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Sample records for receptor pd166866 controls

  1. The synthetic inhibitor of Fibroblast Growth Factor Receptor PD166866 controls negatively the growth of tumor cells in culture

    Directory of Open Access Journals (Sweden)

    Castelli Mauro

    2009-12-01

    Full Text Available Abstract Background Many experimental data evidence that over-expression of various growth factors cause disorders in cell proliferation. The role of the Fibroblast Growth Factors (FGF in growth control is indisputable: in particular, FGF1 and its tyrosine kinase receptor (FGFR1 act through a very complex network of mechanisms and pathways. In this work we have evaluated the antiproliferative activity effect of PD166866, a synthetic molecule inhibiting the tyrosin kinase action of FGFR1. Methods Cells were routinely grown in Dulbecco Modified Eagle's medium supplemented with newborn serum and a penicillin-streptomycin mixture. Cell viability was evaluated by Mosmann assay and by trypan blue staining. DNA damage was assessed by in situ fluorescent staining with Terminal Deoxynucleotidyl Transferase dUTP nick end labeling (TUNEL assay. Assessment of oxidative stress at membrane level was measured by quantitative analysis of the intra-cellular formation of malonyl-dialdheyde (MDA deriving from the decomposition of poly-unsaturated fatty acids. The expression of Poly-ADP-Ribose-Polymerase (PARP, consequent to DNA fragmentation, was evidenced by immuno-histochemistry utilizing an antibody directed against an N-terminal fragment of the enzyme. Results The bioactivity of the drug was investigated on Hela cells. Cytoxicity was assessed by the Mosmann assay and by vital staining with trypan blue. The target of the molecule is most likely the cell membrane as shown by the significant increase of the intracellular concentration of malonyl-dihaldheyde. The increase of this compound, as a consequence of the treatment with PD166866, is suggestive of membrane lipoperoxidation. The TUNEL assay gave a qualitative, though clear, indication of DNA damage. Furthermore we demonstrate intracellular accumulation of poly-ADP-ribose polymerase I. This enzyme is a sensor of nicks on the DNA strands and this supports the idea that treatment with the drug induces cell

  2. Quality control of estrogen receptor assays.

    Science.gov (United States)

    Godolphin, W; Jacobson, B

    1980-01-01

    Four types of material have been used for the quality control of routine assays of estrogen receptors in human breast tumors. Pieces of hormone-dependent Nb rat mammary tumors gave a precision about 40%. Rat uteri and rat tumors pulverized at liquid nitrogen temperature and stored as powder yielded precision about 30%. Powdered and lyophilised human tumors appear the best with precision as good as 17%.

  3. Ghrelin receptor controls obesity by fat burning

    Science.gov (United States)

    Emerging evidence show that brown fat in the body produces heat to burn energy, thus prompting weight loss. Ghrelin is the only known hormone which increases appetite and promotes weight gain. We have reported that mice that lack the receptor which mediates the functions of ghrelin are lean. Our fu...

  4. Receptor control in mesenchymal stem cell engineering

    Science.gov (United States)

    Dalby, Matthew J.; García, Andrés J.; Salmeron-Sanchez, Manuel

    2018-03-01

    Materials science offers a powerful tool to control mesenchymal stem cell (MSC) growth and differentiation into functional phenotypes. A complex interplay between the extracellular matrix and growth factors guides MSC phenotypes in vivo. In this Review, we discuss materials-based bioengineering approaches to direct MSC fate in vitro and in vivo, mimicking cell-matrix-growth factor crosstalk. We first scrutinize MSC-matrix interactions and how the properties of a material can be tailored to support MSC growth and differentiation in vitro, with an emphasis on MSC self-renewal mechanisms. We then highlight important growth factor signalling pathways and investigate various materials-based strategies for growth factor presentation and delivery. Integrin-growth factor crosstalk in the context of MSC engineering is introduced, and bioinspired material designs with the potential to control the MSC niche phenotype are considered. Finally, we summarize important milestones on the road to MSC engineering for regenerative medicine.

  5. The MC4 receptor and control of appetite

    NARCIS (Netherlands)

    Adan, R. A. H.; Tiesjema, B.; Hillebrand, J. J. G.; La Fleur, S. E.; Kas, M. J. H.; de Krom, M.

    2006-01-01

    Mutations in the human melanocortin (MC)4 receptor have been associated with obesity, which underscores the relevance of this receptor as a drug target to treat obesity. Infusion of MC4R agonists decreases food intake, whereas inhibition of MC receptor activity by infusion of an MC receptor

  6. Role of Peroxisome Proliferator-Activated Receptors in Inflammation Control

    Directory of Open Access Journals (Sweden)

    Jihan Youssef

    2004-01-01

    Full Text Available Peroxisome proliferator-activated receptors (PPARs were discovered over a decade ago, and were classified as orphan members of the nuclear receptor superfamily. To date, three PPAR subtypes have been discovered and characterized (PPARα, β/δ, γ. Different PPAR subtypes have been shown to play crucial roles in important diseases and conditions such as obesity, diabetes, atherosclerosis, cancer, and fertility. Among the most studied roles of PPARs is their involvement in inflammatory processes. Numerous studies have revealed that agonists of PPARα and PPARγ exert anti-inflammatory effects both in vitro and in vivo. Using the carrageenan-induced paw edema model of inflammation, a recent study in our laboratories showed that these agonists hinder the initiation phase, but not the late phase of the inflammatory process. Furthermore, in the same experimental model, we recently also observed that activation of PPARδ exerted an anti-inflammatory effect. Despite the fact that exclusive dependence of these effects on PPARs has been questioned, the bulk of evidence suggests that all three PPAR subtypes, PPARα,δ,γ, play a significant role in controlling inflammatory responses. Whether these subtypes act via a common mechanism or are independent of each other remains to be elucidated. However, due to the intensity of research efforts in this area, it is anticipated that these efforts will result in the development of PPAR ligands as therapeutic agents for the treatment of inflammatory diseases.

  7. Control of Transcriptional Repression of the Vitellogenin Receptor Gene in Largemouth Bass (Micropterus Salmoides) by Select Estrogen Receptors Isotypes

    OpenAIRE

    Dominguez, Gustavo A.; Bisesi, Joseph H.; Kroll, Kevin J.; Denslow, Nancy D.; Sabo-Attwood, Tara

    2014-01-01

    The vitellogenin receptor (Vtgr) plays an important role in fish reproduction. This receptor functions to incorporate vitellogenin (Vtg), a macromolecule synthesized and released from the liver in the bloodstream, into oocytes where it is processed into yolk. Although studies have focused on the functional role of Vtgr in fish, the mechanistic control of this gene is still unexplored. Here we report the identification and analysis of the first piscine 5′ regulatory region of the vtgr gene whi...

  8. Hormonal control of spermatogenesis: expression of FSJH receptor and androgen receptor genes

    NARCIS (Netherlands)

    L.J. Blok (Leen)

    1992-01-01

    textabstractFSH and testosterone are the main hormonal regulators of spermatogenesis. The actions of androgens and FSH are mediated by their respective receptors. Receptor gene expression (mRNA and protein). is an important determinant of hormone action. Biochemical aspects of the regulation of

  9. The nuclear receptor NR2E1/TLX controls senescence

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    Krusche, Benjamin; Pemberton, Helen; Alonso, Marta M.; Chandler, Hollie; Brookes, Sharon; Parrinello, Simona; Peters, Gordon; Gil, Jesús

    2014-01-01

    The nuclear receptor NR2E1 (also known as TLX or tailless) controls the self-renewal of neural stem cells (NSCs) and has been implied as an oncogene which initiates brain tumours including glioblastomas. Despite NR2E1 regulating targets like p21CIP1 or PTEN we still lack a full explanation for its role in NSC self-renewal and tumorigenesis. We know that Polycomb repressive complexes (PRC) also control stem cell self-renewal and tumorigenesis, but so far, no formal connection has been established between NR2E1 and PRCs. In a screen for transcription factors regulating the expression of the Polycomb protein CBX7, we identified NR2E1 as one of its more prominent regulators. NR2E1 binds at the CBX7 promoter, inducing its expression. Notably CBX7 represses NR2E1 as part of a regulatory loop. Ectopic NR2E1 expression inhibits cellular senescence, extending cellular lifespan in fibroblasts via CBX7-mediated regulation of p16INK4a and direct repression of p21CIP1. In addition NR2E1 expression also counteracts oncogene-induced senescence (OIS). The importance of NR2E1 to restrain senescence is highlighted through the process of knocking down its expression, which causes premature senescence in human fibroblasts and epithelial cells. We also confirmed that NR2E1 regulates CBX7 and restrains senescence in NSCs. Finally, we observed that the expression of NR2E1 directly correlates with that of CBX7 in human glioblastoma multiforme. Overall we identified control of senescence and regulation of Polycomb action as two possible mechanisms that can join those so far invoked to explain the role of NR2E1 in control of NSC self-renewal and cancer. PMID:25328137

  10. The nuclear receptor NR2E1/TLX controls senescence.

    Science.gov (United States)

    O'Loghlen, Ana; Martin, Nadine; Krusche, Benjamin; Pemberton, Helen; Alonso, Marta M; Chandler, Hollie; Brookes, Sharon; Parrinello, Simona; Peters, Gordon; Gil, Jesús

    2015-07-30

    The nuclear receptor NR2E1 (also known as TLX or tailless) controls the self-renewal of neural stem cells (NSCs) and has been implied as an oncogene which initiates brain tumors including glioblastomas. Despite NR2E1 regulating targets like p21(CIP1) or PTEN we still lack a full explanation for its role in NSC self-renewal and tumorigenesis. We know that polycomb repressive complexes also control stem cell self-renewal and tumorigenesis, but so far, no formal connection has been established between NR2E1 and PRCs. In a screen for transcription factors regulating the expression of the polycomb protein CBX7, we identified NR2E1 as one of its more prominent regulators. NR2E1 binds at the CBX7 promoter, inducing its expression. Notably CBX7 represses NR2E1 as part of a regulatory loop. Ectopic NR2E1 expression inhibits cellular senescence, extending cellular lifespan in fibroblasts via CBX7-mediated regulation of p16(INK4a) and direct repression of p21(CIP1). In addition NR2E1 expression also counteracts oncogene-induced senescence. The importance of NR2E1 to restrain senescence is highlighted through the process of knocking down its expression, which causes premature senescence in human fibroblasts and epithelial cells. We also confirmed that NR2E1 regulates CBX7 and restrains senescence in NSCs. Finally, we observed that the expression of NR2E1 directly correlates with that of CBX7 in human glioblastoma multiforme. Overall we identified control of senescence and regulation of polycomb action as two possible mechanisms that can join those so far invoked to explain the role of NR2E1 in control of NSC self-renewal and cancer.

  11. Presynaptic Ionotropic Receptors Controlling and Modulating the Rules for Spike Timing-Dependent Plasticity

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    Matthijs B. Verhoog

    2011-01-01

    Full Text Available Throughout life, activity-dependent changes in neuronal connection strength enable the brain to refine neural circuits and learn based on experience. In line with predictions made by Hebb, synapse strength can be modified depending on the millisecond timing of action potential firing (STDP. The sign of synaptic plasticity depends on the spike order of presynaptic and postsynaptic neurons. Ionotropic neurotransmitter receptors, such as NMDA receptors and nicotinic acetylcholine receptors, are intimately involved in setting the rules for synaptic strengthening and weakening. In addition, timing rules for STDP within synapses are not fixed. They can be altered by activation of ionotropic receptors located at, or close to, synapses. Here, we will highlight studies that uncovered how network actions control and modulate timing rules for STDP by activating presynaptic ionotropic receptors. Furthermore, we will discuss how interaction between different types of ionotropic receptors may create “timing” windows during which particular timing rules lead to synaptic changes.

  12. [Effects of GLP-1 receptor agonists on carbohydrate metabolism control].

    Science.gov (United States)

    Fernández-García, José Carlos; Colomo, Natalia; Tinahones, Francisco José

    2014-09-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  13. Protein kinase C alpha controls erythropoietin receptor signaling.

    NARCIS (Netherlands)

    M.M. von Lindern (Marieke); M. Parren-Van Amelsvoort (Martine); T.B. van Dijk (Thamar); E. Deiner; B. Löwenberg (Bob); E. van den Akker (Emile); S. van Emst-de Vries (Sjenet); P.J. Willems (Patrick); H. Beug (Hartmut)

    2000-01-01

    textabstractProtein kinase C (PKC) is implied in the activation of multiple targets of erythropoietin (Epo) signaling, but its exact role in Epo receptor (EpoR) signal transduction and in the regulation of erythroid proliferation and differentiation remained elusive. We

  14. Protein kinase C alpha controls erythropoietin receptor signaling

    NARCIS (Netherlands)

    von Lindern, M.; Parren-van Amelsvoort, M.; van Dijk, T.; Deiner, E.; van den Akker, E.; van Emst-de Vries, S.; Willems, P.; Beug, H.; Löwenberg, B.

    2000-01-01

    Protein kinase C (PKC) is implied in the activation of multiple targets of erythropoietin (Epo) signaling, but its exact role in Epo receptor (EpoR) signal transduction and in the regulation of erythroid proliferation and differentiation remained elusive. We analyzed the effect of PKC inhibitors

  15. β-arrestins negatively control human adrenomedullin type 1-receptor internalization

    International Nuclear Information System (INIS)

    Kuwasako, Kenji; Kitamura, Kazuo; Nagata, Sayaka; Sekiguchi, Toshio; Danfeng, Jiang; Murakami, Manabu; Hattori, Yuichi; Kato, Johji

    2017-01-01

    Adrenomedullin (AM) is a potent hypotensive peptide that exerts a powerful variety of protective effects against multiorgan damage through the AM type 1 receptor (AM 1 receptor), which consists of the calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 2 (RAMP2). Two β-arrestin (β-arr) isoforms, β-arr-1 and β-arr-2, play a central role in the agonist-induced internalization of many receptors for receptor resensitization. Notably, β-arr-biased agonists are now being tested in phase II clinical trials, targeting acute pain and acute heart failure. Here, we examined the effects of β-arr-1 and β-arr-2 on human AM 1 receptor internalization. We constructed a V5-tagged chimera in which the cytoplasmic C-terminal tail (C-tail) of CLR was replaced with that of the β 2 -adrenergic receptor (β 2 -AR), and it was transiently transfected into HEK-293 cells that stably expressed RAMP2. The cell-surface expression and internalization of the wild-type or chimeric receptor were quantified by flow cytometric analysis. The [ 125 I]AM binding and the AM-induced cAMP production of these receptors were also determined. Surprisingly, the coexpression of β-arr-1 or -2 resulted in significant decreases in AM 1 receptor internalization without affecting AM binding and signaling prior to receptor internalization. Dominant-negative (DN) β-arr-1 or -2 also significantly decreased AM-induced AM 1 receptor internalization. In contrast, the AM-induced internalization of the chimeric AM 1 receptor was markedly augmented by the cotransfection of β-arr-1 or -2 and significantly reduced by the coexpression of DN-β-arr-1 or -2. These results were consistent with those seen for β 2 -AR. Thus, both β-arrs negatively control AM 1 receptor internalization, which depends on the C-tail of CLR. - Highlights: • We found that β-arrestins 1 and 2 negatively control agonist-induced GPCR internalization. • β-arrestins 1 and 2 significantly inhibits the AM

  16. β-arrestins negatively control human adrenomedullin type 1-receptor internalization.

    Science.gov (United States)

    Kuwasako, Kenji; Kitamura, Kazuo; Nagata, Sayaka; Sekiguchi, Toshio; Danfeng, Jiang; Murakami, Manabu; Hattori, Yuichi; Kato, Johji

    2017-05-27

    Adrenomedullin (AM) is a potent hypotensive peptide that exerts a powerful variety of protective effects against multiorgan damage through the AM type 1 receptor (AM 1 receptor), which consists of the calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 2 (RAMP2). Two β-arrestin (β-arr) isoforms, β-arr-1 and β-arr-2, play a central role in the agonist-induced internalization of many receptors for receptor resensitization. Notably, β-arr-biased agonists are now being tested in phase II clinical trials, targeting acute pain and acute heart failure. Here, we examined the effects of β-arr-1 and β-arr-2 on human AM 1 receptor internalization. We constructed a V5-tagged chimera in which the cytoplasmic C-terminal tail (C-tail) of CLR was replaced with that of the β 2 -adrenergic receptor (β 2 -AR), and it was transiently transfected into HEK-293 cells that stably expressed RAMP2. The cell-surface expression and internalization of the wild-type or chimeric receptor were quantified by flow cytometric analysis. The [ 125 I]AM binding and the AM-induced cAMP production of these receptors were also determined. Surprisingly, the coexpression of β-arr-1 or -2 resulted in significant decreases in AM 1 receptor internalization without affecting AM binding and signaling prior to receptor internalization. Dominant-negative (DN) β-arr-1 or -2 also significantly decreased AM-induced AM 1 receptor internalization. In contrast, the AM-induced internalization of the chimeric AM 1 receptor was markedly augmented by the cotransfection of β-arr-1 or -2 and significantly reduced by the coexpression of DN-β-arr-1 or -2. These results were consistent with those seen for β 2 -AR. Thus, both β-arrs negatively control AM 1 receptor internalization, which depends on the C-tail of CLR. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Parkinson's disease treatment may cause impulse-control disorder via dopamine D3 receptors.

    Science.gov (United States)

    Seeman, Philip

    2015-04-01

    In treating Parkinson's disease with dopaminergic agonists, such as pramipexole, ropinirole, pergolide, rotigotine, apomorphine, or bromocriptine, it has been observed that a significant number of patients develop impulse-control disorders, such as compulsive shopping, pathological gambling, or hypersexuality. Because the dopamine agonists have high affinities for the dopamine D2 and D3 receptors, the drug dissociation constants of these drugs at the functional high-affinity states of these receptors, namely D2High and D3High, were compared. The data show that, compared to the other dopamine agonist drugs, pramipexole has a relatively high selectivity for the dopamine D3 receptor, as compared to D2, suggesting that the D3 receptor may be a primary target for pramipexole. There is a trend showing that the proportion of impulse-control disorders is related to the selectivity for D3 receptors over D2 receptors, with pramipexole having the highest association with, or frequency of, impulse-control disorders. While the number of studies are limited, the proportion of patients with impulse-control disorder in Parkinson patients treated with an add-on agonist were 32% for pramipexole, 25% for ropinirole, 16% for pergolide, 22% for rotigotine, 10% for apomorphine, and 6.8% for bromocriptine. Clinically, temporary replacement of pramipexole by bromocriptine may provide relief or reversal of the impulsive behavior associated with selective D3 stimulation by either pramipexole or ropinirole, while maintaining D2 stimulation needed for the anti-Parkinson action. © 2015 Wiley Periodicals, Inc.

  18. Control of energy balance by hypothalamic gene circuitry involving two nuclear receptors, neuron-derived orphan receptor 1 and glucocorticoid receptor.

    Science.gov (United States)

    Kim, Sun-Gyun; Lee, Bora; Kim, Dae-Hwan; Kim, Juhee; Lee, Seunghee; Lee, Soo-Kyung; Lee, Jae W

    2013-10-01

    Nuclear receptors (NRs) regulate diverse physiological processes, including the central nervous system control of energy balance. However, the molecular mechanisms for the central actions of NRs in energy balance remain relatively poorly defined. Here we report a hypothalamic gene network involving two NRs, neuron-derived orphan receptor 1 (NOR1) and glucocorticoid receptor (GR), which directs the regulated expression of orexigenic neuropeptides agouti-related peptide (AgRP) and neuropeptide Y (NPY) in response to peripheral signals. Our results suggest that the anorexigenic signal leptin induces NOR1 expression likely via the transcription factor cyclic AMP response element-binding protein (CREB), while the orexigenic signal glucocorticoid mobilizes GR to inhibit NOR1 expression by antagonizing the action of CREB. Also, NOR1 suppresses glucocorticoid-dependent expression of AgRP and NPY. Consistently, relative to wild-type mice, NOR1-null mice showed significantly higher levels of AgRP and NPY and were less responsive to leptin in decreasing the expression of AgRP and NPY. These results identify mutual antagonism between NOR1 and GR to be a key rheostat for peripheral metabolic signals to centrally control energy balance.

  19. Serotonin 6 receptor controls alzheimer?s disease and depression

    OpenAIRE

    Yun, Hyung-Mun; Park, Kyung-Ran; Kim, Eun-Cheol; Kim, Sanghyeon; Hong, Jin Tae

    2015-01-01

    Alzheimer?s disease (AD) and depression in late life are one of the most severe health problems in the world disorders. Serotonin 6 receptor (5-HT6R) has caused much interest for potential roles in AD and depression. However, a causative role of perturbed 5-HT6R function between two diseases was poorly defined. In the present study, we found that a 5-HT6R antagonist, SB271036 rescued memory impairment by attenuating the generation of A? via the inhibition of ?-secretase activity and the inact...

  20. Diverse FGF receptor signaling controls astrocyte specification and proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Kyungjun [School of Life Sciences, Gwangju Institute of Science and Technology, Oryong-dong, Buk-gu, Gwangju 500-712 (Korea, Republic of); Song, Mi-Ryoung, E-mail: msong@gist.ac.kr [School of Life Sciences, Gwangju Institute of Science and Technology, Oryong-dong, Buk-gu, Gwangju 500-712 (Korea, Republic of); Bioimaging Research Center and Cell Dynamics Research Center, Gwangju Institute of Science and Technology, Oryong-dong, Buk-gu, Gwangju 500-712 (Korea, Republic of)

    2010-05-07

    During CNS development, pluripotency neuronal progenitor cells give rise in succession to neurons and glia. Fibroblast growth factor-2 (FGF-2), a major signal that maintains neural progenitors in the undifferentiated state, is also thought to influence the transition from neurogenesis to gliogenesis. Here we present evidence that FGF receptors and underlying signaling pathways transmit the FGF-2 signals that regulate astrocyte specification aside from its mitogenic activity. Application of FGF-2 to cortical progenitors suppressed neurogenesis whereas treatment with an FGFR antagonist in vitro promoted neurogenesis. Introduction of chimeric FGFRs with mutated tyrosine residues into cortical progenitors and drug treatments to specifically block individual downstream signaling pathways revealed that the overall activity of FGFR rather than individual autophosphorylation sites is important for delivering signals for glial specification. In contrast, a signal for cell proliferation by FGFR was mainly delivered by MAPK pathway. Together our findings indicate that FGFR activity promotes astrocyte specification in the developing CNS.

  1. Diverse FGF receptor signaling controls astrocyte specification and proliferation

    International Nuclear Information System (INIS)

    Kang, Kyungjun; Song, Mi-Ryoung

    2010-01-01

    During CNS development, pluripotency neuronal progenitor cells give rise in succession to neurons and glia. Fibroblast growth factor-2 (FGF-2), a major signal that maintains neural progenitors in the undifferentiated state, is also thought to influence the transition from neurogenesis to gliogenesis. Here we present evidence that FGF receptors and underlying signaling pathways transmit the FGF-2 signals that regulate astrocyte specification aside from its mitogenic activity. Application of FGF-2 to cortical progenitors suppressed neurogenesis whereas treatment with an FGFR antagonist in vitro promoted neurogenesis. Introduction of chimeric FGFRs with mutated tyrosine residues into cortical progenitors and drug treatments to specifically block individual downstream signaling pathways revealed that the overall activity of FGFR rather than individual autophosphorylation sites is important for delivering signals for glial specification. In contrast, a signal for cell proliferation by FGFR was mainly delivered by MAPK pathway. Together our findings indicate that FGFR activity promotes astrocyte specification in the developing CNS.

