restraint stress cause changes in neuronal morphology in the hippocampus and alter behaviour. These changes are partly mediated by the glucocorticoids. The objective of this study was threefold: (1) to study how this particular chronic ...

  9. Repeated blockade of mineralocorticoid receptors, but not of glucocorticoid receptors impairs food rewarded spatial learning

    NARCIS (Netherlands)

    Douma, B. R.; Korte, S. M.; Buwalda, B.; La Fleur, S. E.; Bohus, B.; Luiten, P. G.

    1998-01-01

    Corticosteroids from the adrenal cortex influence a variety of behaviours including cognition, learning and memory. These hormones act via two intracellular receptors, the mineralo-corticoid receptor (MR) and the glucocorticoid receptor (GR). These two receptor types display a high concentration and

  10. Repeated blockade of mineralocorticoid receptors, but not of glucocorticoid receptors impairs food rewarded spatial learning

    NARCIS (Netherlands)

    Douma, BRK; Korte, SM; Buwalda, B; la Fleur, SE; Bohus, B; Luiten, PGM

    Corticosteroids from the adrenal cortex influence a variety of behaviours including cognition, learning and memory. These hormones act via two intracellular receptors, the mineralo-corticoid receptor (MR) and the glucocorticoid receptor (GR). These two receptor types display a high concentration and

  11. Fast effects of glucocorticoids on memory-related network oscillations in the mouse hippocampus.

    Science.gov (United States)

    Weiss, E K; Krupka, N; Bähner, F; Both, M; Draguhn, A

    2008-05-01

    Transient or lasting increases in glucocorticoids accompany deficits in hippocampus-dependent memory formation. Recent data indicate that the formation and consolidation of declarative and spatial memory are mechanistically related to different patterns of hippocampal network oscillations. These include gamma oscillations during memory acquisition and the faster ripple oscillations (approximately 200 Hz) during subsequent memory consolidation. We therefore analysed the effects of acutely applied glucocorticoids on network activity in mouse hippocampal slices. Evoked field population spikes and paired-pulse responses were largely unaltered by corticosterone or cortisol, respectively, despite a slight increase in maximal population spike amplitude by 10 microm corticosterone. Several characteristics of sharp waves and superimposed ripple oscillations were affected by glucocorticoids, most prominently the frequency of spontaneously occurring sharp waves. At 0.1 microm, corticosterone increased this frequency, whereas maximal (10 microm) concentrations led to a reduction. In addition, gamma oscillations became slightly faster and less regular in the presence of high doses of corticosteroids. The present study describes acute effects of glucocorticoids on sharp wave-ripple complexes and gamma oscillations in mouse hippocampal slices, revealing a potential background for memory deficits in the presence of elevated levels of these hormones.

  12. Regulation of Adult Neurogenesis and Plasticity by (Early) Stress, Glucocorticoids, and Inflammation

    NARCIS (Netherlands)

    Lucassen, P.J.; Oomen, C.A.; Naninck, E.F.G.; Fitzsimons, C.P.; van Dam, A.M.; Czeh, B.; Korosi, A.

    2015-01-01

    Exposure to stress is one of the best-known negative regulators of adult neurogenesis (AN). We discuss changes in neurogenesis in relation to exposure to stress, glucocorticoid hormones, and inflammation, with a particular focus on early development and on lasting effects of stress. Although the

  13. Glucocorticoid metabolism and 11beta-hydroxysteroid dehydrogenase during sepsis and inflammation

    Czech Academy of Sciences Publication Activity Database

    Leden, Pavel; Ergang, Peter; Pácha, Jiří; Kment, M.

    2006-01-01

    Roč. 26, č. S1 (2006), s. 34-34 ISSN 1073-2322. [Congress of the European Shock Society /12./. 14.09.2006-16.09.2006, Ulm] Grant - others:IGA UK(CZ) 77/2006/C Keywords : glucocorticoid * metabolism * sepsis * inflammation Subject RIV: ED - Physiology

  14. Longitudinal changes in glucocorticoid receptor exon 1(F) methylation and psychopathology after military deployment

    NARCIS (Netherlands)

    Schür, R. R.; Boks, M. P.; Rutten, B. P. F.; Daskalakis, N. P.; de Nijs, L.; van Zuiden, M.; Kavelaars, A.; Heijnen, C. J.; Joëls, M.; Kahn, R. S.; Geuze, E.; Vermetten, E.; Vinkers, C. H.