  2. receptores

    Directory of Open Access Journals (Sweden)

    Salete Regina Daronco Benetti

    2006-01-01

    Full Text Available Se trata de un estudio etnográfico, que tuvo lo objetivo de interpretar el sistema de conocimiento y del significado atribuidos a la sangre referente a la transfusión sanguínea por los donadores y receptores de un banco de sangre. Para la colecta de las informaciones se observaron los participantes y la entrevista etnográfica se realizó el análisis de dominio, taxonómicos y temáticos. Los dominios culturales fueron: la sangre es vida: fuente de vida y alimento valioso; creencias religiosas: fuentes simbólicas de apoyos; donación sanguínea: un gesto colaborador que exige cuidarse, gratifica y trae felicidad; donación sanguínea: fuente simbólica de inseguridad; estar enfermo es una condición para realizar transfusión sanguínea; transfusión sanguínea: esperanza de vida; Creencias populares: transfusión sanguínea como riesgo para la salud; donadores de sangre: personas benditas; donar y recibir sangre: como significado de felicidad. Temática: “líquido precioso que origina, sostiene, modifica la vida, provoca miedo e inseguridad”.

  3. Nuclear hormone receptor NHR-49 controls fat consumption and fatty acid composition in C. elegans.

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    Marc R Van Gilst

    2005-02-01

    Full Text Available Mammalian nuclear hormone receptors (NHRs, such as liver X receptor, farnesoid X receptor, and peroxisome proliferator-activated receptors (PPARs, precisely control energy metabolism. Consequently, these receptors are important targets for the treatment of metabolic diseases, including diabetes and obesity. A thorough understanding of NHR fat regulatory networks has been limited, however, by a lack of genetically tractable experimental systems. Here we show that deletion of the Caenorhabditis elegans NHR gene nhr-49 yielded worms with elevated fat content and shortened life span. Employing a quantitative RT-PCR screen, we found that nhr-49 influenced the expression of 13 genes involved in energy metabolism. Indeed, nhr-49 served as a key regulator of fat usage, modulating pathways that control the consumption of fat and maintain a normal balance of fatty acid saturation. We found that the two phenotypes of the nhr-49 knockout were linked to distinct pathways and were separable: The high-fat phenotype was due to reduced expression of enzymes in fatty acid beta-oxidation, and the shortened adult life span resulted from impaired expression of a stearoyl-CoA desaturase. Despite its sequence relationship with the mammalian hepatocyte nuclear factor 4 receptor, the biological activities of nhr-49 were most similar to those of the mammalian PPARs, implying an evolutionarily conserved role for NHRs in modulating fat consumption and composition. Our findings in C. elegans provide novel insights into how NHR regulatory networks are coordinated to govern fat metabolism.

  4. Nuclear hormone receptor NHR-49 controls fat consumption and fatty acid composition in C. elegans.

    Science.gov (United States)

    Van Gilst, Marc R; Hadjivassiliou, Haralambos; Jolly, Amber; Yamamoto, Keith R

    2005-02-01

    Mammalian nuclear hormone receptors (NHRs), such as liver X receptor, farnesoid X receptor, and peroxisome proliferator-activated receptors (PPARs), precisely control energy metabolism. Consequently, these receptors are important targets for the treatment of metabolic diseases, including diabetes and obesity. A thorough understanding of NHR fat regulatory networks has been limited, however, by a lack of genetically tractable experimental systems. Here we show that deletion of the Caenorhabditis elegans NHR gene nhr-49 yielded worms with elevated fat content and shortened life span. Employing a quantitative RT-PCR screen, we found that nhr-49 influenced the expression of 13 genes involved in energy metabolism. Indeed, nhr-49 served as a key regulator of fat usage, modulating pathways that control the consumption of fat and maintain a normal balance of fatty acid saturation. We found that the two phenotypes of the nhr-49 knockout were linked to distinct pathways and were separable: The high-fat phenotype was due to reduced expression of enzymes in fatty acid beta-oxidation, and the shortened adult life span resulted from impaired expression of a stearoyl-CoA desaturase. Despite its sequence relationship with the mammalian hepatocyte nuclear factor 4 receptor, the biological activities of nhr-49 were most similar to those of the mammalian PPARs, implying an evolutionarily conserved role for NHRs in modulating fat consumption and composition. Our findings in C. elegans provide novel insights into how NHR regulatory networks are coordinated to govern fat metabolism.

  5. Memory control by the B cell antigen receptor.

    Science.gov (United States)

    Engels, Niklas; Wienands, Jürgen

    2018-05-01

    The generation of memory B cells (MBCs) that have undergone immunoglobulin class switching from IgM, which dominates primary antibody responses, to other immunoglobulin isoforms is a hallmark of immune memory. Hence, humoral immunological memory is characterized by the presence of serum immunoglobulins of IgG subtypes known as the γ-globulin fraction of blood plasma proteins. These antibodies reflect the antigen experience of B lymphocytes and their repeated triggering. In fact, efficient protection against a previously encountered pathogen is critically linked to the production of pathogen-specific IgG molecules even in those cases where the primary immune response required cellular immunity, for example, T cell-mediated clearance of intracellular pathogens such as viruses. Besides IgG, also IgA and IgE can provide humoral immunity depending on the microbe's nature and infection route. The molecular mechanisms underlying the preponderance of switched immunoglobulin isotypes during memory antibody responses are a matter of active and controversial debate. Here, we summarize the phenotypic characteristics of distinct MBC subpopulations and discuss the decisive roles of different B cell antigen receptor isotypes for the functional traits of class-switched B cell populations. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  6. The inositol trisphosphate receptor in the control of autophagy.

    Science.gov (United States)

    Criollo, Alfredo; Vicencio, José Miguel; Tasdemir, Ezgi; Maiuri, M Chiara; Lavandero, Sergio; Kroemer, Guido

    2007-01-01

    The second messenger myo-inositol-1,4,5-trisphosphate (IP(3)) acts on the IP(3) receptor (IP(3)R), an IP(3)-activated Ca(2+) channel of the endoplasmic reticulum (ER). The IP(3)R agonist IP(3) inhibits starvation-induced autophagy. The IP(3)R antagonist xestospongin B induces autophagy in human cells through a pathway that requires the obligate contribution of Beclin-1, Atg5, Atg10, Atg12 and hVps34, yet is inhibited by ER-targeted Bcl-2 or Bcl-XL, two proteins that physically interact with IP(3)R. Autophagy can also be induced by depletion of the IP(3)R by small interfering RNAs. Autophagy induction by IP(3)R blockade cannot be explained by changes in steady state levels of Ca(2+) in the endoplasmic reticulum (ER) and the cytosol. Autophagy induction by IP(3)R blockade is effective in cells lacking the obligate mediator of ER stress IRE1. In contrast, IRE1 is required for autophagy induced by ER stress-inducing agents such a tunicamycin or thapsigargin. These findings suggest that there are several distinct pathways through which autophagy can be initiated at the level of the ER.

  7. Muscarinic receptors in amygdala control trace fear conditioning.

    Directory of Open Access Journals (Sweden)

    Amber N Baysinger

    Full Text Available Intelligent behavior requires transient memory, which entails the ability to retain information over short time periods. A newly-emerging hypothesis posits that endogenous persistent firing (EPF is the neurophysiological foundation for aspects or types of transient memory. EPF is enabled by the activation of muscarinic acetylcholine receptors (mAChRs and is triggered by suprathreshold stimulation. EPF occurs in several brain regions, including the lateral amygdala (LA. The present study examined the role of amygdalar mAChRs in trace fear conditioning, a paradigm that requires transient memory. If mAChR-dependent EPF selectively supports transient memory, then blocking amygdalar mAChRs should impair trace conditioning, while sparing delay and context conditioning, which presumably do not rely upon transient memory. To test the EPF hypothesis, LA was bilaterally infused, prior to trace or delay conditioning, with either a mAChR antagonist (scopolamine or saline. Computerized video analysis quantified the amount of freezing elicited by the cue and by the training context. Scopolamine infusion profoundly reduced freezing in the trace conditioning group but had no significant effect on delay or context conditioning. This pattern of results was uniquely anticipated by the EPF hypothesis. The present findings are discussed in terms of a systems-level theory of how EPF in LA and several other brain regions might help support trace fear conditioning.

  8. Muscarinic receptors in amygdala control trace fear conditioning.

    Science.gov (United States)

    Baysinger, Amber N; Kent, Brianne A; Brown, Thomas H

    2012-01-01

    Intelligent behavior requires transient memory, which entails the ability to retain information over short time periods. A newly-emerging hypothesis posits that endogenous persistent firing (EPF) is the neurophysiological foundation for aspects or types of transient memory. EPF is enabled by the activation of muscarinic acetylcholine receptors (mAChRs) and is triggered by suprathreshold stimulation. EPF occurs in several brain regions, including the lateral amygdala (LA). The present study examined the role of amygdalar mAChRs in trace fear conditioning, a paradigm that requires transient memory. If mAChR-dependent EPF selectively supports transient memory, then blocking amygdalar mAChRs should impair trace conditioning, while sparing delay and context conditioning, which presumably do not rely upon transient memory. To test the EPF hypothesis, LA was bilaterally infused, prior to trace or delay conditioning, with either a mAChR antagonist (scopolamine) or saline. Computerized video analysis quantified the amount of freezing elicited by the cue and by the training context. Scopolamine infusion profoundly reduced freezing in the trace conditioning group but had no significant effect on delay or context conditioning. This pattern of results was uniquely anticipated by the EPF hypothesis. The present findings are discussed in terms of a systems-level theory of how EPF in LA and several other brain regions might help support trace fear conditioning.

  9. Serotonin 6 receptor controls Alzheimer's disease and depression.

    Science.gov (United States)

    Yun, Hyung-Mun; Park, Kyung-Ran; Kim, Eun-Cheol; Kim, Sanghyeon; Hong, Jin Tae

    2015-09-29

    Alzheimer's disease (AD) and depression in late life are one of the most severe health problems in the world disorders. Serotonin 6 receptor (5-HT6R) has caused much interest for potential roles in AD and depression. However, a causative role of perturbed 5-HT6R function between two diseases was poorly defined. In the present study, we found that a 5-HT6R antagonist, SB271036 rescued memory impairment by attenuating the generation of Aβ via the inhibition of γ-secretase activity and the inactivation of astrocytes and microglia in the AD mouse model. It was found that the reduction of serotonin level was significantly recovered by SB271036, which was mediated by an indirect regulation of serotonergic neurons via GABA. Selective serotonin reuptake inhibitor (SSRI), fluoxetine significantly improved cognitive impairment and behavioral changes. In human brain of depression patients, we then identified the potential genes, amyloid beta (A4) precursor protein-binding, family A, member 2 (APBA2), well known AD modulators by integrating datasets from neuropathology, microarray, and RNA seq. studies with correlation analysis tools. And also, it was demonstrated in mouse models and patients of AD. These data indicate functional network of 5-HT6R between AD and depression.

  10. Modeling Canadian Quality Control Test Program for Steroid Hormone Receptors in Breast Cancer: Diagnostic Accuracy Study.

    Science.gov (United States)

    Pérez, Teresa; Makrestsov, Nikita; Garatt, John; Torlakovic, Emina; Gilks, C Blake; Mallett, Susan

    The Canadian Immunohistochemistry Quality Control program monitors clinical laboratory performance for estrogen receptor and progesterone receptor tests used in breast cancer treatment management in Canada. Current methods assess sensitivity and specificity at each time point, compared with a reference standard. We investigate alternative performance analysis methods to enhance the quality assessment. We used 3 methods of analysis: meta-analysis of sensitivity and specificity of each laboratory across all time points; sensitivity and specificity at each time point for each laboratory; and fitting models for repeated measurements to examine differences between laboratories adjusted by test and time point. Results show 88 laboratories participated in quality control at up to 13 time points using typically 37 to 54 histology samples. In meta-analysis across all time points no laboratories have sensitivity or specificity below 80%. Current methods, presenting sensitivity and specificity separately for each run, result in wide 95% confidence intervals, typically spanning 15% to 30%. Models of a single diagnostic outcome demonstrated that 82% to 100% of laboratories had no difference to reference standard for estrogen receptor and 75% to 100% for progesterone receptor, with the exception of 1 progesterone receptor run. Laboratories with significant differences to reference standard identified with Generalized Estimating Equation modeling also have reduced performance by meta-analysis across all time points. The Canadian Immunohistochemistry Quality Control program has a good design, and with this modeling approach has sufficient precision to measure performance at each time point and allow laboratories with a significantly lower performance to be targeted for advice.

  11. Control of transcriptional repression of the vitellogenin receptor gene in largemouth bass (Micropterus salmoides) by select estrogen receptors isotypes.

    Science.gov (United States)

    Dominguez, Gustavo A; Bisesi, Joseph H; Kroll, Kevin J; Denslow, Nancy D; Sabo-Attwood, Tara

    2014-10-01

    The vitellogenin receptor (Vtgr) plays an important role in fish reproduction. This receptor functions to incorporate vitellogenin (Vtg), a macromolecule synthesized and released from the liver in the bloodstream, into oocytes where it is processed into yolk. Although studies have focused on the functional role of Vtgr in fish, the mechanistic control of this gene is still unexplored. Here we report the identification and analysis of the first piscine 5' regulatory region of the vtgr gene which was cloned from largemouth bass (Micropterus salmoides). Using this putative promoter sequence, we investigated a role for hormones, including insulin and 17β-estradiol (E2), in transcriptional regulation through cell-based reporter assays. No effect of insulin was observed, however, E2 was able to repress transcriptional activity of the vtgr promoter through select estrogen receptor subtypes, Esr1 and Esr2a but not Esr2b. Electrophoretic mobility shift assay demonstrated that Esr1 likely interacts with the vtgr promoter region through half ERE and/or SP1 sites, in part. Finally we also show that ethinylestradiol (EE2), but not bisphenol-A (BPA), represses promoter activity similarly to E2. These results reveal for the first time that the Esr1 isoform may play an inhibitory role in the expression of LMB vtgr mRNA under the influence of E2, and potent estrogens such as EE2. In addition, this new evidence suggests that vtgr may be a target of select endocrine disrupting compounds through environmental exposures. © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  12. Transcription control and neuronal differentiation by agents that activate the LXR nuclear receptor family.

    Science.gov (United States)

    Schmidt, A; Vogel, R; Holloway, M K; Rutledge, S J; Friedman, O; Yang, Z; Rodan, G A; Friedman, E

    1999-09-10

    LXR and PPAR receptors belong to the nuclear receptor superfamily of transcriptional activating factors. Using ligand-dependent transcription assays, we found that 5-tetradecyloxy-2-furancarboxylic acid (TOFA) transactivates chimeric receptors composed of the glucocorticoid receptor DNA binding domain and the ligand binding regions of PPARalpha, PPARbeta (NUC-1) and LXRbeta (NER) receptors. In the same assays, ligands for PPARs (oleic acid, WY-14643 and L-631,033) and LXRs (hydroxycholesterols) maintain their respective receptor selectivity. TOFA and hydroxycholesterols also stimulate transcription from a minimal fibrinogen promoter that is under the control of AP-1 or NF-kappaB transcription factor binding sites. In addition to their effects on transcription, these LXRbeta activators induce neuronal differentiation in rat pheochromocytoma cells. TOFA and the natural LXR agonist, 22 (R)-hydroxycholesterol, stimulate neurite outgrowth in 55 and 28% of cells, respectively. No neurite outgrowth was induced by the related 22(S)-hydroxycholesterol, which does not activate the LXR family. These results suggest that the hydroxycholesterol signaling pathway has a complex effect on transcription that mediates the activity of TOFA and hydroxycholesterol on neuronal differentiation in pheochromocytoma cells.

  13. How membrane lipids control the 3D structure and function of receptors

    Directory of Open Access Journals (Sweden)

    Jacques Fantini

    2018-02-01

    Full Text Available The cohabitation of lipids and proteins in the plasma membrane of mammalian cells is controlled by specific biochemical and biophysical rules. Lipids may be either constitutively tightly bound to cell-surface receptors (non-annular lipids or less tightly attached to the external surface of the protein (annular lipids. The latter are exchangeable with surrounding bulk membrane lipids on a faster time scale than that of non-annular lipids. Not only do non-annular lipids bind to membrane proteins through stereoselective mechanisms, they can also help membrane receptors acquire (or maintain a functional 3D structure. Cholesterol is the prototype of membrane lipids that finely controls the 3D structure and function of receptors. However, several other lipids such as sphingolipids may also modulate the function of membrane proteins though conformational adjustments. All these concepts are discussed in this review in the light of representative examples taken from the literature.

  14. Serotonin receptor 3A controls interneuron migration into the neocortex

    NARCIS (Netherlands)

    Murthy, S.; Niquille, M.; Hurni, N.; Limoni, G.; Frazer, S.; Chameau, P.; van Hooft, J.A.; Vitalis, T.; Dayer, A.

    2014-01-01

    Neuronal excitability has been shown to control the migration and cortical integration of reelin-expressing cortical interneurons (INs) arising from the caudal ganglionic eminence (CGE), supporting the possibility that neurotransmitters could regulate this process. Here we show that the ionotropic

  15. A single amino acid residue controls Ca2+ signaling by an octopamine receptor from Drosophila melanogaster.

    Science.gov (United States)

    Hoff, Max; Balfanz, Sabine; Ehling, Petra; Gensch, Thomas; Baumann, Arnd

    2011-07-01

    Rhythmic activity of cells and cellular networks plays an important role in physiology. In the nervous system oscillations of electrical activity and/or second messenger concentrations are important to synchronize neuronal activity. At the molecular level, rhythmic activity can be initiated by different routes. We have recently shown that an octopamine-activated G-protein-coupled receptor (GPCR; DmOctα1Rb, CG3856) from Drosophila initiates Ca(2+) oscillations. Here, we have unraveled the molecular basis of cellular Ca(2+) signaling controlled by the DmOctα1Rb receptor using a combination of pharmacological intervention, site-directed mutagenesis, and functional cellular Ca(2+) imaging on heterologously expressed receptors. Phosphorylation of a single amino acid residue in the third intracellular loop of the GPCR by PKC is necessary and sufficient to desensitize the receptor. From its desensitized state, DmOctα1Rb is resensitized by dephosphorylation, and a new Ca(2+) signal occurs on octopamine stimulation. Our findings show that transient changes of the receptor's surface profile have a strong effect on its physiological signaling properties. We expect that the detailed knowledge of DmOctα1Rb-dependent signal transduction fosters the identification of specific drugs that can be used for GPCR-mediated pest control, since octopamine serves important physiological and behavioral functions in arthropods.

  16. Remote control of therapeutic T cells through a small molecule-gated chimeric receptor.

    Science.gov (United States)

    Wu, Chia-Yung; Roybal, Kole T; Puchner, Elias M; Onuffer, James; Lim, Wendell A

    2015-10-16

    There is growing interest in using engineered cells as therapeutic agents. For example, synthetic chimeric antigen receptors (CARs) can redirect T cells to recognize and eliminate tumor cells expressing specific antigens. Despite promising clinical results, these engineered T cells can exhibit excessive activity that is difficult to control and can cause severe toxicity. We designed "ON-switch" CARs that enable small-molecule control over T cell therapeutic functions while still retaining antigen specificity. In these split receptors, antigen-binding and intracellular signaling components assemble only in the presence of a heterodimerizing small molecule. This titratable pharmacologic regulation could allow physicians to precisely control the timing, location, and dosage of T cell activity, thereby mitigating toxicity. This work illustrates the potential of combining cellular engineering with orthogonal chemical tools to yield safer therapeutic cells that tightly integrate cell-autonomous recognition and user control. Copyright © 2015, American Association for the Advancement of Science.

  17. Remote control of therapeutic T cells through a small molecule-gated chimeric receptor

    Science.gov (United States)

    Wu, Chia-Yung; Roybal, Kole T.; Puchner, Elias M.; Onuffer, James; Lim, Wendell A.

    2016-01-01

    There is growing promise in using engineered cells as therapeutic agents. For example, synthetic Chimeric Antigen Receptors (CARs) can redirect T cells to recognize and eliminate tumor cells expressing specific antigens. Despite promising clinical results, excessive activity and poor control over such engineered T cells can cause severe toxicities. We present the design of “ON-switch” CARs that enable small molecule-control over T cell therapeutic functions, while still retaining antigen specificity. In these split receptors, antigen binding and intracellular signaling components only assemble in the presence of a heterodimerizing small molecule. This titratable pharmacologic regulation could allow physicians to precisely control the timing, location, and dosage of T cell activity, thereby mitigating toxicity. This work illustrates the potential of combining cellular engineering with orthogonal chemical tools to yield safer therapeutic cells that tightly integrate both cell autonomous recognition and user control. PMID:26405231

  18. Atypical Opioid Mechanisms of Control of Injury-Induced Cutaneous Pain by Delta Receptors

    Science.gov (United States)

    2017-07-01

    i.e. mu opioid receptor agonists such as morphine) cause unacceptable side effects including addiction . Injuries suffered most frequently by active...slides. The slides were then processed for fluorescent in situ hybridization with RNAscope technology (ACD Biosystems) to detect Oprd1 mRNA, as...tissue as done in Bardoni et al., Neuron, 2014) and negative controls (no probe). Controls indicated that the technology and reagents work as expected

  19. Electroacupuncture Potentiates Cannabinoid Receptor-Mediated Descending Inhibitory Control in a Mouse Model of Knee Osteoarthritis

    Directory of Open Access Journals (Sweden)

    Xiao-Cui Yuan

    2018-04-01

    Full Text Available Knee osteoarthritis (KOA is a highly prevalent, chronic joint disorder, which can lead to chronic pain. Although electroacupuncture (EA is effective in relieving chronic pain in the clinic, the involved mechanisms remain unclear. Reduced diffuse noxius inhibitory controls (DNIC function is associated with chronic pain and may be related to the action of endocannabinoids. In the present study, we determined whether EA may potentiate cannabinoid receptor-mediated descending inhibitory control and inhibit chronic pain in a mouse model of KOA. We found that the optimized parameters of EA inhibiting chronic pain were the low frequency and high intensity (2 Hz + 1 mA. EA reversed the reduced expression of CB1 receptors and the 2-arachidonoylglycerol (2-AG level in the midbrain in chronic pain. Microinjection of the CB1 receptor antagonist AM251 into the ventrolateral periaqueductal gray (vlPAG can reversed the EA effect on pain hypersensitivity and DNIC function. In addition, CB1 receptors on GABAergic but not glutamatergic neurons are involved in the EA effect on DNIC function and descending inhibitory control of 5-HT in the medulla, thus inhibiting chronic pain. Our data suggest that endocannabinoid (2-AG-CB1R-GABA-5-HT may be a novel signaling pathway involved in the effect of EA improving DNIC function and inhibiting chronic pain.

  20. Neuropeptide Y2 receptors in anteroventral BNST control remote fear memory depending on extinction training.

    Science.gov (United States)

    Verma, Dilip; Tasan, Ramon; Sperk, Guenther; Pape, Hans-Christian

    2018-03-01

    The anterior bed nucleus of stria terminalis (BNST) is involved in reinstatement of extinguished fear, and neuropeptide Y2 receptors influence local synaptic signaling. Therefore, we hypothesized that Y2 receptors in anteroventral BNST (BNSTav) interfere with remote fear memory and that previous fear extinction is an important variable. C57BL/6NCrl mice were fear-conditioned, and a Y2 receptor-specific agonist (NPY 3-36 ) or antagonist (JNJ-5207787) was applied in BNSTav before fear retrieval at the following day. Remote fear memory was tested on day 16 in two groups of mice, which had (experiment 1) or had not (experiment 2) undergone extinction training after conditioning. In the group with extinction training, tests of remote fear memory revealed partial retrieval of extinction, which was prevented after blockade of Y2 receptors in BNSTav. No such effect was observed in the group with no extinction training, but stimulation of Y2 receptors in BNSTav mimicked the influence of extinction during tests of remote fear memory. Pharmacological manipulation of Y2 receptors in BNSTav before fear acquisition (experiment 3) had no effect on fear memory retrieval, extinction or remote fear memory. Furthermore, partial retrieval of extinction during tests of remote fear memory was associated with changes in number of c-Fos expressing neurons in BNSTav, which was prevented or mimicked upon Y2 blockade or stimulation in BNSTav. These results indicate that Y2 receptor manipulation in BNSTav interferes with fear memory and extinction retrieval at remote stages, likely through controlling neuronal activity in BNSTav during extinction training. Copyright © 2018 Elsevier Inc. All rights reserved.

  1. GABAA receptor subunit gene expression in human prefrontal cortex: comparison of schizophrenics and controls

    Science.gov (United States)

    Akbarian, S.; Huntsman, M. M.; Kim, J. J.; Tafazzoli, A.; Potkin, S. G.; Bunney, W. E. Jr; Jones, E. G.; Bloom, F. E. (Principal Investigator)

    1995-01-01

    The prefrontal cortex of schizophrenics is hypoactive and displays changes related to inhibitory, GABAergic neurons, and GABAergic synapses. These changes include decreased levels of glutamic acid decarboxylase (GAD), the enzyme for GABA synthesis, upregulation of muscimol binding, and downregulation of benzodiazepine binding to GABAA receptors. Studies in the visual cortex of nonhuman primates have demonstrated that gene expression for GAD and for several GABAA receptor subunit polypeptides is under control of neuronal activity, raising the possibility that similar mechanisms in the hypoactive prefrontal cortex of schizophrenics may explain the abnormalities in GAD and in GABAA receptor regulation. In the present study, which is the first of its type on human cerebral cortex, levels of mRNAs for six GABAA receptor subunits (alpha 1, alpha 2, alpha 5, beta 1, beta 2, gamma 2) and their laminar expression patterns were analyzed in the prefrontal cortex of schizophrenics and matched controls, using in situ hybridization histochemistry and densitometry. Three types of laminar expression pattern were observed: mRNAs for the alpha 1, beta 2, and gamma 2 subunits, which are the predominant receptor subunits expressed in the mature cortex, were expressed at comparatively high levels by cells of all six cortical layers, but most intensely by cells in lower layer III and layer IV. mRNAs for the alpha 2, alpha 5, and beta 1 subunits were expressed at lower levels; alpha 2 and beta 1 were expressed predominantly by cells in layers II, III, and IV; alpha 5 was expressed predominantly in layers IV, V, and VI. There were no significant changes in overall mRNA levels for any of the receptor subunits in the prefrontal cortex of schizophrenics, and the laminar expression pattern of all six receptor subunit mRNAs did not differ between schizophrenics and controls. Because gene expression for GABAA receptor subunits is not consistently altered in the prefrontal cortex of

  2. Gene Expression of Leptin and Long Leptin Receptor Isoform in Endometriosis: A Case-Control Study

    Directory of Open Access Journals (Sweden)

    Andrea Prestes Nácul

    2013-01-01

    Full Text Available In this study, leptin/BMI ratio in serum and peritoneal fluid and gene expression of leptin and long form leptin receptor (OB-RL were assessed in eutopic and ectopic endometria of women with endometriosis and controls. Increased serum leptin/BMI ratio was found in endometriosis patients. Leptin and OB-RL gene expression was significantly higher in ectopic versus eutopic endometrium of patients and controls. A positive, significant correlation was observed between leptin and OB-RL transcripts in ectopic endometria and also in eutopic endometria in endometriosis and control groups. A negative and significant correlation was found between OB-RL mRNA expression and peritoneal fluid leptin/BMI ratio only in endometriosis. These data suggest that, through a modulatory interaction with its active receptor, leptin might play a role in the development of endometrial implants.

  3. Kidney branching morphogenesis under the control of a ligand–receptor-based Turing mechanism

    International Nuclear Information System (INIS)

    Menshykau, Denis; Iber, Dagmar

    2013-01-01

    The main signalling proteins that control early kidney branching have been defined. Yet the underlying mechanism is still elusive. We have previously shown that a Schnakenberg-type Turing mechanism can recapitulate the branching and protein expression patterns in wild-type and mutant lungs, but it is unclear whether this mechanism would extend to other branched organs that are regulated by other proteins. Here, we show that the glial cell line-derived neurotrophic factor–RET regulatory interaction gives rise to a Schnakenberg-type Turing model that reproduces the observed budding of the ureteric bud from the Wolffian duct, its invasion into the mesenchyme and the observed branching pattern. The model also recapitulates all relevant protein expression patterns in wild-type and mutant mice. The lung and kidney models are both based on a particular receptor–ligand interaction and require (1) cooperative binding of ligand and receptor, (2) a lower diffusion coefficient for the receptor than for the ligand and (3) an increase in the receptor concentration in response to receptor–ligand binding (by enhanced transcription, more recycling or similar). These conditions are met also by other receptor–ligand systems. We propose that ligand–receptor-based Turing patterns represent a general mechanism to control branching morphogenesis and other developmental processes. (paper)

  4. Nutrient-sensing nuclear receptors PPARα and FXR control liver energy balance.

    Science.gov (United States)

    Preidis, Geoffrey A; Kim, Kang Ho; Moore, David D

    2017-04-03

    The nuclear receptors PPARα (encoded by NR1C1) and farnesoid X receptor (FXR, encoded by NR1H4) are activated in the liver in the fasted and fed state, respectively. PPARα activation induces fatty acid oxidation, while FXR controls bile acid homeostasis, but both nuclear receptors also regulate numerous other metabolic pathways relevant to liver energy balance. Here we review evidence that they function coordinately to control key nutrient pathways, including fatty acid oxidation and gluconeogenesis in the fasted state and lipogenesis and glycolysis in the fed state. We have also recently reported that these receptors have mutually antagonistic impacts on autophagy, which is induced by PPARα but suppressed by FXR. Secretion of multiple blood proteins is a major drain on liver energy and nutrient resources, and we present preliminary evidence that the liver secretome may be directly suppressed by PPARα, but induced by FXR. Finally, previous studies demonstrated a striking deficiency in bile acid levels in malnourished mice that is consistent with results in malnourished children. We present evidence that hepatic targets of PPARα and FXR are dysregulated in chronic undernutrition. We conclude that PPARα and FXR function coordinately to integrate liver energy balance.

  5. Apical membrane P2Y4 purinergic receptor controls K+ secretion by strial marginal cell epithelium

    Directory of Open Access Journals (Sweden)

    Scofield Margaret A

    2005-11-01

    Full Text Available Abstract Background It was previously shown that K+ secretion by strial marginal cell epithelium is under the control of G-protein coupled receptors of the P2Y family in the apical membrane. Receptor activation by uracil nucleotides (P2Y2, P2Y4 or P2Y6 leads to a decrease in the electrogenic K+ secretion. The present study was conducted to determine the subtype of the functional purinergic receptor in gerbil stria vascularis, to test if receptor activation leads to elevation of intracellular [Ca2+] and to test if the response to these receptors undergoes desensitization. Results The transepithelial short circuit current (Isc represents electrogenic K+ secretion and was found to be decreased by uridine 5'-triphosphate (UTP, adenosine 5'-triphosphate (ATP and diadenosine tetraphosphate (Ap4A but not uridine 5'-diphosphate (UDP at the apical membrane of marginal cells of the gerbil stria vascularis. The potencies of these agonists were consistent with rodent P2Y4 and P2Y2 but not P2Y6 receptors. Activation caused a biphasic increase in intracellular [Ca2+] that could be partially blocked by 2-aminoethoxy-diphenyl borate (2-APB, an inhibitor of the IP3 receptor and store-operated channels. Suramin (100 μM did not inhibit the effect of UTP (1 μM. The ineffectiveness of suramin at the concentration used was consistent with P2Y4 but not P2Y2. Transcripts for both P2Y2 and P2Y4 were found in the stria vascularis. Sustained exposure to ATP or UTP for 15 min caused a depression of Isc that appeared to have two components but with apparently no chronic desensitization. Conclusion The results support the conclusion that regulation of K+ secretion across strial marginal cell epithelium occurs by P2Y4 receptors at the apical membrane. The apparent lack of desensitization of the response is consistent with two processes: a rapid-onset phosphorylation of KCNE1 channel subunit and a slower-onset of regulation by depletion of plasma membrane PIP2.

  6. How membrane lipids control the 3D structure and function of receptors

    OpenAIRE

    Jacques Fantini; Francisco J. Barrantes

    2018-01-01

    The cohabitation of lipids and proteins in the plasma membrane of mammalian cells is controlled by specific biochemical and biophysical rules. Lipids may be either constitutively tightly bound to cell-surface receptors (non-annular lipids) or less tightly attached to the external surface of the protein (annular lipids). The latter are exchangeable with surrounding bulk membrane lipids on a faster time scale than that of non-annular lipids. Not only do non-annular lipids bind to membrane prote...

  7. Cardiomyocytes undergo apoptosis in human immunodeficiency virus cardiomyopathy through mitochondrion- and death receptor-controlled pathways.

    Science.gov (United States)

    Twu, Cheryl; Liu, Nancy Q; Popik, Waldemar; Bukrinsky, Michael; Sayre, James; Roberts, Jaclyn; Rania, Shammas; Bramhandam, Vishnu; Roos, Kenneth P; MacLellan, W Robb; Fiala, Milan

    2002-10-29

    We investigated 18 AIDS hearts (5 with and 13 without cardiomyopathy) by using immunocytochemistry and computerized image analysis regarding the roles of HIV-1 proteins and tumor necrosis factor ligands in HIV cardiomyopathy (HIVCM). HIVCM and cardiomyocyte apoptosis were significantly related to each other and to the expression by inflammatory cells of gp120 and tumor necrosis factor-alpha. In HIVCM heart, active caspase 9, a component of the mitochondrion-controlled apoptotic pathway, and the elements of the death receptor-mediated pathway, tumor necrosis factor-alpha and Fas ligand, were expressed strongly on macrophages and weakly on cardiomyocytes. HIVCM showed significantly greater macrophage infiltration and cardiomyocyte apoptosis rate compared with non-HIVCM. HIV-1 entered cultured neonatal rat ventricular myocytes by macropinocytosis but did not replicate. HIV-1- or gp120-induced apoptosis of rat myocytes through a mitochondrion-controlled pathway, which was inhibited by heparin, AOP-RANTES, or pertussis toxin, suggesting that cardiomyocyte apoptosis is induced by signaling through chemokine receptors. In conclusion, in patients with HIVCM, cardiomyocytes die through both mitochondrion- and death receptor-controlled apoptotic pathways.

  8. Endothelin receptor-specific control of endoplasmic reticulum stress and apoptosis in the kidney.

    Science.gov (United States)

    De Miguel, Carmen; Hamrick, William C; Hobbs, Janet L; Pollock, David M; Carmines, Pamela K; Pollock, Jennifer S

    2017-02-23

    Endothelin-1 (ET-1) promotes renal damage during cardiovascular disease; yet, the molecular mechanisms involved remain unknown. Endoplasmic reticulum (ER) stress, triggered by unfolded protein accumulation in the ER, contributes to apoptosis and organ injury. These studies aimed to determine whether the ET-1 system promotes renal ER stress development in response to tunicamycin. ET B deficient (ET B def) or transgenic control (TG-con) rats were used in the presence or absence of ET A receptor antagonism. Tunicamycin treatment similarly increased cortical ER stress markers in both rat genotypes; however, only ET B def rats showed a 14-24 fold increase from baseline for medullary GRP78, sXBP-1, and CHOP. Pre-treatment of TG-con rats with the ET A blocker ABT-627 for 1 week prior to tunicamycin injection significantly reduced the ER stress response in cortex and medulla, and also inhibited renal apoptosis. Pre-treatment with ABT-627 failed to decrease renal ER stress and apoptosis in ET B def rats. In conclusion, the ET-1 system is important for the development of tunicamycin-induced renal ER stress and apoptosis. ET A receptor activation induces renal ER stress genes and apoptosis, while functional activation of the ET B receptor has protective effects. These results highlight targeting the ET A receptor as a therapeutic approach against ER stress-induced kidney injury.

  9. Optogenetic control of chemokine receptor signal and T-cell migration

    Science.gov (United States)

    Xu, Yuexin; Hyun, Young-Min; Lim, Kihong; Lee, Hyunwook; Cummings, Ryan J.; Gerber, Scott A.; Bae, Seyeon; Cho, Thomas Yoonsang; Lord, Edith M.; Kim, Minsoo

    2014-01-01

    Adoptive cell transfer of ex vivo-generated immune-promoting or tolerogenic T cells to either enhance immunity or promote tolerance in patients has been used with some success. However, effective trafficking of the transferred cells to the target tissue sites is the main barrier to achieving successful clinical outcomes. Here we developed a strategy for optically controlling T-cell trafficking using a photoactivatable (PA) chemokine receptor. Photoactivatable-chemokine C-X-C motif receptor 4 (PA-CXCR4) transmitted intracellular CXCR4 signals in response to 505-nm light. Localized activation of PA-CXCR4 induced T-cell polarization and directional migration (phototaxis) both in vitro and in vivo. Directing light onto the melanoma was sufficient to recruit PA-CXCR4–expressing tumor-targeting cytotoxic T cells and improved the efficacy of adoptive T-cell transfer immunotherapy, with a significant reduction in tumor growth in mice. These findings suggest that the use of photoactivatable chemokine receptors allows remotely controlled leukocyte trafficking with outstanding spatial resolution in tissues and may be feasible in other cell transfer therapies. PMID:24733886

  10. GABAB receptor cell surface export is controlled by an endoplasmic reticulum gatekeeper

    Science.gov (United States)

    Doly, Stéphane; Shirvani, Hamasseh; Gäta, Gabriel; Meye, Frank; Emerit, Michel-Boris; Enslen, Hervé; Achour, Lamia; Pardo-Lopez, Liliana; Kwon, Yang Seung; Armand, Vincent; Gardette, Robert; Giros, Bruno; Gassmann, Martin; Bettler, Bernhard; Mameli, Manuel; Darmon, Michèle; Marullo, Stefano

    2016-01-01

    Summary Endoplasmic reticulum (ER) release and cell surface export of many G protein-coupled receptors (GPCRs), are tightly regulated. For GABAB receptors of GABA, the major mammalian inhibitory neurotransmitter, the ligand-binding GB1 subunit is maintained in the ER by unknown mechanisms in the absence of hetero-dimerization with the GB2 subunit. We report that GB1 retention is regulated by a specific gatekeeper, PRAF2. This ER resident transmembrane protein binds to GB1, preventing its progression in the biosynthetic pathway. GB1 release occurs upon competitive displacement from PRAF2 by GB2. PRAF2 concentration, relative to that of GB1 and GB2, tightly controls cell surface receptor density and controls GABAB function in neurons. Experimental perturbation of PRAF2 levels in vivo caused marked hyperactivity disorders in mice. These data reveal an unanticipated major impact of specific ER gate-keepers on GPCR function and identify PRAF2 as a new molecular target with therapeutic potential for psychiatric and neurological diseases involving GABAB function. PMID:26033241

  11. The Ly49E receptor inhibits the immune control of acute Trypanosoma cruzi infection

    Directory of Open Access Journals (Sweden)

    Jessica Filtjens

    2016-11-01

    Full Text Available The protozoan parasite Trypanosoma cruzi (T. cruzi circulates in the blood upon infection and invades a variety of cells. Parasites intensively multiply during the acute phase of infection and persist lifelong at low levels in tissues and blood during the chronic phase. Natural killer (NK and NKT cells play an important role in the immune control of T. cruzi infection, mainly by releasing the cytokine IFN-γ that activates the microbicidal action of macrophages and other cells and shapes a protective type 1 immune response. The mechanisms by which immune cells are regulated to produce IFN-γ during T. cruzi infection are still incompletely understood. Here, we show that urokinase plasminogen activator (uPA is induced early upon T. cruzi infection, and remains elevated until day 20 post inoculation. We previously demonstrated that the inhibitory receptor Ly49E, which is expressed, among others, on NK and NKT cells, is triggered by uPA. Therefore, we compared wild type (WT to Ly49E knockout (KO mice for their control of experimental T. cruzi infection. Our results show that young, i.e. 4- and 6-week-old, Ly49E KO mice control the infection better than WT mice, indicated by a lower parasite load and less cachexia. The beneficial effect of Ly49E depletion is more obvious in 4-week-old male than in female mice and weakens in 8-week-old mice. In young mice, the lower T. cruzi parasitemia in Ly49E KO mice is paralleled by higher IFN-γ production compared to their WT controls. Our data indicate that Ly49E receptor expression inhibits the immune control of T. cruzi infection. This is the first demonstration that the inhibitory Ly49E receptor can interfere with the immune response to a pathogen in vivo.

  12. MET receptor tyrosine kinase controls dendritic complexity, spine morphogenesis, and glutamatergic synapse maturation in the hippocampus.

    Science.gov (United States)

    Qiu, Shenfeng; Lu, Zhongming; Levitt, Pat

    2014-12-03

    The MET receptor tyrosine kinase (RTK), implicated in risk for autism spectrum disorder (ASD) and in functional and structural circuit integrity in humans, is a temporally and spatially regulated receptor enriched in dorsal pallial-derived structures during mouse forebrain development. Here we report that loss or gain of function of MET in vitro or in vivo leads to changes, opposite in nature, in dendritic complexity, spine morphogenesis, and the timing of glutamatergic synapse maturation onto hippocampus CA1 neurons. Consistent with the morphological and biochemical changes, deletion of Met in mutant mice results in precocious maturation of excitatory synapse, as indicated by a reduction of the proportion of silent synapses, a faster GluN2A subunit switch, and an enhanced acquisition of AMPA receptors at synaptic sites. Thus, MET-mediated signaling appears to serve as a mechanism for controlling the timing of neuronal growth and functional maturation. These studies suggest that mistimed maturation of glutamatergic synapses leads to the aberrant neural circuits that may be associated with ASD risk. Copyright © 2014 the authors 0270-6474/14/3416166-14$15.00/0.

  13. Thyrotropin receptor autoantibodies and early miscarriages in patients with Hashimoto thyroiditis: a case-control study.

    Science.gov (United States)

    Toulis, Konstantinos A; Goulis, Dimitrios G; Tsolakidou, Konstantina; Hilidis, Ilias; Fragkos, Marios; Polyzos, Stergios A; Gerofotis, Antonios; Kita, Marina; Bili, Helen; Vavilis, Dimitrios; Daniilidis, Michail; Tarlatzis, Basil C; Papadimas, Ioannis

    2013-08-01

    We have previously hypothesized that early miscarriage in women with Hashimoto thyroiditis might be the result of a cross-reactivity process, in which blocking autoantibodies against thyrotropin receptor (TSHr-Ab) antagonize hCG action on its receptor on the corpus luteum. To test this hypothesis from the clinical perspective, we investigated the presence of TSHr-Ab in Hashimoto thyroiditis patients with apparently unexplained, first-trimester recurrent miscarriages compared to that in Hashimoto thyroiditis patients with documented normal fertility. A total of 86 subjects (43 cases and 43 age-matched controls) were finally included in a case-control study. No difference in the prevalence of TSHr-Ab positivity was detected between cases and controls (Fisher's exact test, p value = 1.00). In patients with recurrent miscarriages, TSHr-Ab concentrations did not predict the number of miscarriages (univariate linear regression, p value = 0.08). These results were robust in sensitivity analyses, including only cases with full investigation or those with three or more miscarriages. We conclude that no role could be advocated for TSHr-Ab in the aetiology of recurrent miscarriages in women with Hashimoto thyroiditis.

  14. Striatal Dopamine D2/D3 Receptor Availability Is Associated with Executive Function in Healthy Controls but Not Methamphetamine Users.

    Directory of Open Access Journals (Sweden)

    Michael E Ballard

    Full Text Available Dopamine D2/D3 receptor availability in the striatum has been linked with executive function in healthy individuals, and is below control levels among drug addicts, possibly contributing to diminished executive function in the latter group. This study tested for an association of striatal D2/D3 receptor availability with a measure of executive function among research participants who met DSM-IV criteria for methamphetamine dependence.Methamphetamine users and non-user controls (n = 18 per group completed the Wisconsin Card Sorting Test and positron emission tomography with [18F]fallypride.The methamphetamine users displayed significantly lower striatal D2/D3 receptor availability on average than controls after controlling for age and education (p = 0.008, but they did not register greater proportions of either perseverative or non-perseverative errors when controlling for education (both ps ≥ 0.622. The proportion of non-perseverative, but not perseverative, errors was negatively correlated with striatal D2/D3 receptor availability among controls (r = -0.588, p = 0.010, but not methamphetamine users (r = 0.281, p = 0.258, and the group-wise interaction was significant (p = 0.030.These results suggest that cognitive flexibility, as measured by perseverative errors on the Wisconsin Card Sorting Test, is not determined by signaling through striatal D2/D3 receptors in healthy controls, and that in stimulant abusers, who have lower D2/D3 receptor availability, compensation can effectively maintain other executive functions, which are associated with D2/D3 receptor signaling in controls.