    2017-01-01

    Several cross-sectional studies have demonstrated the relevance of DNA methylation of the glucocorticoid receptor exon 1(F) region (GR-1(F)) for trauma-related psychopathology. We conducted a longitudinal study to examine GR-1(F) methylation changes over time in relation to trauma exposure and the

  15. Stress, glucocorticoid hormones, and hippocampal neural progenitor cells: implications to mood disorders.

    Science.gov (United States)

    Kino, Tomoshige

    2015-01-01

    The hypothalamic-pituitary-adrenal (HPA) axis and its end-effectors glucocorticoid hormones play central roles in the adaptive response to numerous stressors that can be either internal or external. Thus, this system has a strong impact on the brain hippocampus and its major functions, such as cognition, memory as well as behavior, and mood. The hippocampal area of the adult brain contains neural stem cells or more committed neural progenitor cells, which retain throughout the human life the ability of self-renewal and to differentiate into multiple neural cell lineages, such as neurons, astrocytes, and oligodendrocytes. Importantly, these characteristic cells contribute significantly to the above-indicated functions of the hippocampus, while various stressors and glucocorticoids influence proliferation, differentiation, and fate of these cells. This review offers an overview of the current understanding on the interactions between the HPA axis/glucocorticoid stress-responsive system and hippocampal neural progenitor cells by focusing on the actions of glucocorticoids. Also addressed is a further discussion on the implications of such interactions to the pathophysiology of mood disorders.

  16. A model for population dynamics of the mimetic butterfly Papilio polytes in the Sakishima Islands, Japan.

    Science.gov (United States)

    Sekimura, Toshio; Fujihashi, Yuta; Takeuchi, Yasuhiro

    2014-11-21

    We present a mathematical model for population dynamics of the mimetic swallowtail butterfly Papilio polytes in the Sakishima Islands, Japan. The model includes four major variables, that is, population densities of three kinds of butterflies (two female forms f. cyrus, f. polytes and the unpalatable butterfly Pachliopta aristolochiae) and their predator. It is well-known that the non-mimic f. cyrus resembles and attracts the male most, and the mimic f. polytes mimics the model butterfly P. aristolochiae. Based on experimental evidence, we assume that two forms f. cyrus and f. polytes interact under intraspecific competition for resources including the male, and the growth rate of f. cyrus is higher than that of f. polytes. We further assume that both the benefit of mimicry for the mimic f. polytes and the cost for the model are dependent on their relative frequencies, i.e. the motality of the mimic by predation decreases with increase in frequency of the model, while the motality of the model increases as the frequency of the mimic increases. Taking the density-dependent effect through carrying capacity into account, we set up a model system consisting of three ordinary differential equations (ODEs), analyze it mathematically and provide computer simulations that confirm the analytical results. Our results reproduce field records on population dynamics of P. polytes in the Miyako-jima Island. They also explain the positive dependence of the relative abundance (RA) of the mimic on the advantage index (AI) of the mimicry in the Sakishima Islands defined in Section 2. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. Continuous volatile fatty acid production from lignocellulosic biomass by a novel rumen-mimetic bioprocess.

    Science.gov (United States)

    Agematu, Hitosi; Takahashi, Takehiko; Hamano, Yoshio

    2017-11-01

    Lignocellulosic biomass is an attractive source of biofuels and biochemicals, being abundant in various plant sources. However, processing this type of biomass requires hydrolysis of cellulose. The proposed rumen-mimetic bioprocess consists of dry-pulverization of lignocellulosic biomass and pH-controlled continuous cultivation of ruminal bacteria using ammonium as a nitrogen source. In this study, ruminal bacteria were continuously cultivated for over 60 days and used to digest microcrystalline cellulose, rice straw, and Japanese cedar to produce volatile fatty acids (VFAs). The ruminal bacteria grew well in the chemically defined medium. The amounts of VFAs produced from 20 g of cellulose, rice straw, and Japanese cedar were 183 ± 29.7, 69.6 ± 12.2, and 21.8 ± 12.9 mmol, respectively. Each digestion completed within 24 h. The carbon yield was 60.6% when 180 mmol of VFAs was produced from 20 g of cellulose. During the cultivation, the bacteria were observed to form flocs that enfolded the feed particles. These flocs likely contain all of the bacterial species necessary to convert lignocellulosic biomass to VFAs and microbial protein symbiotically. Denaturing gradient gel electrophoresis (DGGE) analysis of PCR-amplified 16S rDNA fragments revealed that the bacterial community was relatively stable after 1 week in cultivation, though it was different from the original community structure. Furthermore, sequence analysis of the DGGE bands indicates that the microbial community includes a cellulolytic bacterium, a bacterium acting synergistically with cellulolytic bacteria, and a propionate-producing bacterium, as well as other anaerobic bacteria. Copyright © 2017 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

  18. Perylene Diimide as a Precise Graphene-like Superoxide Dismutase Mimetic

    Energy Technology Data Exchange (ETDEWEB)

    Jalilov, Almaz S.; Nilewski, Lizanne G.; Berka, Vladimir [Hematology,; Zhang, Chenhao; Yakovenko, Andrey A. [Argonne National Laboratory, X-ray Science Division,; Wu, Gang [Hematology,; Kent, Thomas A. [Department; Center for Translational Research in Inflammatory Diseases, Michel E. DeBakey VA Medical Center, Houston, Texas 77030, United States; Tsai, Ah-Lim [Hematology,; Tour, James M.