  15. Receptor activation and 2 distinct COOH-terminal motifs control G-CSF receptor distribution and internalization kinetics

    NARCIS (Netherlands)

    L.H.J. Aarts (Bart); O. Roovers (Onno); A.C. Ward (Alister); I.P. Touw (Ivo)

    2004-01-01

    textabstractWe have studied the intracellular distribution and internalization kinetics of the granulocyte colony-stimulating factor receptor (G-CSF-R) in living cells using fusion constructs of wild-type or mutant G-CSF-R and enhanced green fluorescent protein (EGFP). Under

  16. Serotonin Signaling in Schistosoma mansoni: A Serotonin–Activated G Protein-Coupled Receptor Controls Parasite Movement

    Science.gov (United States)

    Rashid, Mohammed; Ribeiro, Paula

    2014-01-01

    Serotonin is an important neuroactive substance in all the parasitic helminths. In Schistosoma mansoni, serotonin is strongly myoexcitatory; it potentiates contraction of the body wall muscles and stimulates motor activity. This is considered to be a critical mechanism of motor control in the parasite, but the mode of action of serotonin is poorly understood. Here we provide the first molecular evidence of a functional serotonin receptor (Sm5HTR) in S. mansoni. The schistosome receptor belongs to the G protein-coupled receptor (GPCR) superfamily and is distantly related to serotonergic type 7 (5HT7) receptors from other species. Functional expression studies in transfected HEK 293 cells showed that Sm5HTR is a specific serotonin receptor and it signals through an increase in intracellular cAMP, consistent with a 5HT7 signaling mechanism. Immunolocalization studies with a specific anti-Sm5HTR antibody revealed that the receptor is abundantly distributed in the worm's nervous system, including the cerebral ganglia and main nerve cords of the central nervous system and the peripheral innervation of the body wall muscles and tegument. RNA interference (RNAi) was performed both in schistosomulae and adult worms to test whether the receptor is required for parasite motility. The RNAi-suppressed adults and larvae were markedly hypoactive compared to the corresponding controls and they were also resistant to exogenous serotonin treatment. These results show that Sm5HTR is at least one of the receptors responsible for the motor effects of serotonin in S. mansoni. The fact that Sm5HTR is expressed in nerve tissue further suggests that serotonin stimulates movement via this receptor by modulating neuronal output to the musculature. Together, the evidence identifies Sm5HTR as an important neuronal protein and a key component of the motor control apparatus in S. mansoni. PMID:24453972

  17. Studying cerebellar circuits by remote control of selected neuronal types with GABA-A receptors

    Directory of Open Access Journals (Sweden)

    William Wisden

    2009-12-01

    Full Text Available Although GABA-A receptor-mediated inhibition of cerebellar Purkinje cells by molecular layer interneurons (MLIs has been studied intensely on the cellular level, it has remained unclear how this inhibition regulates cerebellum-dependent behaviour. We have implemented two complementary approaches to investigate the function of the MLI-Purkinje cell synapse on the behavioral level. In the first approach we permanently disrupted inhibitory fast synaptic transmission at the synapse by genetically removing the postsynaptic GABA-A receptors from Purkinje cells (PC-Δγ2 mice. We found that chronic disruption of the MLI-Purkinje cell synapse strongly impaired cerebellar learning of the vestibular occular reflex (VOR, presumably by disrupting the temporal patterns of Purkinje cell activity. However, in PC-Δγ2 mice the baseline VOR reflex was only mildly affected; indeed PC-Δγ2 mice showed no ataxia or gait abnormalities suggesting that MLI control of Purkinje cell activity is either not involved in ongoing motor tasks or that the system has found a way to compensate for its loss. To investigate the latter possibility we have developed an alternative genetic technique; we made the MLI-Purkinje cell synapse selectively sensitive to rapid manipulation with the GABAA receptor modulator zolpidem (PC-γ2-swap mice. Minutes after intraperitoneal zolpidem injection, these PC-γ2-swap mice developed severe motor abnormalities, revealing a substantial contribution of the MLI-Purkinje cell synapse to real time motor control. The cell-type selective permanent knockout of synaptic GABAergic input, and the fast reversible modulation of GABAergic input at the same synapse illustrate how pursuing both strategies gives a fuller view.

  18. Controlled-Deactivation CB1 Receptor Ligands as a Novel Strategy to Lower Intraocular Pressure

    Directory of Open Access Journals (Sweden)

    Sally Miller

    2018-05-01

    Full Text Available Nearly half a century has passed since the demonstration that cannabis and its chief psychoactive component Δ9-THC lowers intraocular pressure (IOP. Elevated IOP remains the chief hallmark and therapeutic target for glaucoma, a condition that places millions at risk of blindness. It is likely that Δ9-THC exerts much of its IOP-lowering effects via the activation of CB1 cannabinoid receptors. However, the initial promise of CB1 as a target for treating glaucoma has not thus far translated into a credible therapeutic strategy. We have recently shown that blocking monoacylglycerol lipase (MAGL, an enzyme that breaks the endocannabinoid 2-arachidonoyl glycerol (2-AG, substantially lowers IOP. Another strategy is to develop cannabinoid CB1 receptor agonists that are optimized for topical application to the eye. Recently we have reported on a controlled-deactivation approach where the “soft” drug concept of enzymatic deactivation was combined with a “depot effect” that is commonly observed with Δ9-THC and other lipophilic cannabinoids. This approach allowed us to develop novel cannabinoids with a predictable duration of action and is particularly attractive for the design of CB1 activators for ophthalmic use with limited or no psychoactive effects. We have tested a novel class of compounds using a combination of electrophysiology in autaptic hippocampal neurons, a well-characterized model of endogenous cannabinoid signaling, and measurements of IOP in a mouse model. We now report that AM7410 is a reasonably potent and efficacious agonist at CB1 in neurons and that it substantially (30% lowers IOP for as long as 5 h after a single topical treatment. This effect is absent in CB1 knockout mice. Our results indicate that the direct targeting of CB1 receptors with controlled-deactivation ligands is a viable approach to lower IOP in a murine model and merits further study in other model systems.

  19. Identification of G Protein-Coupled Receptors (GPCRs in Primary Cilia and Their Possible Involvement in Body Weight Control.

    Directory of Open Access Journals (Sweden)

    Yoshihiro Omori

    Full Text Available Primary cilia are sensory organelles that harbor various receptors such as G protein-coupled receptors (GPCRs. We analyzed subcellular localization of 138 non-odorant GPCRs. We transfected GPCR expression vectors into NIH3T3 cells, induced ciliogenesis by serum starvation, and observed subcellular localization of GPCRs by immunofluorescent staining. We found that several GPCRs whose ligands are involved in feeding behavior, including prolactin-releasing hormone receptor (PRLHR, neuropeptide FF receptor 1 (NPFFR1, and neuromedin U receptor 1 (NMUR1, localized to the primary cilia. In addition, we found that a short form of dopamine receptor D2 (DRD2S is efficiently transported to the primary cilia, while a long form of dopamine receptor D2 (DRD2L is rarely transported to the primary cilia. Using an anti-Prlhr antibody, we found that Prlhr localized to the cilia on the surface of the third ventricle in the vicinity of the hypothalamic periventricular nucleus. We generated the Npy2r-Cre transgenic mouse line in which Cre-recombinase is expressed under the control of the promoter of Npy2r encoding a ciliary GPCR. By mating Npy2r-Cre mice with Ift80 flox mice, we generated Ift80 conditional knockout (CKO mice in which Npy2r-positive cilia were diminished in number. We found that Ift80 CKO mice exhibited a body weight increase. Our results suggest that Npy2r-positive cilia are important for body weight control.

  20. Identification of G Protein-Coupled Receptors (GPCRs) in Primary Cilia and Their Possible Involvement in Body Weight Control.

    Science.gov (United States)

    Omori, Yoshihiro; Chaya, Taro; Yoshida, Satoyo; Irie, Shoichi; Tsujii, Toshinori; Furukawa, Takahisa

    2015-01-01

    Primary cilia are sensory organelles that harbor various receptors such as G protein-coupled receptors (GPCRs). We analyzed subcellular localization of 138 non-odorant GPCRs. We transfected GPCR expression vectors into NIH3T3 cells, induced ciliogenesis by serum starvation, and observed subcellular localization of GPCRs by immunofluorescent staining. We found that several GPCRs whose ligands are involved in feeding behavior, including prolactin-releasing hormone receptor (PRLHR), neuropeptide FF receptor 1 (NPFFR1), and neuromedin U receptor 1 (NMUR1), localized to the primary cilia. In addition, we found that a short form of dopamine receptor D2 (DRD2S) is efficiently transported to the primary cilia, while a long form of dopamine receptor D2 (DRD2L) is rarely transported to the primary cilia. Using an anti-Prlhr antibody, we found that Prlhr localized to the cilia on the surface of the third ventricle in the vicinity of the hypothalamic periventricular nucleus. We generated the Npy2r-Cre transgenic mouse line in which Cre-recombinase is expressed under the control of the promoter of Npy2r encoding a ciliary GPCR. By mating Npy2r-Cre mice with Ift80 flox mice, we generated Ift80 conditional knockout (CKO) mice in which Npy2r-positive cilia were diminished in number. We found that Ift80 CKO mice exhibited a body weight increase. Our results suggest that Npy2r-positive cilia are important for body weight control.

  1. Dopamine D(1) receptor-mediated control of striatal acetylcholine release by endogenous dopamine.

    Science.gov (United States)

    Acquas, E; Di Chiara, G

    1999-10-27

    The role of dopamine D(1) and D(2) receptors in the control of acetylcholine release in the dorsal striatum by endogenous dopamine was investigated by monitoring with microdialysis the effect of the separate or combined administration of the dopamine D(1) receptor antagonist, SCH 39166 ¿(-)-trans-6,7,7a,8,9, 13b-exahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo-[d]-nap hto-[2, 1b]-azepine hydrochloride¿ (50 microg/kg subcutaneous (s.c.)), of the dopamine D(2)/D(3) receptor agonist, quinpirole (trans-(-)-4aR, 4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo-(3,4-g)-quinoline hydrochloride) (5 and 10 microg/kg s.c.), and of the D(3) receptor selective agonist, PD 128,907 [S(+)-(4aR,10bR)-3,4,4a, 10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin -9-ol hydrochloride] (50 microg/kg s.c.), on in vivo dopamine and acetylcholine release. Microdialysis was performed with a Ringer containing low concentrations (0.01 microM) of the acetylcholinesterase inhibitor, neostigmine. Quinpirole (10 microg/kg s.c.) decreased striatal dopamine and acetylcholine release. Administration of PD 128,907 (50 microg/kg) decreased dopamine but failed to affect acetylcholine release. SCH 39166 (50 microg/kg s.c.) stimulated dopamine release and reduced acetylcholine release. Pretreatment with quinpirole reduced (5 microg/kg s.c.) or completely prevented (10 microg/kg s.c.) the stimulation of dopamine release elicited by SCH 39166 (50 microg/kg s.c.); on the other hand, pretreatment with quinpirole (5 and 10 microg/kg) potentiated the reduction of striatal acetylcholine release induced by SCH 39166 (50 microg/kg s.c.). Similarly, pretreatment with PD 128,907 (50 microg/kg) which prevented the increase of dopamine release induced by SCH 39166 (50 microg/kg), potentiated the reduction of striatal acetylcholine transmission elicited by SCH 39166. Thus, pretreatment with low doses of quinpirole or PD 128,907 influences in opposite manner the effect of SCH 39166 on striatal dopamine and

  2. Surface receptor Toso controls B cell-mediated regulation of T cell immunity.

    Science.gov (United States)

    Yu, Jinbo; Duong, Vu Huy Hoang; Westphal, Katrin; Westphal, Andreas; Suwandi, Abdulhadi; Grassl, Guntram A; Brand, Korbinian; Chan, Andrew C; Föger, Niko; Lee, Kyeong-Hee

    2018-05-01

    The immune system is tightly controlled by regulatory processes that allow for the elimination of invading pathogens, while limiting immunopathological damage to the host. In the present study, we found that conditional deletion of the cell surface receptor Toso on B cells unexpectedly resulted in impaired proinflammatory T cell responses, which led to impaired immune protection in an acute viral infection model and was associated with reduced immunopathological tissue damage in a chronic inflammatory context. Toso exhibited its B cell-inherent immunoregulatory function by negatively controlling the pool of IL-10-competent B1 and B2 B cells, which were characterized by a high degree of self-reactivity and were shown to mediate immunosuppressive activity on inflammatory T cell responses in vivo. Our results indicate that Toso is involved in the differentiation/maintenance of regulatory B cells by fine-tuning B cell receptor activation thresholds. Furthermore, we showed that during influenza A-induced pulmonary inflammation, the application of Toso-specific antibodies selectively induced IL-10-competent B cells at the site of inflammation and resulted in decreased proinflammatory cytokine production by lung T cells. These findings suggest that Toso may serve as a novel therapeutic target to dampen pathogenic T cell responses via the modulation of IL-10-competent regulatory B cells.

  3. Growth and gene expression are predominantly controlled by distinct regions of the human IL-4 receptor.

    Science.gov (United States)

    Ryan, J J; McReynolds, L J; Keegan, A; Wang, L H; Garfein, E; Rothman, P; Nelms, K; Paul, W E

    1996-02-01

    IL-4 causes hematopoietic cells to proliferate and express a series of genes, including CD23. We examined whether IL-4-mediated growth, as measured by 4PS phosphorylation, and gene induction were similarly controlled. Studies of M12.4.1 cells expressing human IL-4R truncation mutants indicated that the region between amino acids 557-657 is necessary for full gene expression, which correlated with Stat6 DNA binding activity. This region was not required for 4PS phosphorylation. Tyrosine-to-phenylalanine mutations in the interval between amino acids 557-657 revealed that as long as one tyrosine remained unmutated, CD23 was fully induced. When all three tyrosines were mutated, the receptor was unable to induce CD23. The results indicate that growth regulation and gene expression are principally controlled by distinct regions of IL-4R.

  4. Prefrontal gamma-aminobutyric acid type A receptor insertion controls cue-induced relapse to nicotine seeking.

    Science.gov (United States)

    Lubbers, Bart R; van Mourik, Yvar; Schetters, Dustin; Smit, August B; De Vries, Taco J; Spijker, Sabine

    2014-11-01

    Current smoking cessation therapies offer limited success, as relapse rates remain high. Nicotine, which is the major component of tobacco smoke, is thought to be primarily responsible for the addictive properties of tobacco. However, little is known about the molecular mechanisms underlying nicotine relapse, hampering development of more effective therapies. The objective of this study was to elucidate the role of medial prefrontal cortex (mPFC) glutamatergic and gamma-aminobutyric acid (GABA)ergic receptors in controlling relapse to nicotine seeking. Using an intravenous self-administration model, we studied glutamate and gamma-aminobutyric acid receptor regulation in the synaptic membrane fraction of the rat mPFC following extinction and cue-induced relapse to nicotine seeking. Subsequently, we locally intervened at the level of GABAergic signaling by using a mimetic peptide of the GABA receptor associated protein-interacting domain of GABA type A (GABAA) receptor subunit γ2 (TAT-GABAγ2) and muscimol, a GABAA receptor agonist. Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid and N-methyl-D-aspartate receptors were not regulated after the 30-min relapse test. However, GABAA receptor subunits α1 and γ2 were upregulated, and interference with GABAA receptor insertion in the cell membrane using the TAT-GABAγ2 peptide in the dorsal mPFC, but not the ventral mPFC, significantly increased responding during relapse. Increasing GABAA transmission with muscimol in the dorsal and ventral mPFC attenuated relapse. These data indicate that cue-induced relapse entails a GABAergic plasticity mechanism that limits nicotine seeking by restoring inhibitory control in the dorsal mPFC. GABAA receptor-mediated neurotransmission in the dorsal mPFC constitutes a possible future therapeutic target for maintaining smoking abstinence. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  5. Oestrogen receptor α gene haplotype and postmenopausal breast cancer risk: a case control study

    International Nuclear Information System (INIS)

    Wedrén, Sara; Stiger, Fredrik; Persson, Ingemar; Baron, John; Weiderpass, Elisabete; Lovmar, Lovisa; Humphreys, Keith; Magnusson, Cecilia; Melhus, Håkan; Syvänen, Ann-Christine; Kindmark, Andreas; Landegren, Ulf; Fermér, Maria Lagerström

    2004-01-01

    Oestrogen receptor α, which mediates the effect of oestrogen in target tissues, is genetically polymorphic. Because breast cancer development is dependent on oestrogenic influence, we have investigated whether polymorphisms in the oestrogen receptor α gene (ESR1) are associated with breast cancer risk. We genotyped breast cancer cases and age-matched population controls for one microsatellite marker and four single-nucleotide polymorphisms (SNPs) in ESR1. The numbers of genotyped cases and controls for each marker were as follows: TA n , 1514 cases and 1514 controls; c.454-397C → T, 1557 cases and 1512 controls; c.454-351A → G, 1556 cases and 1512 controls; c.729C → T, 1562 cases and 1513 controls; c.975C → G, 1562 cases and 1513 controls. Using logistic regression models, we calculated odds ratios (ORs) and 95% confidence intervals (CIs). Haplotype effects were estimated in an exploratory analysis, using expectation-maximisation algorithms for case-control study data. There were no compelling associations between single polymorphic loci and breast cancer risk. In haplotype analyses, a common haplotype of the c.454-351A → G or c.454-397C → T and c.975C → G SNPs appeared to be associated with an increased risk for ductal breast cancer: one copy of the c.454-351A → G and c.975C → G haplotype entailed an OR of 1.19 (95% CI 1.06–1.33) and two copies with an OR of 1.42 (95% CI 1.15–1.77), compared with no copies, under a model of multiplicative penetrance. The association with the c.454-397C → T and c.975C → G haplotypes was similar. Our data indicated that these haplotypes were more influential in women with a high body mass index. Adjustment for multiple comparisons rendered the associations statistically non-significant. We found suggestions of an association between common haplotypes in ESR1 and the risk for ductal breast cancer that is stronger in heavy women

  6. Interacting cannabinoid and opioid receptors in the nucleus accumbens core control adolescent social play

    Directory of Open Access Journals (Sweden)

    Antonia Manduca

    2016-11-01

    Full Text Available Social play behavior is a highly rewarding, developmentally important form of social interaction in young mammals. However, its neurobiological underpinnings remain incompletely understood. Previous work has suggested that opioid and endocannabinoid neurotransmission interact in the modulation of social play. Therefore, we combined behavioral, pharmacological, electrophysiological and genetic approaches to elucidate the role of the endocannabinoid 2-arachidonoylglycerol (2-AG in social play, and how cannabinoid and opioid neurotransmission interact to control social behavior in adolescent rodents. Systemic administration of the 2-AG hydrolysis inhibitor JZL184 or the opioid receptor agonist morphine increased social play behavior in adolescent rats. These effects were blocked by systemic pretreatment with either CB1 cannabinoid receptor (CB1R or mu-opioid receptor (MOR antagonists. The social play-enhancing effects of systemic morphine or JZL184 treatment were also prevented by direct infusion of the CB1R antagonist SR141716 and the MOR antagonist naloxone into the nucleus accumbens core (NAcC. Searching for synaptic correlates of these effects in adolescent NAcC excitatory synapses, we observed that CB1R antagonism blocked the effect of the MOR agonist DAMGO and, conversely, that naloxone reduced the effect of a cannabinoid agonist. These results were recapitulated in mice, and completely abolished in CB1R and MOR knockout mice, suggesting that the functional interaction between CB1R and MOR in the NAcC in the modulation of mediates social behavior is widespread in rodents. The data shed new light on the mechanism by which endocannabinoid lipids and opioid peptides interact to orchestrate rodent socioemotional behaviors.

  7. Involvement of β3-adrenergic receptors in the control of food intake in rats.

    Science.gov (United States)

    Kanzler, S A; Januario, A C; Paschoalini, M A

    2011-11-01

    This study examined the food intake changes evoked by intracerebroventricular (icv) injection of a selective agonist (BRL37344, 2 and 20 nmol) or antagonist (SR59230A, 10 and 50 nmol) of β3-adrenergic receptors in 24-h fasted rats (adult male Wistar rats, 200-350 g, N = 6/treatment). The animals were also pretreated with saline icv (SAL) or SR59230A (50 nmol) followed by BRL37344 (20 nmol) or SAL in order to determine the selectivity of the effects evoked by BRL37344 on food intake or the selectivity of the effects evoked by SR59230A on risk assessment (RA) behavior. The highest dose of BRL37344 (N = 7) decreased food intake 1 h after the treatment (6.4 ± 0.5 g in SAL-treated vs 4.2 ± 0.8 g in drug-treated rats). While both doses of SR59230A failed to affect food intake (5.1 ± 1.1 g for 10 nmol and 6.0 ± 1.8 g for 50 nmol), this treatment reduced the RA frequency (number/30 min) (4 ± 2 for SAL-treated vs 1 ± 1 for 10 nmol and 0.5 ± 1 for 50 nmol SR59230A-treated rats), an ethological parameter related to anxiety. While pretreatment with SR59230A (7.0 ± 0.5 g) abolished the hypophagia induced by BRL37344 (3.6 ± 0.9 g), BRL37344 suppressed the reduction in RA frequency caused by SR59230A. These results show that the hypophagia caused by BRL37344 is selectively mediated by β3-adrenergic receptors within the central nervous system. Moreover, they suggest the involvement of these receptors in the control of anxiety.

  8. Involvement of β3-adrenergic receptors in the control of food intake in rats

    Directory of Open Access Journals (Sweden)

    S.A. Kanzler

    2011-11-01

    Full Text Available This study examined the food intake changes evoked by intracerebroventricular (icv injection of a selective agonist (BRL37344, 2 and 20 nmol or antagonist (SR59230A, 10 and 50 nmol of β3-adrenergic receptors in 24-h fasted rats (adult male Wistar rats, 200-350 g, N = 6/treatment. The animals were also pretreated with saline icv (SAL or SR59230A (50 nmol followed by BRL37344 (20 nmol or SAL in order to determine the selectivity of the effects evoked by BRL37344 on food intake or the selectivity of the effects evoked by SR59230A on risk assessment (RA behavior. The highest dose of BRL37344 (N = 7 decreased food intake 1 h after the treatment (6.4 ± 0.5 g in SAL-treated vs 4.2 ± 0.8 g in drug-treated rats. While both doses of SR59230A failed to affect food intake (5.1 ± 1.1 g for 10 nmol and 6.0 ± 1.8 g for 50 nmol, this treatment reduced the RA frequency (number/30 min (4 ± 2 for SAL-treated vs 1 ± 1 for 10 nmol and 0.5 ± 1 for 50 nmol SR59230A-treated rats, an ethological parameter related to anxiety. While pretreatment with SR59230A (7.0 ± 0.5 g abolished the hypophagia induced by BRL37344 (3.6 ± 0.9 g, BRL37344 suppressed the reduction in RA frequency caused by SR59230A. These results show that the hypophagia caused by BRL37344 is selectively mediated by β3-adrenergic receptors within the central nervous system. Moreover, they suggest the involvement of these receptors in the control of anxiety.

  9. Estrogen receptor alpha gene polymorphism and endometrial cancer risk – a case-control study

    International Nuclear Information System (INIS)

    Wedrén, Sara; Stiger, Fredrik; Persson, Ingemar; Baron, John A; Weiderpass, Elisabete; Lovmar, Lovisa; Humphreys, Keith; Magnusson, Cecilia; Melhus, Håkan; Syvänen, Ann-Christine; Kindmark, Andreas; Landegren, Ulf; Fermér, Maria Lagerström

    2008-01-01

    Estrogen is an established endometrial carcinogen. One of the most important mediators of estrogenic action is the estrogen receptor alpha. We have investigated whether polymorphic variation in the estrogen receptor alpha gene (ESR1) is associated with endometrial cancer risk. In 702 cases with invasive endometrial cancer and 1563 controls, we genotyped five markers in ESR1 and used logistic regression models to estimate odds ratios (OR) and 95 percent confidence intervals (CI). We found an association between rs2234670, rs2234693, as well as rs9340799, markers in strong linkage disequilibrium (LD), and endometrial cancer risk. The association with rs9340799 was the strongest, OR 0.75 (CI 0.60–0.93) for heterozygous and OR 0.53 (CI 0.37–0.77) for homozygous rare compared to those homozygous for the most common allele. Haplotype models did not fit better to the data than single marker models. We found that intronic variation in ESR1 was associated with endometrial cancer risk

  10. Prokineticin receptor 1 as a novel suppressor of preadipocyte proliferation and differentiation to control obesity.

    Directory of Open Access Journals (Sweden)

    Cécilia Szatkowski

    Full Text Available BACKGROUND: Adipocyte renewal from preadipocytes occurs throughout the lifetime and contributes to obesity. To date, little is known about the mechanisms that control preadipocyte proliferation and differentiation. Prokineticin-2 is an angiogenic and anorexigenic hormone that activate two G protein-coupled receptors (GPCRs: PKR1 and PKR2. Prokineticin-2 regulates food intake and energy metabolism via central mechanisms (PKR2. The peripheral effect of prokineticin-2 on adipocytes/preadipocytes has not been studied yet. METHODOLOGY/PRINCIPAL FINDINGS: Since adipocytes and preadipocytes express mainly prokineticin receptor-1 (PKR1, here, we explored the role of PKR1 in adipose tissue expansion, generating PKR1-null (PKR1(-/- and adipocyte-specific (PKR1(ad-/- mutant mice, and using murine and human preadipocyte cell lines. Both PKR1(-/- and PKR1(ad-/- had excessive abdominal adipose tissue, but only PKR1(-/- mice showed severe obesity and diabetes-like syndrome. PKR1(ad-/- mice had increased proliferating preadipocytes and newly formed adipocyte levels, leading to expansion of adipose tissue. Using PKR1-knockdown in 3T3-L1 preadipocytes, we show that PKR1 directly inhibits preadipocyte proliferation and differentiation. These PKR1 cell autonomous actions appear targeted at preadipocyte cell cycle regulatory pathways, through reducing cyclin D, E, cdk2, c-Myc levels. CONCLUSIONS/SIGNIFICANCE: These results suggest PKR1 to be a crucial player in the preadipocyte proliferation and differentiation. Our data should facilitate studies of both the pathogenesis and therapy of obesity in humans.

  11. Parsing pyrogenic polycyclic aromatic hydrocarbons: forensic chemistry, receptor models, and source control policy.

    Science.gov (United States)

    O'Reilly, Kirk T; Pietari, Jaana; Boehm, Paul D

    2014-04-01

    A realistic understanding of contaminant sources is required to set appropriate control policy. Forensic chemical methods can be powerful tools in source characterization and identification, but they require a multiple-lines-of-evidence approach. Atmospheric receptor models, such as the US Environmental Protection Agency (USEPA)'s chemical mass balance (CMB), are increasingly being used to evaluate sources of pyrogenic polycyclic aromatic hydrocarbons (PAHs) in sediments. This paper describes the assumptions underlying receptor models and discusses challenges in complying with these assumptions in practice. Given the variability within, and the similarity among, pyrogenic PAH source types, model outputs are sensitive to specific inputs, and parsing among some source types may not be possible. Although still useful for identifying potential sources, the technical specialist applying these methods must describe both the results and their inherent uncertainties in a way that is understandable to nontechnical policy makers. The authors present an example case study concerning an investigation of a class of parking-lot sealers as a significant source of PAHs in urban sediment. Principal component analysis is used to evaluate published CMB model inputs and outputs. Targeted analyses of 2 areas where bans have been implemented are included. The results do not support the claim that parking-lot sealers are a significant source of PAHs in urban sediments. © 2013 SETAC.

  12. Double-Nanodomain Coupling of Calcium Channels, Ryanodine Receptors, and BK Channels Controls the Generation of Burst Firing.

    Science.gov (United States)

    Irie, Tomohiko; Trussell, Laurence O

    2017-11-15

    Action potentials clustered into high-frequency bursts play distinct roles in neural computations. However, little is known about ionic currents that control the duration and probability of these bursts. We found that, in cartwheel inhibitory interneurons of the dorsal cochlear nucleus, the likelihood of bursts and the interval between their spikelets were controlled by Ca 2+ acting across two nanodomains, one between plasma membrane P/Q Ca 2+ channels and endoplasmic reticulum (ER) ryanodine receptors and another between ryanodine receptors and large-conductance, voltage- and Ca 2+ -activated K + (BK) channels. Each spike triggered Ca 2+ -induced Ca 2+ release (CICR) from the ER immediately beneath somatic, but not axonal or dendritic, plasma membrane. Moreover, immunolabeling demonstrated close apposition of ryanodine receptors and BK channels. Double-nanodomain coupling between somatic plasma membrane and hypolemmal ER cisterns provides a unique mechanism for rapid control of action potentials on the millisecond timescale. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. SMRT repression of nuclear receptors controls the adipogenic set point and metabolic homeostasis

    NARCIS (Netherlands)

    Nofsinger, Russell R.; Li, Pingping; Hong, Suk-Hyun; Jonker, Johan W.; Barish, Grant D.; Ying, Hao; Cheng, Sheue-Yann; LeBlanc, Mathias; Xu, Wei; Pei, Liming; Kang, Yeon-Joo; Nelson, Michael; Downes, Michael; Yu, Ruth T.; Olefsky, Jerrold M.; Lee, Chih-Hao; Evans, Ronald M.

    2008-01-01

    The nuclear receptor corepressor, silencing mediator of retinoid and thyroid hormone receptors (SMRT), is recruited by a plethora of transcription factors to mediate lineage and signal-dependent transcriptional repression. We generated a knockin mutation in the receptor interaction domain (RID) of

  14. The insect ecdysone receptor is a good potential target for RNAi-based pest control.

    Science.gov (United States)

    Yu, Rong; Xu, Xinping; Liang, Yongkang; Tian, Honggang; Pan, Zhanqing; Jin, Shouheng; Wang, Na; Zhang, Wenqing

    2014-01-01

    RNA interference (RNAi) has great potential for use in insect pest control. However, some significant challenges must be overcome before RNAi-based pest control can become a reality. One challenge is the proper selection of a good target gene for RNAi. Here, we report that the insect ecdysone receptor (EcR) is a good potential target for RNAi-based pest control in the brown planthopper Nilaparvata lugens, a serious insect pest of rice plants. We demonstrated that the use of a 360 bp fragment (NlEcR-c) that is common between NlEcR-A and NlEcR-B for feeding RNAi experiments significantly decreased the relative mRNA expression levels of NlEcR compared with those in the dsGFP control. Feeding RNAi also resulted in a significant reduction in the number of offspring per pair of N. lugens. Consequently, a transgenic rice line expressing NlEcR dsRNA was constructed by Agrobacterium- mediated transformation. The results of qRT-PCR showed that the total copy number of the target gene in all transgenic rice lines was 2. Northern blot analysis showed that the small RNA of the hairpin dsNlEcR-c was successfully expressed in the transgenic rice lines. After newly hatched nymphs of N. lugens fed on the transgenic rice lines, effective RNAi was observed. The NlEcR expression levels in all lines examined were decreased significantly compared with the control. In all lines, the survival rate of the nymphs was nearly 90%, and the average number of offspring per pair in the treated groups was significantly less than that observed in the control, with a decrease of 44.18-66.27%. These findings support an RNAi-based pest control strategy and are also important for the management of rice insect pests.

  15. Vascular Endothelial Growth Factor Receptor 3 Controls Neural Stem Cell Activation in Mice and Humans

    Directory of Open Access Journals (Sweden)

    Jinah Han

    2015-02-01

    Full Text Available Neural stem cells (NSCs continuously produce new neurons within the adult mammalian hippocampus. NSCs are typically quiescent but activated to self-renew or differentiate into neural progenitor cells. The molecular mechanisms of NSC activation remain poorly understood. Here, we show that adult hippocampal NSCs express vascular endothelial growth factor receptor (VEGFR 3 and its ligand VEGF-C, which activates quiescent NSCs to enter the cell cycle and generate progenitor cells. Hippocampal NSC activation and neurogenesis are impaired by conditional deletion of Vegfr3 in NSCs. Functionally, this is associated with compromised NSC activation in response to VEGF-C and physical activity. In NSCs derived from human embryonic stem cells (hESCs, VEGF-C/VEGFR3 mediates intracellular activation of AKT and ERK pathways that control cell fate and proliferation. These findings identify VEGF-C/VEGFR3 signaling as a specific regulator of NSC activation and neurogenesis in mammals.

  16. Leptin receptor Gln223Arg polymorphism and breast cancer risk in Nigerian women: A case control study

    International Nuclear Information System (INIS)

    Okobia, Michael N; Taioli, Emanuela; Bunker, Clareann H; Garte, Seymour J; Zmuda, Joseph M; Ezeome, Emmanuel R; Anyanwu, Stanley N; Uche, Emmanuel E; Kuller, Lewis H; Ferrell, Robert E

    2008-01-01

    Leptin, a 16 kDa polypeptide hormone, implicated in various physiological processes, exerts its action through the leptin receptor, a member of the class I cytokine receptor family. Both leptin and leptin receptor have recently been implicated in processes leading to breast cancer initiation and progression in animal models and humans. An A to G transition mutation in codon 223 in exon 6 of the leptin receptor gene, resulting in glutamine to arginine substitution (Gln223Arg), lies within the first of two putative leptin-binding regions and may be associated with impaired signaling capacity of the leptin receptor. This study was designed to assess the role of this polymorphism in breast cancer susceptibility in Nigerian women. We utilized a polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) assay to evaluate the association between the Gln223Arg polymorphism of the leptin receptor gene and breast risk in Nigeria in a case control study involving 209 women with breast cancer and 209 controls without the disease. Study participants were recruited from surgical outpatient clinics and surgical wards of four University Teaching Hospitals located in Midwestern and southeastern Nigeria between September 2002 and April 2004. Premenopausal women carrying at least one LEPR 223Arg allele were at a modestly increased risk of breast cancer after adjusting for confounders (OR = 1.8, 95% confidence interval [CI] 1.0–3.2, p = 0.07). There was no association with postmenopausal breast cancer risk (OR = 0.9, 95% CI 0.4–1.8, p = 0.68). Our results suggest that the LEPR Gln223Arg polymorphism in the extracellular domain of the LEPR receptor gene is associated with a modestly increased risk of premenopausal breast cancer in Nigerian women

  17. Vitamin D receptor-mediated control of Soggy, Wise, and Hairless gene expression in keratinocytes.

    Science.gov (United States)

    Hsieh, Jui-Cheng; Estess, Rudolf C; Kaneko, Ichiro; Whitfield, G Kerr; Jurutka, Peter W; Haussler, Mark R

    2014-02-01

    The vitamin D receptor (VDR), but not its hormonal ligand, 1,25-dihydroxyvitamin D3 (1,25D), is required for the progression of the mammalian hair cycle. We studied three genes relevant to hair cycle signaling, DKKL1 (Soggy), SOSTDC1 (Wise), and HR (Hairless), to determine whether their expression is regulated by VDR and/or its 1,25D ligand. DKKL1 mRNA was repressed 49-72% by 1,25D in primary human and CCD-1106 KERTr keratinocytes; a functional vitamin D responsive element (VDRE) was identified at -9590 bp in murine Soggy. Similarly, SOSTDC1 mRNA was repressed 41-59% by 1,25D in KERTr and primary human keratinocytes; a functional VDRE was located at -6215 bp in human Wise. In contrast, HR mRNA was upregulated 1.56- to 2.77-fold by 1,25D in primary human and KERTr keratinocytes; a VDRE (TGGTGAgtgAGGACA) consisting of an imperfect direct repeat separated by three nucleotides (DR3) was identified at -7269 bp in the human Hairless gene that mediated dramatic induction, even in the absence of 1,25D ligand. In parallel, a DR4 thyroid hormone responsive element, TGGTGAggccAGGACA, was identified at +1304 bp in the human HR gene that conferred tri-iodothyronine (T3)-independent transcriptional activation. Because the thyroid hormone receptor controls HR expression in the CNS, whereas VDR functions in concert with the HR corepressor specifically in skin, a model is proposed wherein unliganded VDR upregulates the expression of HR, the gene product of which acts as a downstream comodulator to feedback-repress DKKL1 and SOSTDC1, resulting in integration of bone morphogenic protein and Wnt signaling to drive the mammalian hair cycle and/or influencing epidermal function.

  18. Vascular Type 1A Angiotensin II Receptors Control BP by Regulating Renal Blood Flow and Urinary Sodium Excretion.

    Science.gov (United States)

    Sparks, Matthew A; Stegbauer, Johannes; Chen, Daian; Gomez, Jose A; Griffiths, Robert C; Azad, Hooman A; Herrera, Marcela; Gurley, Susan B; Coffman, Thomas M

    2015-12-01

    Inappropriate activation of the type 1A angiotensin (AT1A) receptor contributes to the pathogenesis of hypertension and its associated complications. To define the role for actions of vascular AT1A receptors in BP regulation and hypertension pathogenesis, we generated mice with cell-specific deletion of AT1A receptors in smooth muscle cells (SMKO mice) using Loxp technology and Cre transgenes with robust expression in both conductance and resistance arteries. We found that elimination of AT1A receptors from vascular smooth muscle cells (VSMCs) caused a modest (approximately 7 mmHg) yet significant reduction in baseline BP and exaggerated sodium sensitivity in mice. Additionally, the severity of angiotensin II (Ang II)-dependent hypertension was dramatically attenuated in SMKO mice, and this protection against hypertension was associated with enhanced urinary excretion of sodium. Despite the lower BP, acute vasoconstrictor responses to Ang II in the systemic vasculature were largely preserved (approximately 80% of control levels) in SMKO mice because of exaggerated activity of the sympathetic nervous system rather than residual actions of AT1B receptors. In contrast, Ang II-dependent responses in the renal circulation were almost completely eliminated in SMKO mice (approximately 5%-10% of control levels). These findings suggest that direct actions of AT1A receptors in VSMCs are essential for regulation of renal blood flow by Ang II and highlight the capacity of Ang II-dependent vascular responses in the kidney to effect natriuresis and BP control. Copyright © 2015 by the American Society of Nephrology.

  19. Human Immunodeficiency Virus Type-1 Elite Controllers Maintain Low Co-Expression of Inhibitory Receptors on CD4+ T Cells.

    Science.gov (United States)

    Noyan, Kajsa; Nguyen, Son; Betts, Michael R; Sönnerborg, Anders; Buggert, Marcus

    2018-01-01

    Human immunodeficiency virus type-1 (HIV-1) elite controllers (ELCs) represent a unique population that control viral replication in the absence of antiretroviral therapy (cART). It is well established that expression of multiple inhibitory receptors on CD8+ T cells is associated with HIV-1 disease progression. However, whether reduced co-expression of inhibitory receptors on CD4+ T cells is linked to natural viral control and slow HIV-1 disease progression remains undefined. Here, we report on the expression pattern of numerous measurable inhibitory receptors, associated with T cell exhaustion (programmed cell death-1, CTLA-4, and TIGIT), on different CD4+ T cell memory populations in ELCs and HIV-infected subjects with or without long-term cART. We found that the co-expression pattern of inhibitory receptors was significantly reduced in ELCs compared with HIV-1 cART-treated and viremic subjects, and similar to healthy controls. Markers associated with T cell exhaustion varied among different memory CD4+ T cell subsets and highest levels were found mainly on transitional memory T cells. CD4+ T cells co-expressing all inhibitory markers were positively correlated to T cell activation (CD38+ HLA-DR+) as well as the transcription factors Helios and FoxP3. Finally, clinical parameters such as CD4 count, HIV-1 viral load, and the CD4/CD8 ratio all showed significant associations with CD4+ T cell exhaustion. We demonstrate that ELCs are able to maintain lower levels of CD4+ T cell exhaustion despite years of ongoing viral replication compared with successfully cART-treated subjects. Our findings suggest that ELCs harbor a "healthy" state of inhibitory receptor expression on CD4+ T cells that might play part in maintenance of their control status.

  20. Activity-dependent control of NMDA receptor subunit composition at hippocampal mossy fibre synapses.

    Science.gov (United States)

    Carta, Mario; Srikumar, Bettadapura N; Gorlewicz, Adam; Rebola, Nelson; Mulle, Christophe

    2018-02-15

    CA3 pyramidal cells display input-specific differences in the subunit composition of synaptic NMDA receptors (NMDARs). Although at low density, GluN2B contributes significantly to NMDAR-mediated EPSCs at mossy fibre synapses. Long-term potentiation (LTP) of NMDARs triggers a modification in the subunit composition of synaptic NMDARs by insertion of GluN2B. GluN2B subunits are essential for the expression of LTP of NMDARs at mossy fibre synapses. Single neurons express NMDA receptors (NMDARs) with distinct subunit composition and biophysical properties that can be segregated in an input-specific manner. The dynamic control of the heterogeneous distribution of synaptic NMDARs is crucial to control input-dependent synaptic integration and plasticity. In hippocampal CA3 pyramidal cells from mice of both sexes, we found that mossy fibre (MF) synapses display a markedly lower proportion of GluN2B-containing NMDARs than associative/commissural synapses. The mechanism involved in such heterogeneous distribution of GluN2B subunits is not known. Here we show that long-term potentiation (LTP) of NMDARs, which is selectively expressed at MF-CA3 pyramidal cell synapses, triggers a modification in the subunit composition of synaptic NMDARs by insertion of GluN2B. This activity-dependent recruitment of GluN2B at mature MF-CA3 pyramidal cell synapses contrasts with the removal of GluN2B subunits at other glutamatergic synapses during development and in response to activity. Furthermore, although expressed at low levels, GluN2B is necessary for the expression of LTP of NMDARs at MF-CA3 pyramidal cell synapses. Altogether, we reveal a previously unknown activity-dependent regulation and function of GluN2B subunits that may contribute to the heterogeneous plasticity induction rules in CA3 pyramidal cells. © 2017 Centre Nationnal de la Recherche Scientifique. The Journal of Physiology © 2017 The Physiological Society.

  1. Enhanced inhibitory control by neuropeptide Y Y5 receptor blockade in rats.

    Science.gov (United States)

    Bari, A; Dec, A; Lee, A W; Lee, J; Song, D; Dale, E; Peterson, J; Zorn, S; Huang, X; Campbell, B; Robbins, T W; West, A R

    2015-03-01

    The neuropeptide Y (NPY) system acts in synergy with the classic neurotransmitters to regulate a large variety of functions including autonomic, affective, and cognitive processes. Research on the effects of NPY in the central nervous system has focused on food intake control and affective processes, but growing evidence of NPY involvement in attention-deficit/hyperactivity disorder (ADHD) and other psychiatric conditions motivated the present study. We tested the effects of the novel and highly selective NPY Y5 receptor antagonist Lu AE00654 on impulsivity and the underlying cortico-striatal circuitry in rats to further explore the possible involvement of the NPY system in pathologies characterized by inattention and impulsive behavior. A low dose of Lu AE00654 (0.03 mg/kg) selectively facilitated response inhibition as measured by the stop-signal task, whereas no effects were found at higher doses (0.3 and 3 mg/kg). Systemic administration of Lu AE00654 also enhanced the inhibitory influence of the dorsal frontal cortex on neurons in the caudate-putamen, this fronto-striatal circuitry being implicated in the executive control of behavior. Finally, by locally injecting a Y5 agonist, we observed reciprocal activation between dorsal frontal cortex and caudate-putamen neurons. Importantly, the effects of the Y5 agonist were attenuated by pretreatment with Lu AE00654, confirming the presence of Y5 binding sites modulating functional interactions within frontal-subcortical circuits. These results suggest that the NPY system modulates inhibitory neurotransmission in brain areas important for impulse control, and may be relevant for the treatment of pathologies such as ADHD and drug abuse.

  2. The receptor kinase FER is a RALF-regulated scaffold controlling plant immune signaling

    NARCIS (Netherlands)

    Stegmann, Martin; Monaghan, Jacqueline; Smakowska-Luzan, Elwira; Rovenich, Hanna; Lehner, Anita; Holton, Nicholas; Belkhadir, Youssef; Zipfel, Cyril

    2017-01-01

    In plants, perception of invading pathogens involves cell-surface immune receptor kinases. Here, we report that the Arabidopsis SITE-1 PROTEASE (S1P) cleaves endogenous RAPID ALKALINIZATION FACTOR (RALF) propeptides to inhibit plant immunity. This inhibition is mediated by the malectin-like receptor

  3. Confinement of activating receptors at the plasma membrane controls natural killer cell tolerance.

    Science.gov (United States)

    Guia, Sophie; Jaeger, Baptiste N; Piatek, Stefan; Mailfert, Sébastien; Trombik, Tomasz; Fenis, Aurore; Chevrier, Nicolas; Walzer, Thierry; Kerdiles, Yann M; Marguet, Didier; Vivier, Eric; Ugolini, Sophie

    2011-04-05

    Natural killer (NK) cell tolerance to self is partly ensured by major histocompatibility complex (MHC) class I-specific inhibitory receptors on NK cells, which dampen their reactivity when engaged. However, NK cells that do not detect self MHC class I are not autoreactive. We used dynamic fluorescence correlation spectroscopy to show that MHC class I-independent NK cell tolerance in mice was associated with the presence of hyporesponsive NK cells in which both activating and inhibitory receptors were confined in an actin meshwork at the plasma membrane. In contrast, the recognition of self MHC class I by inhibitory receptors "educated" NK cells to become fully reactive, and activating NK cell receptors became dynamically compartmentalized in membrane nanodomains. We propose that the confinement of activating receptors at the plasma membrane is pivotal to ensuring the self-tolerance of NK cells.

  4. Brain IGF-1 receptors control mammalian growth and lifespan through a neuroendocrine mechanism.

    Directory of Open Access Journals (Sweden)

    Laurent Kappeler

    2008-10-01

    Full Text Available Mutations that decrease insulin-like growth factor (IGF and growth hormone signaling limit body size and prolong lifespan in mice. In vertebrates, these somatotropic hormones are controlled by the neuroendocrine brain. Hormone-like regulations discovered in nematodes and flies suggest that IGF signals in the nervous system can determine lifespan, but it is unknown whether this applies to higher organisms. Using conditional mutagenesis in the mouse, we show that brain IGF receptors (IGF-1R efficiently regulate somatotropic development. Partial inactivation of IGF-1R in the embryonic brain selectively inhibited GH and IGF-I pathways after birth. This caused growth retardation, smaller adult size, and metabolic alterations, and led to delayed mortality and longer mean lifespan. Thus, early changes in neuroendocrine development can durably modify the life trajectory in mammals. The underlying mechanism appears to be an adaptive plasticity of somatotropic functions allowing individuals to decelerate growth and preserve resources, and thereby improve fitness in challenging environments. Our results also suggest that tonic somatotropic signaling entails the risk of shortened lifespan.

  5. Parvovirus Capsid Structures Required for Infection: Mutations Controlling Receptor Recognition and Protease Cleavages.