    2017-01-31

    Here we show that the active portion of a graphitic nanoparticle can be mimicked by a perylene diimide (PDI) to explain the otherwise elusive biological and electrocatalytic activity of the nanoparticle construct. Development of molecular analogues that mimic the antioxidant properties of oxidized graphenes, in this case the poly(ethylene glycolated) hydrophilic carbon clusters (PEG–HCCs), will afford important insights into the highly efficient activity of PEG–HCCs and their graphitic analogues. PEGylated perylene diimides (PEGn–PDI) serve as well-defined molecular analogues of PEG–HCCs and oxidized graphenes in general, and their antioxidant and superoxide dismutase-like (SOD-like) properties were studied. PEGn–PDIs have two reversible reduction peaks, which are more positive than the oxidation peak of superoxide (O2•–). This is similar to the reduction peak of the HCCs. Thus, as with PEG–HCCs, PEGn–PDIs are also strong single-electron oxidants of O2•–. Furthermore, reduced PEGn–PDI, PEGn–PDI•–, in the presence of protons, was shown to reduce O2•– to H2O2 to complete the catalytic cycle in this SOD analogue. The kinetics of the conversion of O2•– to O2 and H2O2 by PEG8–PDI was measured using freeze-trap EPR experiments to provide a turnover number of 133 s–1; the similarity in kinetics further supports that PEG8–PDI is a true SOD mimetic. Finally, PDIs can be used as catalysts in the electrochemical oxygen reduction reaction in water, which proceeds by a two-electron process with the production of H2O2, mimicking graphene oxide nanoparticles that are otherwise difficult to study spectroscopically.

  19. Three-Dimensional Elastomeric Scaffolds Designed with Cardiac-Mimetic Structural and Mechanical Features

    Science.gov (United States)

    Neal, Rebekah A.; Jean, Aurélie; Park, Hyoungshin; Wu, Patrick B.; Hsiao, James; Engelmayr, George C.; Langer, Robert

    2013-01-01

    Tissue-engineered constructs, at the interface of material science, biology, engineering, and medicine, have the capacity to improve outcomes for cardiac patients by providing living cells and degradable biomaterials that can regenerate the native myocardium. With an ultimate goal of both delivering cells and providing mechanical support to the healing heart, we designed three-dimensional (3D) elastomeric scaffolds with (1) stiffnesses and anisotropy mimicking explanted myocardial specimens as predicted by finite-element (FE) modeling, (2) systematically varied combinations of rectangular pore pattern, pore aspect ratio, and strut width, and (3) structural features approaching tissue scale. Based on predicted mechanical properties, three scaffold designs were selected from eight candidates for fabrication from poly(glycerol sebacate) by micromolding from silicon wafers. Large 20×20 mm scaffolds with high aspect ratio features (5:1 strut height:strut width) were reproducibly cast, cured, and demolded at a relatively high throughput. Empirically measured mechanical properties demonstrated that scaffolds were cardiac mimetic and validated FE model predictions. Two-layered scaffolds providing fully interconnected pore networks were fabricated by layer-by-layer assembly. C2C12 myoblasts cultured on one-layered scaffolds exhibited specific patterns of cell elongation and interconnectivity that appeared to be guided by the scaffold pore pattern. Neonatal rat heart cells cultured on two-layered scaffolds for 1 week were contractile, both spontaneously and in response to electrical stimulation, and expressed sarcomeric α-actinin, a cardiac biomarker. This work not only demonstrated several scaffold designs that promoted functional assembly of rat heart cells, but also provided the foundation for further computational and empirical investigations of 3D elastomeric scaffolds for cardiac tissue engineering. PMID:23190320

  20. Bio-Mimetics of Disaster Anticipation-Learning Experience and Key-Challenges.

    Science.gov (United States)

    Tributsch, Helmut

    2013-03-19

    Anomalies in animal behavior and meteorological phenomena before major earthquakes have been reported throughout history. Bio-mimetics or bionics aims at learning disaster anticipation from animals. Since modern science is reluctant to address this problem an effort has been made to track down the knowledge available to ancient natural philosophers. Starting with an archaeologically documented human sacrifice around 1700 B.C. during the Minoan civilization immediately before a large earthquake, which killed the participants, earthquake prediction knowledge throughout antiquity is evaluated. Major practical experience with this phenomenon has been gained from a Chinese earthquake prediction initiative nearly half a century ago. Some quakes, like that of Haicheng, were recognized in advance. However, the destructive Tangshan earthquake was not predicted, which was interpreted as an inherent failure of prediction based on animal phenomena. This is contradicted on the basis of reliable Chinese documentation provided by the responsible earthquake study commission. The Tangshan earthquake was preceded by more than 2,000 reported animal anomalies, some of which were of very dramatic nature. They are discussed here. Any physical phenomenon, which may cause animal unrest, must involve energy turnover before the main earthquake event. The final product, however, of any energy turnover is heat. Satellite based infrared measurements have indeed identified significant thermal anomalies before major earthquakes. One of these cases, occurring during the 2001 Bhuj earthquake in Gujarat, India, is analyzed together with parallel animal anomalies observed in the Gir national park. It is suggested that the time window is identical and that both phenomena have the same geophysical origin. It therefore remains to be demonstrated that energy can be released locally before major earthquake events. It is shown that by considering appropriate geophysical feedback processes, this is