    Science.gov (United States)

    Callaway, Heather M; Feng, Kurtis H; Lee, Donald W; Allison, Andrew B; Pinard, Melissa; McKenna, Robert; Agbandje-McKenna, Mavis; Hafenstein, Susan; Parrish, Colin R

    2017-01-15

    Parvovirus capsids are small but complex molecular machines responsible for undertaking many of the steps of cell infection, genome packing, and cell-to-cell as well as host-to-host transfer. The details of parvovirus infection of cells are still not fully understood, but the processes must involve small changes in the capsid structure that allow the endocytosed virus to escape from the endosome, pass through the cell cytoplasm, and deliver the single-stranded DNA (ssDNA) genome to the nucleus, where viral replication occurs. Here, we examine capsid substitutions that eliminate canine parvovirus (CPV) infectivity and identify how those mutations changed the capsid structure or altered interactions with the infectious pathway. Amino acid substitutions on the exterior surface of the capsid (Gly299Lys/Ala300Lys) altered the binding of the capsid to transferrin receptor type 1 (TfR), particularly during virus dissociation from the receptor, but still allowed efficient entry into both feline and canine cells without successful infection. These substitutions likely control specific capsid structural changes resulting from TfR binding required for infection. A second set of changes on the interior surface of the capsid reduced viral infectivity by >100-fold and included two cysteine residues and neighboring residues. One of these substitutions, Cys270Ser, modulates a VP2 cleavage event found in ∼10% of the capsid proteins that also was shown to alter capsid stability. A neighboring substitution, Pro272Lys, significantly reduced capsid assembly, while a Cys273Ser change appeared to alter capsid transport from the nucleus. These mutants reveal additional structural details that explain cell infection processes of parvovirus capsids. Parvoviruses are commonly found in both vertebrate and invertebrate animals and cause widespread disease. They are also being developed as oncolytic therapeutics and as gene therapy vectors. Most functions involved in infection or transduction

  6. Parvovirus Capsid Structures Required for Infection: Mutations Controlling Receptor Recognition and Protease Cleavages

    Science.gov (United States)

    Callaway, Heather M.; Feng, Kurtis H.; Lee, Donald W.; Pinard, Melissa; McKenna, Robert; Agbandje-McKenna, Mavis; Hafenstein, Susan

    2016-01-01

    ABSTRACT Parvovirus capsids are small but complex molecular machines responsible for undertaking many of the steps of cell infection, genome packing, and cell-to-cell as well as host-to-host transfer. The details of parvovirus infection of cells are still not fully understood, but the processes must involve small changes in the capsid structure that allow the endocytosed virus to escape from the endosome, pass through the cell cytoplasm, and deliver the single-stranded DNA (ssDNA) genome to the nucleus, where viral replication occurs. Here, we examine capsid substitutions that eliminate canine parvovirus (CPV) infectivity and identify how those mutations changed the capsid structure or altered interactions with the infectious pathway. Amino acid substitutions on the exterior surface of the capsid (Gly299Lys/Ala300Lys) altered the binding of the capsid to transferrin receptor type 1 (TfR), particularly during virus dissociation from the receptor, but still allowed efficient entry into both feline and canine cells without successful infection. These substitutions likely control specific capsid structural changes resulting from TfR binding required for infection. A second set of changes on the interior surface of the capsid reduced viral infectivity by >100-fold and included two cysteine residues and neighboring residues. One of these substitutions, Cys270Ser, modulates a VP2 cleavage event found in ∼10% of the capsid proteins that also was shown to alter capsid stability. A neighboring substitution, Pro272Lys, significantly reduced capsid assembly, while a Cys273Ser change appeared to alter capsid transport from the nucleus. These mutants reveal additional structural details that explain cell infection processes of parvovirus capsids. IMPORTANCE Parvoviruses are commonly found in both vertebrate and invertebrate animals and cause widespread disease. They are also being developed as oncolytic therapeutics and as gene therapy vectors. Most functions involved in

  7. Peripheral and central CB1 cannabinoid receptors control stress-induced impairment of memory consolidation.

    Science.gov (United States)

    Busquets-Garcia, Arnau; Gomis-González, Maria; Srivastava, Raj Kamal; Cutando, Laura; Ortega-Alvaro, Antonio; Ruehle, Sabine; Remmers, Floortje; Bindila, Laura; Bellocchio, Luigi; Marsicano, Giovanni; Lutz, Beat; Maldonado, Rafael; Ozaita, Andrés

    2016-08-30

    Stressful events can generate emotional memories linked to the traumatic incident, but they also can impair the formation of nonemotional memories. Although the impact of stress on emotional memories is well studied, much less is known about the influence of the emotional state on the formation of nonemotional memories. We used the novel object-recognition task as a model of nonemotional memory in mice to investigate the underlying mechanism of the deleterious effect of stress on memory consolidation. Systemic, hippocampal, and peripheral blockade of cannabinoid type-1 (CB1) receptors abolished the stress-induced memory impairment. Genetic deletion and rescue of CB1 receptors in specific cell types revealed that the CB1 receptor population specifically in dopamine β-hydroxylase (DBH)-expressing cells is both necessary and sufficient for stress-induced impairment of memory consolidation, but CB1 receptors present in other neuronal populations are not involved. Strikingly, pharmacological manipulations in mice expressing CB1 receptors exclusively in DBH(+) cells revealed that both hippocampal and peripheral receptors mediate the impact of stress on memory consolidation. Thus, CB1 receptors on adrenergic and noradrenergic cells provide previously unrecognized cross-talk between central and peripheral mechanisms in the stress-dependent regulation of nonemotional memory consolidation, suggesting new potential avenues for the treatment of cognitive aspects on stress-related disorders.

  8. Mu opioid receptor availability in people with psychiatric disorders who died by suicide: a case control study.

    Science.gov (United States)

    Scarr, Elizabeth; Money, Tammie Terese; Pavey, Geoffrey; Neo, Jaclyn; Dean, Brian

    2012-08-28

    Mu opioid receptors have previously been shown to be altered in people with affective disorders who died as a result of suicide. We wished to determine whether these changes were more widespread and independent of psychiatric diagnoses. Mu receptor levels were determined using [3 H]DAMGO binding in BA24 from 51 control subjects; 38 people with schizophrenia (12 suicides); 20 people with major depressive disorder (15 suicides); 13 people with bipolar disorder (5 suicides) and 9 people who had no history of psychiatric disorders but who died as a result of suicide. Mu receptor levels were further determined in BA9 and caudate-putamen from 38 people with schizophrenia and 20 control subjects using [3 H]DAMGO binding and, in all three regions, using Western blots. Data was analysed using one-way ANOVAs with Bonferroni's Multiple Comparison Test or, where data either didn't approximate to a binomial distribution or the sample size was too small to determine distribution, a Kruskal-Wallis test with Dunn's Multiple Comparison Test. [3 H]DAMGO binding density was lower in people who had died as a result of suicide (pendogenous ligands occupying these receptors.

  9. Hypothalamic growth hormone receptor (GHR controls hepatic glucose production in nutrient-sensing leptin receptor (LepRb expressing neurons

    Directory of Open Access Journals (Sweden)

    Gillian Cady

    2017-05-01

    Full Text Available Objective: The GH/IGF-1 axis has important roles in growth and metabolism. GH and GH receptor (GHR are active in the central nervous system (CNS and are crucial in regulating several aspects of metabolism. In the hypothalamus, there is a high abundance of GH-responsive cells, but the role of GH signaling in hypothalamic neurons is unknown. Previous work has demonstrated that the Ghr gene is highly expressed in LepRb neurons. Given that leptin is a key regulator of energy balance by acting on leptin receptor (LepRb-expressing neurons, we tested the hypothesis that LepRb neurons represent an important site for GHR signaling to control body homeostasis. Methods: To determine the importance of GHR signaling in LepRb neurons, we utilized Cre/loxP technology to ablate GHR expression in LepRb neurons (LeprEYFPΔGHR. The mice were generated by crossing the Leprcre on the cre-inducible ROSA26-EYFP mice to GHRL/L mice. Parameters of body composition and glucose homeostasis were evaluated. Results: Our results demonstrate that the sites with GHR and LepRb co-expression include ARH, DMH, and LHA neurons. Leptin action was not altered in LeprEYFPΔGHR mice; however, GH-induced pStat5-IR in LepRb neurons was significantly reduced in these mice. Serum IGF-1 and GH levels were unaltered, and we found no evidence that GHR signaling regulates food intake and body weight in LepRb neurons. In contrast, diminished GHR signaling in LepRb neurons impaired hepatic insulin sensitivity and peripheral lipid metabolism. This was paralleled with a failure to suppress expression of the gluconeogenic genes and impaired hepatic insulin signaling in LeprEYFPΔGHR mice. Conclusion: These findings suggest the existence of GHR-leptin neurocircuitry that plays an important role in the GHR-mediated regulation of glucose metabolism irrespective of feeding. Keywords: Growth hormone receptor, Hypothalamus, Leptin receptor, Glucose production, Liver

  10. Atypical Opioid Mechanisms of Control of Injury-Induced Cutaneous Pain by Delta Receptors

    Science.gov (United States)

    2016-07-01

    treat, and current opioids (i.e. mu opioid receptor agonists such as morphine) cause unacceptable side effects including addiction . Injuries suffered...treat, and current opioids that act on mu opioid receptors such as morphine generate significant side effects including addiction . War-related...al., J Neurosci Methods, 1994), starting with 0.1 g and ending with 2.0 g filament as cutoff value. As shown in Figure 2, our preliminary experiments

  11. Estrogen and progesterone receptor levels in nonneoplastic breast epithelium of breast cancer cases versus benign breast biopsy controls

    International Nuclear Information System (INIS)

    Woolcott, Christy G; SenGupta, Sandip K; Hanna, Wedad M; Aronson, Kristan J

    2008-01-01

    Previous studies and biological mechanisms of carcinogenesis suggest that the steroid receptor content of benign breast epithelium may be related to breast cancer risk. The objective in this study was to compare the levels of estrogen receptor-α (ER) and progesterone receptor (PR) in nonneoplastic breast epithelium between breast cancer cases and biopsy controls. Between 1995 and 1997 at two sites (Women's College Hospital in Toronto and Kingston General Hospital), 667 women who were scheduled for diagnostic excisional breast biopsies completed a questionnaire providing personal information and agreed to allow analysis of routinely resected tissue. Histological slides with nonneoplastic epithelium were available for 101 cancer cases and 200 biopsy controls in Toronto and for 105 cancer cases and 119 controls in Kingston. Nonneoplastic epithelium was examined with immunohistochemical assays to determine the percent of epithelial cells staining for ER and PR. Unconditional logistic regression was used to calculate odds ratios (OR) stratified by study site. The ER content of nonneoplastic tissue was higher in cases than biopsy controls in unadjusted analyses; after adjustment for age, however, a weak association remained in only one of the study sites. After adjustment for age, the PR content of nonneoplastic tissue was slightly lower in breast cancer cases than controls in one study site. Furthermore, this inverse association was confined to women with PR negative breast cancer in comparison to the controls. No interaction between ER and PR content of nonneoplastic tissue was observed in relation to the odds of having breast cancer. The results of this study are consistent with only a slight indication of increased ER levels in nonneoplastic tissue in breast cancer cases relative to controls. This study contributes to the understanding of breast cancer by examining both ER and PR in nonneoplastic tissue. Limitations remain, however, such as the necessity of

  12. Mu opioid receptor availability in people with psychiatric disorders who died by suicide: a case control study

    Directory of Open Access Journals (Sweden)

    Scarr Elizabeth

    2012-08-01

    Full Text Available Abstract Background Mu opioid receptors have previously been shown to be altered in people with affective disorders who died as a result of suicide. We wished to determine whether these changes were more widespread and independent of psychiatric diagnoses. Methods Mu receptor levels were determined using [3 H]DAMGO binding in BA24 from 51 control subjects; 38 people with schizophrenia (12 suicides; 20 people with major depressive disorder (15 suicides; 13 people with bipolar disorder (5 suicides and 9 people who had no history of psychiatric disorders but who died as a result of suicide. Mu receptor levels were further determined in BA9 and caudate-putamen from 38 people with schizophrenia and 20 control subjects using [3 H]DAMGO binding and, in all three regions, using Western blots. Data was analysed using one-way ANOVAs with Bonferroni’s Multiple Comparison Test or, where data either didn’t approximate to a binomial distribution or the sample size was too small to determine distribution, a Kruskal-Wallis test with Dunn’s Multiple Comparison Test. Results [3 H]DAMGO binding density was lower in people who had died as a result of suicide (p3 H]DAMGO binding densities, but not mu protein levels, were significantly decreased in BA9 from people with schizophrenia who died as a result of suicide (p Conclusions Overall these data suggest that mu opioid receptor availability is decreased in the brains of people with schizophrenia who died as a result of suicide, which would be consistent with increased levels of endogenous ligands occupying these receptors.

  13. HIV-1, HTLV-I and the interleukin-2 receptor: insights into transcriptional control.

    Science.gov (United States)

    Böhnlein, E; Lowenthal, J W; Wano, Y; Franza, B R; Ballard, D W; Greene, W C

    1989-01-01

    In this study, we present direct evidence for the binding of the inducible cellular protein, HIVEN86A, to a 12-bp element present in the IL-2R alpha promoter. This element shares significant sequence similarity with the NF-kappa B binding sites present in the HIV-1 and kappa immunoglobulin enhancers. Transient transfection studies indicate that this kappa B element is both necessary and sufficient to confer tax or mitogen inducibility to a heterologous promoter. As summarized schematically in Fig. 5, the findings suggest that the HIVEN86A protein may play a central role in the activation of cellular genes required for T-cell growth, specifically the IL-2R alpha gene. In addition, the induced HIVEN86A protein also binds to a similar sequence present in the HIV-1 LTR leading to enhanced viral gene expression and ultimately T-cell death. Thus, mitogen activation of the HIV-1 LTR appears to involve the same inducible transcription factor(s) that normally regulates IL-2R alpha gene expression and T-cell growth. These findings further underscore the importance of the state of T-cell activation in the regulation of HIV-1 replication. Our results also demonstrate that HIVEN86A is induced by the tax protein of HTLV-I. Thus, in HTLV-I infected cells, normally the tight control of the transient expression of the IL-2R alpha gene is lost. The constitutive high-level display of IL-2 receptors may play a role in leukemic transformation mediated by HTLV-I (ATL). Apparently by the same mechanism, the tax protein also activates the HIV-1 LTR through the induction of HIVEN86A.(ABSTRACT TRUNCATED AT 250 WORDS)

  14. Floral organ abscission peptide IDA and its HAE/HSL2 receptors control cell separation during lateral root emergence

    OpenAIRE

    Kumpf, Robert P.; Shi, Chun-Lin; Larrieu, Antoine; Stø, Ida Myhrer; Butenko, Melinka A.; Péret, Benjamin; Riiser, Even Sannes; Bennett, Malcolm J.; Aalen, Reidunn B.

    2013-01-01

    Throughout their life cycle, plants produce new organs, such as leaves, flowers, and lateral roots. Organs that have served their purpose may be shed after breakdown of primary cell walls between adjacent cell files at the site of detachment. In Arabidopsis, floral organs abscise after pollination, and this cell separation event is controlled by the peptide INFLORESCENCE DEFICIENT IN ABSCISSION (IDA), which signals through the leucine-rich repeat receptor-like kinases HAESA (HAE) and HAESA-LI...

  15. Identification and expression of the CCAP receptor in the Chagas' disease vector, Rhodnius prolixus, and its involvement in cardiac control.

    Directory of Open Access Journals (Sweden)

    Dohee Lee

    Full Text Available Rhodnius prolixus is the vector of Chagas' disease, by virtue of transmitting the parasite Trypanosoma cruzi. There is no cure for Chagas' disease and therefore controlling R. prolixus is currently the only method of prevention. Understanding the physiology of the disease vector is an important step in developing control measures. Crustacean cardioactive peptide (CCAP is an important neuropeptide in insects because it has multiple physiological roles such as controlling heart rate and modulating ecdysis behaviour. In this study, we have cloned the cDNA sequence of the CCAP receptor (RhoprCCAPR from 5(th instar R. prolixus and found it to be a G-protein coupled receptor (GPCR. The spatial expression pattern in 5(th instars reveals that the RhoprCCAPR transcript levels are high in the central nervous system, hindgut and female reproductive systems, and lower in the salivary glands, male reproductive tissues and a pool of tissues including the dorsal vessel, trachea, and fat body. Interestingly, the RhoprCCAPR expression is increased prior to ecdysis and decreased post-ecdysis. A functional receptor expression assay confirms that the RhoprCCAPR is activated by CCAP (EC50 = 12 nM but not by adipokinetic hormone, corazonin or an extended FMRFamide. The involvement of CCAP in controlling heartbeat frequency was studied in vivo and in vitro by utilizing RNA interference. In vivo, the basal heartbeat frequency is decreased by 31% in bugs treated with dsCCAPR. Knocking down the receptor in dsCCAPR-treated bugs also resulted in loss of function of applied CCAP in vitro. This is the first report of a GPCR knock-down in R. prolixus and the first report showing that a reduction in CCAPR transcript levels leads to a reduction in cardiac output in any insect.

  16. Changes in Angiotensin Receptor Distribution and in Aortic Morphology Are Associated with Blood Pressure Control in Aged Metabolic Syndrome Rats

    Directory of Open Access Journals (Sweden)

    Verónica Guarner-Lans

    2016-01-01

    Full Text Available The role of the renin-angiotensin system (RAS in blood pressure regulation in MS during aging is unknown. It participates in metabolic syndrome (MS and aging regulating vascular tone and remodeling. RAS might participate in a compensatory mechanism decreasing blood pressure and allowing MS rats to reach 18 months of age and it might form part of therapeutical procedures to ameliorate MS. We studied histological changes and distribution of RAS receptors in aortas of MS aged rats. Electron microscopy images showed premature aging in MS since the increased fibrosis, enlarged endothelium, and invasion of this layer by muscle cells that was present in control 18-month-old aortas were also found in 6-month-old aortas from MS rats. AT1, AT2, and Mas receptors mediate the effects of Ang II and Ang 1-7, respectively. Fluorescence from AT2 decreased with age in control and MS aortas, while fluorescence of AT1 increased in aortas from MS rats at 6 months and diminished during aging. Mas expression increased in MS rats and remained unchanged in control rats. In conclusion, there is premature aging in the aortas from MS rats and the elevated expression of Mas receptor might contribute to decrease blood pressure during aging in MS.

  17. Orphan Nuclear Receptor ERRα Controls Macrophage Metabolic Signaling and A20 Expression to Negatively Regulate TLR-Induced Inflammation.

    Science.gov (United States)

    Yuk, Jae-Min; Kim, Tae Sung; Kim, Soo Yeon; Lee, Hye-Mi; Han, Jeongsu; Dufour, Catherine Rosa; Kim, Jin Kyung; Jin, Hyo Sun; Yang, Chul-Su; Park, Ki-Sun; Lee, Chul-Ho; Kim, Jin-Man; Kweon, Gi Ryang; Choi, Hueng-Sik; Vanacker, Jean-Marc; Moore, David D; Giguère, Vincent; Jo, Eun-Kyeong

    2015-07-21

    The orphan nuclear receptor estrogen-related receptor α (ERRα; NR3B1) is a key metabolic regulator, but its function in regulating inflammation remains largely unknown. Here, we demonstrate that ERRα negatively regulates Toll-like receptor (TLR)-induced inflammation by promoting Tnfaip3 transcription and fine-tuning of metabolic reprogramming in macrophages. ERRα-deficient (Esrra(-/-)) mice showed increased susceptibility to endotoxin-induced septic shock, leading to more severe pro-inflammatory responses than control mice. ERRα regulated macrophage inflammatory responses by directly binding the promoter region of Tnfaip3, a deubiquitinating enzyme in TLR signaling. In addition, Esrra(-/-) macrophages showed an increased glycolysis, but impaired mitochondrial respiratory function and biogenesis. Further, ERRα was required for the regulation of NF-κB signaling by controlling p65 acetylation via maintenance of NAD(+) levels and sirtuin 1 activation. These findings unravel a previously unappreciated role for ERRα as a negative regulator of TLR-induced inflammatory responses through inducing Tnfaip3 transcription and controlling the metabolic reprogramming. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Provision of a simplified methodology for determining estradiol and progesterone receptors in human breast tumours. Internal and external quality control

    International Nuclear Information System (INIS)

    Farinate, Z.

    1990-10-01

    A simplified assay for the detection of progesterone receptors (PR) in human breast tissue is described. Tissue storage is at -20 deg. C rather than -70 deg. C and a centrifugation speed of 20,000 rpm avoids requirement of an ultracentrifuge. Cytosol preparations obtained from homogenized oestradiol benzoate primed wistar rat uteri performed satisfactorily as positive controls with stability of two months in liquid nitrogen. The use of iodinated tracer (progesterone 11 alpha glucuronide 125 I iodotyramine) proved disappointing in the progesterone receptor assay in contrast to 125 I oestradiol which worked well in a oestrogen receptor assay, previously developed. Hydroxyl-apatite was a better separating agent than dextran coated charcoal in both assays and yielded better sensitivity, particularly when protein concentrations were low. Five breast cancer specimens assayed yielded, by Scatchard analysis, Kd values between 12 to 22x10 -9 m|h, comparable to the positive controls. However, two of these had binding site capacity of less than 5 fmol/mg cytosol as compared to the three others and the positive controls where values ranged from 47-196 fmol/mg cytosol. 28 refs, 6 figs, 14 tabs

  19. Residues remote from the binding pocket control the antagonist selectivity towards the corticotropin-releasing factor receptor-1

    Science.gov (United States)

    Sun, Xianqiang; Cheng, Jianxin; Wang, Xu; Tang, Yun; Ågren, Hans; Tu, Yaoquan

    2015-01-01

    The corticotropin releasing factors receptor-1 and receptor-2 (CRF1R and CRF2R) are therapeutic targets for treating neurological diseases. Antagonists targeting CRF1R have been developed for the potential treatment of anxiety disorders and alcohol addiction. It has been found that antagonists targeting CRF1R always show high selectivity, although CRF1R and CRF2R share a very high rate of sequence identity. This has inspired us to study the origin of the selectivity of the antagonists. We have therefore built a homology model for CRF2R and carried out unbiased molecular dynamics and well-tempered metadynamics simulations for systems with the antagonist CP-376395 in CRF1R or CRF2R to address this issue. We found that the side chain of Tyr6.63 forms a hydrogen bond with the residue remote from the binding pocket, which allows Tyr6.63 to adopt different conformations in the two receptors and results in the presence or absence of a bottleneck controlling the antagonist binding to or dissociation from the receptors. The rotameric switch of the side chain of Tyr3566.63 allows the breaking down of the bottleneck and is a perquisite for the dissociation of CP-376395 from CRF1R.

  20. Purinergic control of inflammation and thrombosis: Role of P2X1 receptors

    Directory of Open Access Journals (Sweden)

    Cécile Oury

    2015-01-01

    Full Text Available Inflammation shifts the hemostatic mechanisms in favor of thrombosis. Upon tissue damage or infection, a sudden increase of extracellular ATP occurs, that might contribute to the crosstalk between inflammation and thrombosis. On platelets, P2X1 receptors act to amplify platelet activation and aggregation induced by other platelet agonists. These receptors critically contribute to thrombus stability in small arteries. Besides platelets, studies by our group indicate that these receptors are expressed by neutrophils. They promote neutrophil chemotaxis, both in vitro and in vivo. In a laser-induced injury mouse model of thrombosis, it appears that neutrophils are required to initiate thrombus formation and coagulation activation on inflamed arteriolar endothelia. In this model, by using P2X1−/− mice, we recently showed that P2X1 receptors, expressed on platelets and neutrophils, play a key role in thrombus growth and fibrin generation. Intriguingly, in a model of endotoxemia, P2X1−/− mice exhibited aggravated oxidative tissue damage, along with exacerbated thrombocytopenia and increased activation of coagulation, which translated into higher susceptibility to septic shock. Thus, besides its ability to recruit neutrophils and platelets on inflamed endothelia, the P2X1 receptor also contributes to limit the activation of circulating neutrophils under systemic inflammatory conditions. Taken together, these data suggest that P2X1 receptors are involved in the interplay between platelets, neutrophils and thrombosis. We propose that activation of these receptors by ATP on neutrophils and platelets represents a new mechanism that regulates thrombo-inflammation.

  1. Impaired virus control and severe CD8+ T-cell-mediated immunopathology in chimeric mice deficient in gamma interferon receptor expression on both parenchymal and hematopoietic cells

    DEFF Research Database (Denmark)

    Henrichsen, Pernille; Bartholdy, Christina; Christensen, Jan Pravsgaard

    2005-01-01

    be capable of responding to IFN-gamma, but expression of the relevant receptor on non-T cells could be experimentally controlled. Only when the IFN-gamma receptor is absent on both radioresistant parenchymal and bone marrow-derived cells will chimeric mice challenged with a highly invasive, noncytolytic...

  2. NMDA receptor antagonists interventions in schizophrenia: Meta-analysis of randomized, placebo-controlled trials.

    Science.gov (United States)

    Kishi, Taro; Iwata, Nakao

    2013-09-01

    We examined whether N-methyl d-aspartate (NMDA) receptor antagonists as adjunctive therapy have therapeutic potential for schizophrenia treatment. Systematic review of PubMed, Cochrane Library, PsycINFO and Google Scholar up until October 2012 and meta-analysis of randomized placebo-controlled trials were performed. Risk ratio (RR), 95% confidence intervals (CI), numbers-needed-to-harm (NNH), and standardized mean difference (SMD) were calculated. Results were across 8 studies and 406 patients (85.5% schizophrenia related disorder and 14.5% bipolar disorder) were included (amantadine: 5 trials and 220 patients, memantine: 3 trials and 186 patients). NMDA receptor antagonists (NMDAR-ANTs) as adjunctive therapy were not superior to placebo in overall (SMD = -0.25, CI = -0.72, 0.23, p = 0.31, N = 6, n = 347), positive symptoms (SMD = -0.20, CI = -0.70, 0.31, p = 0.44, N = 4, n = 205), and negative symptoms (SMD = -0.69, CI = -1.65, 0.27, p = 0.16, N = 4, n = 205), and Clinical Global Impression Severity scale (SMD = -0.27, CI = -1.20, 0.65, p = 0.56, N = 3, n = 177). There was also no significant difference in discontinuation rate between NMDAR-ANTs and placebo treatments (all cause: RR = 1.23, CI = 0.89-1.70, p = 0.20, N = 8, n = 396, side effects: RR = 1.86, CI = 0.84-4.13, p = 0.13, N = 6, n = 359, inefficacy/worsening psychosis: RR = 0.70, CI = 0.20-2.38, p = 0.56, N = 7, n = 380). However, memantine was favorable compared with placebo in Mini-Mental State Examination in schizophrenia (SMD = -0.77, CI = -1.27, -0.28, p = 0.002, N = 3, n = 71). While NMDAR-ANTs caused weight loss compared with placebo (SMD = -0.42, CI = -0.73, -0.11, p = 0.008, N = 3, n = 165), amantadine caused more frequent insomnia than placebo (RR = 3.83, CI = 1.41-10.38, p = 0.008, NNH = 9, p = 0.002, N = 2, n = 147). Our results indicate that NMDAR-ANTs as adjunctive therapy may improve

  3. Classical and Non-Classical Roles for Pre-Receptor Control of DHT Metabolism in Prostate Cancer Progression.

    Science.gov (United States)

    Zhang, Ailin; Zhang, Jiawei; Plymate, Stephen; Mostaghel, Elahe A

    2016-04-01

    Androgens play an important role in prostate cancer (PCa) development and progression. Accordingly, androgen deprivation therapy remains the front-line treatment for locally recurrent or advanced PCa, but patients eventually relapse with the lethal form of the disease termed castration resistant PCa (CRPC). Importantly, castration does not eliminate androgens from the prostate tumor microenvironment which is characterized by elevated tissue androgens that are well within the range capable of activating the androgen receptor (AR). In this mini-review, we discuss emerging data that suggest a role for the enzymes mediating pre-receptor control of dihydrotestosterone (DHT) metabolism, including AKR1C2, HSD17B6, HSD17B10, and the UGT family members UGT2B15 and UGT2B17, in controlling intratumoral androgen levels, and thereby influencing PCa progression. We review the expression of steroidogenic enzymes involved in this pathway in primary PCa and CRPC, the activity and regulation of these enzymes in PCa experimental models, and the impact of genetic variation in genes mediating pre-receptor DHT metabolism on PCa risk. Finally, we discuss recent data that suggests several of these enzymes may also play an unrecognized role in CRPC progression separate from their role in androgen inactivation.

  4. Hypothalamic growth hormone receptor (GHR) controls hepatic glucose production in nutrient-sensing leptin receptor (LepRb) expressing neurons.

    Science.gov (United States)

    Cady, Gillian; Landeryou, Taylor; Garratt, Michael; Kopchick, John J; Qi, Nathan; Garcia-Galiano, David; Elias, Carol F; Myers, Martin G; Miller, Richard A; Sandoval, Darleen A; Sadagurski, Marianna

    2017-05-01

    The GH/IGF-1 axis has important roles in growth and metabolism. GH and GH receptor (GHR) are active in the central nervous system (CNS) and are crucial in regulating several aspects of metabolism. In the hypothalamus, there is a high abundance of GH-responsive cells, but the role of GH signaling in hypothalamic neurons is unknown. Previous work has demonstrated that the Ghr gene is highly expressed in LepRb neurons. Given that leptin is a key regulator of energy balance by acting on leptin receptor (LepRb)-expressing neurons, we tested the hypothesis that LepRb neurons represent an important site for GHR signaling to control body homeostasis. To determine the importance of GHR signaling in LepRb neurons, we utilized Cre/loxP technology to ablate GHR expression in LepRb neurons (Lepr EYFPΔGHR ). The mice were generated by crossing the Lepr cre on the cre-inducible ROSA26-EYFP mice to GHR L/L mice. Parameters of body composition and glucose homeostasis were evaluated. Our results demonstrate that the sites with GHR and LepRb co-expression include ARH, DMH, and LHA neurons. Leptin action was not altered in Lepr EYFPΔGHR mice; however, GH-induced pStat5-IR in LepRb neurons was significantly reduced in these mice. Serum IGF-1 and GH levels were unaltered, and we found no evidence that GHR signaling regulates food intake and body weight in LepRb neurons. In contrast, diminished GHR signaling in LepRb neurons impaired hepatic insulin sensitivity and peripheral lipid metabolism. This was paralleled with a failure to suppress expression of the gluconeogenic genes and impaired hepatic insulin signaling in Lepr EYFPΔGHR mice. These findings suggest the existence of GHR-leptin neurocircuitry that plays an important role in the GHR-mediated regulation of glucose metabolism irrespective of feeding.

  5. Role of cardiac volume receptors in the control of ADH release during acute simulated weightlessness in man

    Science.gov (United States)

    Convertino, V. A.; Benjamin, B. A.; Keil, L. C.; Sandler, H.

    1984-01-01

    Hemodynamic responses and antidiuretic hormone (ADH) were measured during body position changes, designed to induce central blood volume shifts in ten cardiac and one heart-lung transplant recipients, to assess the contribution of cardiac volume receptors in the control of ADH release during the initial acute phase of exposure to weightlessness. Each subject underwent 15 min of a sitting-control period (C) followed by 30 min of 6 deg headdown tilt (T) and 30 min of resumed sitting (S). Venous blood samples and cardiac dimensions were taken at 0 and 15 min of C; 5, 15, and 30 min of T; and 5, 15, and 30 min of S. Blood samples were analyzed for hematocrit, plasma osmolality, plasma renin activity (PRA), and ADH. Heart rate and blood pressure were recorded every two min. Plasma osmolality was not altered by posture changes. Mean left ventricular end-diastolic volume increased (P less than 0.05) from 90 ml in C to 106 ml in T and returned to 87 ml in S. Plasma ADH was reduced by 20 percent (P less than 0.05) with T, and returned to control levels with S. These responses were similar in six normal cardiac-innervated control subjects. These data may suggest that cardiac volume receptors are not the primary mechanism for the control of ADH release during acute central volume shifts in man.

  6. Y2 receptor signalling in NPY neurons controls bone formation and fasting induced feeding but not spontaneous feeding.

    Science.gov (United States)

    Qi, Yue; Fu, Melissa; Herzog, Herbert

    2016-02-01

    Y2 receptors have been implicated in the development of obesity and are a potential target for obesity treatment due to their known role of inhibiting neuropeptide Y (NPY) induced feeding responses. However, the precise neuronal population on which Y2 receptors act to fulfil this role is less clear. Here we utilise a novel inducible, postnatal onset NPY neurons specific deletion model to investigate the functional consequences of loss of Y2 signalling in this population of neurons on feeding and energy homeostasis regulation. While the consequences of lack of Y2 signalling in NPY neurons are confirmed in terms of the uncoupling of suppression/increasing of NPY and pro-opiomelanocortin (POMC) mRNA expression in the arcuate nuclei (Arc), respectively, this lack of Y2 signalling surprisingly does not have any significant effect on spontaneous food intake. Fasting induced food intake, however, is strongly increased but only in the first 1h after re-feeding. Consequently no significant changes in body weight are being observed although body weight gain is increased in male mice after postnatal onset Y2 deletion. Importantly, another known function of central Y2 receptor signalling, the suppression of bone formation is conserved in this conditional model with whole body bone mineral content being decreased. Taken together this model confirms the critical role of Y2 signalling to control NPY and associated POMC expression in the Arc, but also highlights the possibility that others, non-NPY neuronal Y2 receptors, are also involved in controlling feeding and energy homeostasis regulation. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Nicotinic acetylcholine receptor β2-subunits in the medial prefrontal cortex control attention

    NARCIS (Netherlands)

    Guillem, K.; Bloem, B.; Poorthuis, R.B.; Loos, M.; Smit, A.B.; Maskos, U.; Spijker, S.; Mansvelder, H.D.

    2011-01-01

    More than one-third of all people are estimated to experience mild to severe cognitive impairment as they age. Acetylcholine (ACh) levels in the brain diminish with aging, and nicotinic ACh receptor (nAChR) stimulation is known to enhance cognitive performance. The prefrontal cortex (PFC) is

  8. Protease-activated receptor-1 impairs host defense in murine pneumococcal pneumonia: a controlled laboratory study

    NARCIS (Netherlands)

    Schouten, Marcel; van't Veer, Cornelis; Roelofs, Joris J. T. H.; Levi, Marcel; van der Poll, Tom

    2012-01-01

    Streptococcus pneumoniae is the most common causative pathogen in community-acquired pneumonia. Protease-activated receptor-1 (PAR-1) is expressed by multiple cell types present in the lungs and can be activated by various proteases generated during acute inflammation. The cellular effect of PAR-1

  9. Endogenous Glucagon-like Peptide-1 Receptor Signaling in the Nucleus Tractus Solitarius is Required for Food Intake Control.

    Science.gov (United States)

    Alhadeff, Amber L; Mergler, Blake D; Zimmer, Derek J; Turner, Christopher A; Reiner, David J; Schmidt, Heath D; Grill, Harvey J; Hayes, Matthew R

    2017-06-01

    Alhough the glucagon-like peptide-1 (GLP-1) system is critical to energy balance control and is a target for obesity pharmacotherapies, the receptor-population-mediating effects of endogenous GLP-1 signaling are not fully understood. To address this, we developed a novel adeno-associated virus (AAV-GLP-1R) that utilizes short hairpin RNA to chronically knock down GLP-1 receptors (GLP-1R) in rats. As pharmacological studies highlight the hindbrain nucleus tractus solitarius (NTS) as a brain region important for GLP-1R-mediated effects on energy balance, AAV-GLP-1R was injected into the NTS to examine the role of endogenous NTS GLP-1R signaling in energy balance control. Chow intake and meal size were significantly increased following chronic NTS GLP-1R knockdown. In addition, NTS GLP-1R knockdown significantly increased self-administration of palatable food under both fixed and progressive ratio schedules of reinforcement. Collectively, these data demonstrate that endogenous NTS GLP-1R signaling is required for the control of food intake and motivation to feed, and provide a new strategy to investigate the importance of distinct GLP-1R populations in the control of a variety of functions.

  10. The farnesoid-X-receptor in myeloid cells controls CNS autoimmunity in an IL-10-dependent fashion.

    Science.gov (United States)

    Hucke, Stephanie; Herold, Martin; Liebmann, Marie; Freise, Nicole; Lindner, Maren; Fleck, Ann-Katrin; Zenker, Stefanie; Thiebes, Stephanie; Fernandez-Orth, Juncal; Buck, Dorothea; Luessi, Felix; Meuth, Sven G; Zipp, Frauke; Hemmer, Bernhard; Engel, Daniel Robert; Roth, Johannes; Kuhlmann, Tanja; Wiendl, Heinz; Klotz, Luisa

    2016-09-01

    Innate immune responses by myeloid cells decisively contribute to perpetuation of central nervous system (CNS) autoimmunity and their pharmacologic modulation represents a promising strategy to prevent disease progression in Multiple Sclerosis (MS). Based on our observation that peripheral immune cells from relapsing-remitting and primary progressive MS patients exhibited strongly decreased levels of the bile acid receptor FXR (farnesoid-X-receptor, NR1H4), we evaluated its potential relevance as therapeutic target for control of established CNS autoimmunity. Pharmacological FXR activation promoted generation of anti-inflammatory macrophages characterized by arginase-1, increased IL-10 production, and suppression of T cell responses. In mice, FXR activation ameliorated CNS autoimmunity in an IL-10-dependent fashion and even suppressed advanced clinical disease upon therapeutic administration. In analogy to rodents, pharmacological FXR activation in human monocytes from healthy controls and MS patients induced an anti-inflammatory phenotype with suppressive properties including control of effector T cell proliferation. We therefore, propose an important role of FXR in control of T cell-mediated autoimmunity by promoting anti-inflammatory macrophage responses.

  11. Receptor kinase-mediated control of primary active proton pumping at the plasma membrane

    DEFF Research Database (Denmark)

    Fuglsang, Anja Thoe; Kristensen, Astrid; Cuin, Tracey A.

    2014-01-01

    Acidification of the cell wall space outside the plasma membrane is required for plant growth and is the result of proton extrusion by the plasma membrane-localized H+-ATPases. Here we show that the major plasma membrane proton pumps in Arabidopsis, AHA1 and AHA2, interact directly in vitro...... and in planta with PSY1R, a receptor kinase of the plasma membrane that serves as a receptor for the peptide growth hormone PSY1. The intracellular protein kinase domain of PSY1R phosphorylates AHA2/AHA1 at Thr-881, situated in the autoinhibitory region I of the C-terminal domain. When expressed in a yeast...... heterologous expression system, the introduction of a negative charge at this position caused pump activation. Application of PSY1 to plant seedlings induced rapid in planta phosphorylation at Thr-881, concomitant with an instantaneous increase in proton efflux from roots. The direct interaction between AHA2...

  12. Vitamin D controls T cell antigen receptor signaling and activation of human T cells

    DEFF Research Database (Denmark)

    von Essen, Marina Rode; Kongsbak-Wismann, Martin; Schjerling, Peter

    2010-01-01

    Phospholipase C (PLC) isozymes are key signaling proteins downstream of many extracellular stimuli. Here we show that naive human T cells had very low expression of PLC-gamma1 and that this correlated with low T cell antigen receptor (TCR) responsiveness in naive T cells. However, TCR triggering...... led to an upregulation of approximately 75-fold in PLC-gamma1 expression, which correlated with greater TCR responsiveness. Induction of PLC-gamma1 was dependent on vitamin D and expression of the vitamin D receptor (VDR). Naive T cells did not express VDR, but VDR expression was induced by TCR...... signaling via the alternative mitogen-activated protein kinase p38 pathway. Thus, initial TCR signaling via p38 leads to successive induction of VDR and PLC-gamma1, which are required for subsequent classical TCR signaling and T cell activation....

  13. Behavioral control by striatal adenosine A2A -dopamine D2 receptor heteromers.

    Science.gov (United States)

    Taura, J; Valle-León, M; Sahlholm, K; Watanabe, M; Van Craenenbroeck, K; Fernández-Dueñas, V; Ferré, S; Ciruela, F

    2018-04-01

    G protein-coupled receptors (GPCR) exhibit the ability to form receptor complexes that include molecularly different GPCR (ie, GPCR heteromers), which endow them with singular functional and pharmacological characteristics. The relative expression of GPCR heteromers remains a matter of intense debate. Recent studies support that adenosine A 2A receptors (A 2A R) and dopamine D 2 receptors (D 2 R) predominantly form A 2A R-D 2 R heteromers in the striatum. The aim of the present study was evaluating the behavioral effects of pharmacological manipulation and genetic blockade of A 2A R and D 2 R within the frame of such a predominant striatal heteromeric population. First, in order to avoid possible strain-related differences, a new D 2 R-deficient mouse with the same genetic background (CD-1) than the A 2A R knock-out mouse was generated. Locomotor activity, pre-pulse inhibition (PPI) and drug-induced catalepsy were then evaluated in wild-type, A 2A R and D 2 R knock-out mice, with and without the concomitant administration of either the D 2 R agonist sumanirole or the A 2A R antagonist SCH442416. SCH442416-mediated locomotor effects were demonstrated to be dependent on D 2 R signaling. Similarly, a significant dependence on A 2A R signaling was observed for PPI and for haloperidol-induced catalepsy. The results could be explained by the existence of one main population of striatal postsynaptic A 2A R-D 2 R heteromers, which may constitute a relevant target for the treatment of Parkinson's disease and other neuropsychiatric disorders. © 2017 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  14. A single amino acid residue controls Ca2+ signaling by an octopamine receptor from Drosophila melanogaster

    OpenAIRE

    Hoff, Max; Balfanz, Sabine; Ehling, Petra; Gensch, Thomas; Baumann, Arnd

    2011-01-01

    Rhythmic activity of cells and cellular networks plays an important role in physiology. In the nervous system oscillations of electrical activity and/or second messenger concentrations are important to synchronize neuronal activity. At the molecular level, rhythmic activity can be initiated by different routes. We have recently shown that an octopamine-activated G-protein-coupled receptor (GPCR; DmOctα1Rb, CG3856) from Drosophila initiates Ca2+ oscillations. Here, we have unraveled the molecu...

  15. Bradykinin receptor blockade restores the baroreflex control of renal sympathetic nerve activity in cisplatin-induced renal failure rats.

    Science.gov (United States)

    Abdulla, M H; Duff, M; Swanton, H; Johns, E J

    2016-11-01

    This study investigated the effect of renal bradykinin B1 and B2 receptor blockade on the high- and low-pressure baroreceptor reflex regulation of renal sympathetic nerve activity (RSNA) in rats with cisplatin-induced renal failure. Cisplatin (5 mg/kg) or saline was given intraperitoneally 4 days prior to study. Following chloralose/urethane anaesthesia, rats were prepared for measurement of mean arterial pressure (MAP), heart rate and RSNA and received intrarenal infusions of either Lys-[des-Arg 9 , Leu 8 ]-bradykinin (LBK), a bradykinin B1 receptor blocker, or bradyzide (BZ), a bradykinin B2 receptor blocker. RSNA baroreflex gain curves and renal sympatho-inhibitory responses to volume expansion (VE) were obtained. In the control and renal failure groups, basal MAP (89 ± 3 vs. 80 ± 8 mmHg) and RSNA (2.0 ± 0.3 vs. 1.7 ± 0.6 μV.s) were similar but HR was lower in the latter group (331 ± 8 vs. 396 ± 9 beats/min). The baroreflex gain for RSNA in the renal failure rats was 39% (P renal failure rats. Intrarenal LBK infusion in the renal failure rats normalized the VE induced renal sympatho-inhibition whereas BZ only partially restored the response. These findings suggest that pro-inflammatory bradykinin acting at different receptors within the kidney generates afferent neural signals which impact differentially within the central nervous system on high- and low-pressure regulation of RSNA. © 2016 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

  16. Spinal cord compression injury in lysophosphatidic acid 1 receptor-null mice promotes maladaptive pronociceptive descending control.

    Science.gov (United States)

    Suardíaz, M; Galan-Arriero, I; Avila-Martin, G; Estivill-Torrús, G; de Fonseca, F R; Chun, J; Gómez-Soriano, J; Bravo-Esteban, E; Taylor, J

    2016-02-01

    Although activation of the lysophosphatidic acid receptor 1 (LPA1) is known to mediate pronociceptive effects in peripheral pain models, the role of this receptor in the modulation of spinal nociception following spinal cord injury (SCI) is unknown. In this study, LPA1 regulation of spinal excitability mediated by supraspinal descending antinociceptive control systems was assessed following SCI in both wild-type (WT) and maLPA1-null receptor mice. The effect of a T8 spinal compression in WT and maLPA1-null mice was assessed up to 1 month after SCI using histological, immunohistochemical and behavioural techniques analysis including electrophysiological recording of noxious toes-Tibialis Anterior (TA) stimulus-response reflex activity. The effect of a T3 paraspinal transcutaneous electrical conditioning stimulus on TA noxious reflex temporal summation was also assessed. Histological analysis demonstrated greater dorsolateral funiculus damage after SCI in maLPA1-null mice, without a change in the stimulus-response function of the TA noxious reflex when compared to WT mice. While T3 conditioning stimulation in the WT group inhibited noxious TA reflex temporal summation after SCI, this stimulus strongly excited TA reflex temporal summation in maLPA1-null mice. The functional switch from descending inhibition to maladaptive facilitation of central excitability of spinal nociception demonstrated in maLPA1-null mice after SCI was unrelated to a general change in reflex activity. These data suggest that the LPA1 receptor is necessary for inhibition of temporal summation of noxious reflex activity, partly mediated via long-tract descending modulatory systems acting at the spinal level. © 2015 European Pain Federation - EFIC®

  17. DMPD: The involvement of the interleukin-1 receptor-associated kinases (IRAKs) incellular signaling networks controlling inflammation. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available ncellular signaling networks controlling inflammation. Ringwood L, Li L. Cytokine. 2008 Apr;42(1):1-7. Epub ...ases (IRAKs) incellular signaling networks controlling inflammation. PubmedID 182...49132 Title The involvement of the interleukin-1 receptor-associated kinases (IRAKs) incellular signaling networks controlling

  18. Habit learning and the genetics of the dopamine D3 receptor: evidence from patients with schizophrenia and healthy controls.

    Science.gov (United States)

    Kéri, Szabolcs; Juhász, Anna; Rimanóczy, Agnes; Szekeres, György; Kelemen, Oguz; Cimmer, Csongor; Szendi, István; Benedek, György; Janka, Zoltán

    2005-06-01

    In this study, the authors investigated the relationship between the Ser9Gly (SG) polymorphism of the dopamine D3 receptor (DRD3) and striatal habit learning in healthy controls and patients with schizophrenia. Participants were given the weather prediction task, during which probabilistic cue-response associations were learned for tarot cards and weather outcomes (rain or sunshine). In both healthy controls and patients with schizophrenia, participants with Ser9Ser (SS) genotype did not learn during the early phase of the task (1-50 trials), whereas participants with SG genotype did so. During the late phase of the task (51-100 trials), both participants with SS and SG genotype exhibited significant learning. Learning rate was normal in patients with schizophrenia. These results suggest that the DRD3 variant containing glycine is associated with more efficient striatal habit learning in healthy controls and patients with schizophrenia. (c) 2005 APA, all rights reserved.

  19. Modeling the receptor pharmacology, pharmacokinetics, and pharmacodynamics of NKTR-214, a kinetically-controlled interleukin-2 (IL2 receptor agonist for cancer immunotherapy.

    Directory of Open Access Journals (Sweden)

    Deborah Charych

    Full Text Available Cytokines are potent immune modulating agents but are not ideal medicines in their natural form due to their short half-life and pleiotropic systemic effects. NKTR-214 is a clinical-stage biologic that comprises interleukin-2 (IL2 protein bound by multiple releasable polyethylene glycol (PEG chains. In this highly PEG-bound form, the IL2 is inactive; therefore, NKTR-214 is a biologic prodrug. When administered in vivo, the PEG chains slowly release, creating a cascade of increasingly active IL2 protein conjugates bound by fewer PEG chains. The 1-PEG-IL2 and 2-PEG-IL2 species derived from NKTR-214 are the most active conjugated-IL2 species. Free-IL2 protein is undetectable in vivo as it is eliminated faster than formed. The PEG chains on NKTR-214 are located at the region of IL2 that contacts the alpha (α subunit of the heterotrimeric IL2 receptor complex, IL2Rαβγ, reducing its ability to bind and activate the heterotrimer. The IL2Rαβγ complex is constitutively expressed on regulatory T cells (Tregs. Therefore, without the use of mutations, PEGylation reduces the affinity for IL2Rαβγ to a greater extent than for IL2Rβγ, the receptor complex predominant on CD8 T cells. NKTR-214 treatment in vivo favors activation of CD8 T cells over Tregs in the tumor microenvironment to provide anti-tumor efficacy in multiple syngeneic models. Mechanistic modeling based on in vitro and in vivo kinetic data provides insight into the mechanism of NKTR-214 pharmacology. The model reveals that conjugated-IL2 protein derived from NKTR-214 occupy IL-2Rβγ to a greater extent compared to free-IL2 protein. The model accurately describes the sustained in vivo signaling observed after a single dose of NKTR-214 and explains how the properties of NKTR-214 impart a unique kinetically-controlled immunological mechanism of action.

  20. Modeling the receptor pharmacology, pharmacokinetics, and pharmacodynamics of NKTR-214, a kinetically-controlled interleukin-2 (IL2) receptor agonist for cancer immunotherapy.

    Science.gov (United States)

    Charych, Deborah; Khalili, Samira; Dixit, Vidula; Kirk, Peter; Chang, Thomas; Langowski, John; Rubas, Werner; Doberstein, Stephen K; Eldon, Michael; Hoch, Ute; Zalevsky, Jonathan

    2017-01-01

    Cytokines are potent immune modulating agents but are not ideal medicines in their natural form due to their short half-life and pleiotropic systemic effects. NKTR-214 is a clinical-stage biologic that comprises interleukin-2 (IL2) protein bound by multiple releasable polyethylene glycol (PEG) chains. In this highly PEG-bound form, the IL2 is inactive; therefore, NKTR-214 is a biologic prodrug. When administered in vivo, the PEG chains slowly release, creating a cascade of increasingly active IL2 protein conjugates bound by fewer PEG chains. The 1-PEG-IL2 and 2-PEG-IL2 species derived from NKTR-214 are the most active conjugated-IL2 species. Free-IL2 protein is undetectable in vivo as it is eliminated faster than formed. The PEG chains on NKTR-214 are located at the region of IL2 that contacts the alpha (α) subunit of the heterotrimeric IL2 receptor complex, IL2Rαβγ, reducing its ability to bind and activate the heterotrimer. The IL2Rαβγ complex is constitutively expressed on regulatory T cells (Tregs). Therefore, without the use of mutations, PEGylation reduces the affinity for IL2Rαβγ to a greater extent than for IL2Rβγ, the receptor complex predominant on CD8 T cells. NKTR-214 treatment in vivo favors activation of CD8 T cells over Tregs in the tumor microenvironment to provide anti-tumor efficacy in multiple syngeneic models. Mechanistic modeling based on in vitro and in vivo kinetic data provides insight into the mechanism of NKTR-214 pharmacology. The model reveals that conjugated-IL2 protein derived from NKTR-214 occupy IL-2Rβγ to a greater extent compared to free-IL2 protein. The model accurately describes the sustained in vivo signaling observed after a single dose of NKTR-214 and explains how the properties of NKTR-214 impart a unique kinetically-controlled immunological mechanism of action.

  1. Extracellular signal-regulated kinases control expression of G protein-coupled receptor kinase 2 (GRK2)

    DEFF Research Database (Denmark)

    Theilade, Juliane; Lerche Hansen, Jakob; Haunsø, Stig

    2002-01-01

    G protein-coupled receptor kinase 2 (GRK2) phosphorylates G protein-coupled receptors resulting in uncoupling from G proteins. Receptors modulate GRK2 expression, however the mechanistic basis for this effect is largely unknown. Here we report a novel mechanism by which receptors use...

  2. Fyn kinase controls Fc{epsilon}RI receptor-operated calcium entry necessary for full degranulation in mast cells

    Energy Technology Data Exchange (ETDEWEB)

    Sanchez-Miranda, Elizabeth; Ibarra-Sanchez, Alfredo [Departamento de Farmacobiologia, Centro de Investigacion y de Estudios Avanzados (Cinvestav), Sede Sur, Calzada de los Tenorios 235, Col. Granjas Coapa, CP 14330 Mexico City (Mexico); Gonzalez-Espinosa, Claudia, E-mail: cgonzal@cinvestav.mx [Departamento de Farmacobiologia, Centro de Investigacion y de Estudios Avanzados (Cinvestav), Sede Sur, Calzada de los Tenorios 235, Col. Granjas Coapa, CP 14330 Mexico City (Mexico)

    2010-01-22

    IgE-antigen-dependent crosslinking of the high affinity IgE receptor (Fc{epsilon}RI) on mast cells leads to degranulation, leukotriene synthesis and cytokine production. Calcium (Ca{sup 2+}) mobilization is a sine qua non requisite for degranulation, allowing the rapid secretion of stored pro-inflammatory mediators responsible for allergy symptoms. Fyn is a Src-family kinase that positively controls Fc{epsilon}RI-induced mast cell degranulation. However, our understanding of the mechanism connecting Fyn activation to secretion of pre-synthesized mediators is very limited. We analyzed Fc{epsilon}RI-dependent Ca{sup 2+} mobilization in bone marrow-derived mast cells (BMMCs) differentiated from WT and Fyn -/- knock out mice. Fyn -/- BMMCs showed a marked defect in extracellular Ca{sup 2+} influx after Fc{epsilon}RI crosslinking but not after thapsigargin addition. High concentrations of Gadolinium (Gd{sup 3+}) partially blocked Fc{epsilon}RI-induced Ca{sup 2+} influx in WT cells but, in contrast, completely inhibited Ca{sup 2+} mobilization in Fyn -/- cells. Low concentrations of an inhibitor of the canonical transient receptor potential (TRPC) Ca{sup 2+} channels (2-aminoethoxyphenyl-borane, 2-APB) blocked Fc{epsilon}RI-induced maximal Ca{sup 2+} rise in WT but not in Fyn -/- cells. Ca{sup 2+} entry through Fyn-controlled, 2-APB sensitive channels was found to be important for full degranulation and IL-2 mRNA accumulation in WT cells. Immunoprecipitation assays showed that Fyn kinase interacts with TRPC 3/6/7 channels after IgE-antigen stimulation, but its association is not related to protein tyrosine phosphorylation. Results indicate Fyn kinase mediates the receptor-dependent activation of TRPC channels that contribute to degranulation in Fc{epsilon}RI-stimulated mast cells.

  3. The sympathetic nervous system is controlled by transient receptor potential vanilloid 1 in the regulation of body temperature

    Science.gov (United States)

    Alawi, Khadija M.; Aubdool, Aisah A.; Liang, Lihuan; Wilde, Elena; Vepa, Abhinav; Psefteli, Maria-Paraskevi; Brain, Susan D.; Keeble, Julie E.

    2015-01-01

    Transient receptor potential vanilloid 1 (TRPV1) is involved in sensory nerve nociceptive signaling. Recently, it has been discovered that TRPV1 receptors also regulate basal body temperature in multiple species from mice to humans. In the present study, we investigated whether TRPV1 modulates basal sympathetic nervous system (SNS) activity. C57BL6/J wild-type (WT) mice and TRPV1 knockout (KO) mice were implanted with radiotelemetry probes for measurement of core body temperature. AMG9810 (50 mg/kg) or vehicle (2% DMSO/5% Tween 80/10 ml/kg saline) was injected intraperitoneally. Adrenoceptor antagonists or vehicle (5 ml/kg saline) was injected subcutaneously. In WT mice, the TRPV1 antagonist, AMG9810, caused significant hyperthermia, associated with increased noradrenaline concentrations in brown adipose tissue. The hyperthermia was significantly attenuated by the β-adrenoceptor antagonist propranolol, the mixed α-/β-adrenoceptor antagonist labetalol, and the α1-adrenoceptor antagonist prazosin. TRPV1 KO mice have a normal basal body temperature, indicative of developmental compensation. d-Amphetamine (potent sympathomimetic) caused hyperthermia in WT mice, which was reduced in TRPV1 KO mice, suggesting a decreased sympathetic drive in KOs. This study provides new evidence that TRPV1 controls thermoregulation upstream of the SNS, providing a potential therapeutic target for sympathetic hyperactivity thermoregulatory disorders.—Alawi, K. M., Aubdool, A. A., Liang, L., Wilde, E., Vepa, A., Psefteli, M.-P., Brain, S. D., Keeble, J. E. The sympathetic nervous system is controlled by transient receptor potential vanilloid 1 in the regulation of body temperature. PMID:26136480

  4. Peripheral tissue homing receptor control of naïve, effector, and memory CD8 T cell localization in lymphoid and non-lymphoid tissues.

    Science.gov (United States)

    Brinkman, C Colin; Peske, J David; Engelhard, Victor Henry

    2013-01-01

    T cell activation induces homing receptors that bind ligands on peripheral tissue vasculature, programing movement to sites of infection and injury. There are three major types of CD8 effector T cells based on homing receptor expression, which arise in distinct lymphoid organs. Recent publications indicate that naïve, effector, and memory T cell migration is more complex than once thought; while many effectors enter peripheral tissues, some re-enter lymph nodes (LN), and contain central memory precursors. LN re-entry can depend on CD62L or peripheral tissue homing receptors. Memory T cells in LN tend to express the same homing receptors as their forebears, but often are CD62Lneg. Homing receptors also control CD8 T cell tumor entry. Tumor vasculature has low levels of many peripheral tissue homing receptor ligands, but portions of it resemble high endothelial venules (HEV), enabling naïve T cell entry, activation, and subsequent effector activity. This vasculature is associated with positive prognoses in humans, suggesting it may sustain ongoing anti-tumor responses. These findings reveal new roles for homing receptors expressed by naïve, effector, and memory CD8 T cells in controlling entry into lymphoid and non-lymphoid tissues.

  5. PEST Motif Serine and Tyrosine Phosphorylation Controls Vascular Endothelial Growth Factor Receptor 2 Stability and Downregulation ▿

    Science.gov (United States)

    Meyer, Rosana D.; Srinivasan, Srimathi; Singh, Amrik J.; Mahoney, John E.; Gharahassanlou, Kobra Rezazadeh; Rahimi, Nader

    2011-01-01

    The internalization and degradation of vascular endothelial growth factor receptor 2 (VEGFR-2), a potent angiogenic receptor tyrosine kinase, is a central mechanism for the regulation of the coordinated action of VEGF in angiogenesis. Here, we show that VEGFR-2 is ubiquitinated in response to VEGF, and Lys 48-linked polyubiquitination controls its degradation via the 26S proteosome. The degradation and ubiquitination of VEGFR-2 is controlled by its PEST domain, and the phosphorylation of Ser1188/Ser1191 is required for the ubiquitination of VEGFR-2. F-box-containing β-Trcp1 ubiquitin E3 ligase is recruited to S1188/S1191 VEGFR-2 and mediates the ubiquitination and degradation of VEGFR-2. The PEST domain also controls the activation of p38 mitogen-activated protein kinase (MAPK) through phospho-Y1173. The activation of p38 stabilizes VEGFR-2, and its inactivation accelerates VEGFR-2 downregulation. The VEGFR-2-mediated activation of p38 is established through the protein kinase A (PKA)/MKK6 pathway. PKA is recruited to VEGFR-2 through AKAP1/AKAP149, and its phosphorylation requires Y1173 of VEGFR-2. The study has identified a unique mechanism in which VEGFR-2 stability and degradation is modulated. The PEST domain acts as a dual modulator of VEGFR-2; the phosphorylation of S1188/S1191 controls ubiquitination and degradation via β-Trcp1, where the phosphorylation of Y1173 through PKA/p38 MAPK controls the stability of VEGFR-2. PMID:21402774

  6. Estrogen-Related Receptors and the control of bone cell fate.

    Science.gov (United States)

    Carnesecchi, Julie; Vanacker, Jean-Marc

    2016-09-05

    Bone loss is naturally occurring in aging males and females and exacerbated in the latter after menopause, altogether leading to cumulative skeleton fragility and increased fracture risk. Two types of therapeutic strategies can be envisioned to counteract age- or menopause-associated bone loss, aiming at either reducing bone resorption exerted by osteoclasts or, alternatively, promoting bone formation by osteoblasts. We here summarize data suggesting that inhibition of the Estrogen-Related Receptors α and/or γ could promote bone formation and compensate for bone loss induced by ageing or estrogen-deficiency. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  7. IP3 Receptor-Dependent Cytoplasmic Ca2+ Signals Are Tightly Controlled by Cavβ3

    Directory of Open Access Journals (Sweden)

    Anouar Belkacemi

    2018-01-01

    Full Text Available Voltage-gated calcium channels (Cavs are major Ca2+ entry pathways in excitable cells. Their β subunits facilitate membrane trafficking of the channel’s ion-conducting α1 pore and modulate its gating properties. We report that one β subunit, β3, reduces Ca2+ release following stimulation of phospholipase C-coupled receptors and inositol 1,4,5-trisphosphate (IP3 formation. This effect requires the SH3-HOOK domain of Cavβ3, includes physical β3/IP3 receptor interaction, and prevails when agonist-induced IP3 formation is bypassed by photolysis of caged IP3. In agreement with β3 acting as a brake on Ca2+ release, fibroblast migration is enhanced in vitro, and in vivo, closure of skin wounds is accelerated in the absence of β3. To mediate specific physiological responses and to prevent Ca2+ toxicity, cytoplasmic Ca2+ signals must be tightly controlled. The described function of β3, unrelated to its function as a Cav subunit, adds to this tight control.

  8. The impact of luteal phase support on endometrial estrogen and progesterone receptor expression: a randomized control trial

    Directory of Open Access Journals (Sweden)

    Brezina Paul R

    2012-02-01

    Full Text Available Abstract Background To assess the impact of luteal phase support on the expression of estrogen receptor (ER alpha and progesterone receptors B (PR-B on the endometrium of oocyte donors undergoing controlled ovarian hyperstimulation (COH. Methods A prospective, randomized study was conducted in women undergoing controlled ovarian hyperstimulation for oocyte donation. Participants were randomized to receive no luteal support, vaginal progesterone alone, or vaginal progesterone plus orally administered 17 Beta estradiol. Endometrial biopsies were obtained at 4 time points in the luteal phase and evaluated by tissue microarray for expression of ER alpha and PR-B. Results One-hundred and eight endometrial tissue samples were obtained from 12 patients. No differences were found in expression of ER alpha and PR-B among all the specimens with the exception of one sample value. Conclusions The administration of progesterone during the luteal phase of COH for oocyte donor cycles, either with or without estrogen, does not significantly affect the endometrial expression of ER alpha and PR.

  9. The therapeutic potential of nicotinic acetylcholine receptor agonists for pain control.

    Science.gov (United States)

    Decker, M W; Meyer, M D; Sullivan, J P

    2001-10-01

    Due to the limitations of currently available analgesics, a number of novel alternatives are currently under investigation, including neuronal nicotinic acetylcholine receptor (nAChR) agonists. During the 1990s, the discovery of the antinociceptive properties of the potent nAChR agonist epibatidine in rodents sparked interest in the analgesic potential of this class of compounds. Although epibatidine also has several mechanism-related toxicities, the identification of considerable nAChR diversity suggested that the toxicities and therapeutic actions of the compound might be mediated by distinct receptor subtypes. Consistent with this view, a number of novel nAChR agonists with antinociceptive activity and improved safety profiles in preclinical models have now been identified, including A-85380, ABT-594, DBO-83, SIB-1663 and RJR-2403. Of these, ABT-594 is the most advanced and is currently in Phase II clinical evaluation. Nicotinically-mediated antinociception has been demonstrated in a variety of rodent pain models and is likely mediated by the activation of descending inhibitory pathways originating in the brainstem with the predominant high-affinity nicotine site in brain, the alpha4beta2 subtype, playing a critical role. Thus, preclinical findings suggest that nAChR agonists have the potential to be highly efficacious treatments in a variety of pain states. However, clinical proof-of-principle studies will be required to determine if nAChR agonists are active in pathological pain.

  10. Stability of tramadol with three 5-HT3 receptor antagonists in polyolefin bags for patient-controlled delivery systems

    Directory of Open Access Journals (Sweden)

    Chen FC

    2016-06-01

    Full Text Available Fu-chao Chen,1 Jun Zhu,1 Bin Li,1 Fang-jun Yuan,1 Lin-hai Wang2 1Department of Pharmacy, Dongfeng Hospital, 2Department of Pharmacy, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, People’s Republic of China Background: Mixing 5-hydroxytryptamine-3 (5-HT3 receptor antagonists with patient-controlled analgesia (PCA solutions of tramadol has been shown to decrease the incidence of nausea and vomiting associated with the use of tramadol PCA for postoperative pain. However, such mixtures are not commercially available, and the stability of the drug combinations has not been duly studied. The study aimed to evaluate the stability of tramadol with three 5-HT3 receptor antagonists in 0.9% sodium chloride injection for PCA administration.Materials and methods: Test samples were prepared by adding 1,000 mg tramadol hydrochloride, 8 mg ondansetron hydrochloride, and 6 mg granisetron hydrochloride or 5 mg tropisetron hydrochloride to 100 mL of 0.9% sodium chloride injection in polyolefin bags. The samples were prepared in triplicates, stored at either 25°C or 4°C for 14 days, and assessed using the following compatibility parameters: precipitation, cloudiness, discoloration, and pH. Chemical stability was also determined using a validated high-pressure liquid chromatography method.Results: All of the mixtures were clear and colorless throughout the initial observation period. No change in the concentration of tramadol hydrochloride occurred with any of the 5-HT3 receptor antagonists during the 14 days. Similarly, little or no loss of the 5-HT3 receptor antagonists occurred over the 14-day period.Conclusion: Our results suggest that mixtures of tramadol hydrochloride, ondansetron hydrochloride, granisetron hydrochloride, or tropisetron hydrochloride in 0.9% sodium chloride injection were physically and chemically stable for 14 days when stored in polyolefin bags at both 4°C and 25°C. Keywords: tramadol, ondansetron, granisetron

  11. Floral organ abscission peptide IDA and its HAE/HSL2 receptors control cell separation during lateral root emergence.

    Science.gov (United States)

    Kumpf, Robert P; Shi, Chun-Lin; Larrieu, Antoine; Stø, Ida Myhrer; Butenko, Melinka A; Péret, Benjamin; Riiser, Even Sannes; Bennett, Malcolm J; Aalen, Reidunn B

    2013-03-26

    Throughout their life cycle, plants produce new organs, such as leaves, flowers, and lateral roots. Organs that have served their purpose may be shed after breakdown of primary cell walls between adjacent cell files at the site of detachment. In Arabidopsis, floral organs abscise after pollination, and this cell separation event is controlled by the peptide INFLORESCENCE DEFICIENT IN ABSCISSION (IDA), which signals through the leucine-rich repeat receptor-like kinases HAESA (HAE) and HAESA-LIKE2 (HSL2). Emergence of new lateral root primordia, initiated deep inside the root under the influence of auxin, is similarly dependent on cell wall dissolution between cells in the overlaying endodermal, cortical, and epidermal tissues. Here we show that this process requires IDA, HAE, and HSL2. Mutation in these genes constrains the passage of the growing lateral root primordia through the overlaying layers, resulting in altered shapes of the lateral root primordia and of the overlaying cells. The HAE and HSL2 receptors are redundant in function during floral organ abscission, but during lateral root emergence they are differentially involved in regulating cell wall remodeling genes. In the root, IDA is strongly auxin-inducible and dependent on key regulators of lateral root emergence--the auxin influx carrier LIKE AUX1-3 and AUXIN RESPONSE FACTOR7. The expression levels of the receptor genes are only transiently induced by auxin, suggesting they are limiting factors for cell separation. We conclude that elements of the same cell separation signaling module have been adapted to function in different developmental programs.

  12. An alpha-adrenergic receptor mechanism controlling potassium permeability in the rat lacrimal gland acinar cell

    International Nuclear Information System (INIS)

    Parod, R.J.; Putney, J.W. Jr.

    1978-01-01

    Rat lacrimal gland slices, incubated in a balanced, buffered salt solution, were found to be physiologically stable for up to 2 hr with respect to 0 2 consumption, extracellular space, and water and ion content. The release of 86 Rb serves as a good substitute for 42 K in monitoring the movement of K through the cell membrane. Adrenaline appears to increase membrane permeability to K as evidenced by an increase in the rate of 86 Rb efflux. This response to adrenaline was blocked by phentolamine but not by propranolol and was mimicked by phenylephrine but not by isoprenaline. The magnitude of the 86 Rb release indicates that it is being released, at least in part, from the lacrimal gland acinar cell. It is concluded that the lacrimal gland acinar cell has an α-adrenergic receptor, activation of which leads to an increase in membrane permeability to K. (author)

  13. [¹¹C]-(+)-PHNO PET imaging of dopamine D(2/3) receptors in Parkinson's disease with impulse control disorders.

    Science.gov (United States)

    Payer, Doris E; Guttman, Mark; Kish, Stephen J; Tong, Junchao; Strafella, Antonio; Zack, Martin; Adams, John R; Rusjan, Pablo; Houle, Sylvain; Furukawa, Yoshiaki; Wilson, Alan A; Boileau, Isabelle

    2015-02-01

    Dopamine agonist medications with high affinity for the D3 dopamine receptor are commonly used to treat Parkinson's disease, and have been associated with pathological behaviors categorized under the umbrella of impulse control disorders (ICD). The aim of this study was to investigate whether ICD in Parkinson's patients are associated with greater D3 dopamine receptor availability. We used positron emission tomography (PET) radioligand imaging with the D3 dopamine receptor preferring agonist [¹¹C]-(+)-propyl-hexahydro-naphtho-oxazin (PHNO) in Parkinson's patients with (n = 11) and without (n = 21) ICD, and age-, sex-, and education-matched healthy control subjects (n = 18). Contrary to hypotheses, [¹¹C]-(+)-PHNO binding in D3 -rich brain areas was not elevated in Parkinson's patients with ICD compared with those without; instead, [¹¹C]-(+)-PHNO binding in ventral striatum was 20% lower (P = 0.011), correlating with two measures of ICD severity (r = -0.8 and -0.9), which may reflect higher dopamine tone in ventral striatum. In dorsal striatum, where [¹¹C]-(+)-PHNO binding is associated with D2 receptor levels, [¹¹C]-(+)-PHNO binding was elevated across patients compared with controls. We conclude that although D3 dopamine receptors have been linked to the occurrence of ICD in Parkinson's patients. Our findings do not support the hypothesis that D3 receptor levels are elevated in Parkinson's patients with ICD. We also did not find ICD-related abnormalities in D2 receptor levels. Our findings argue against the possibility that differences in D2/3 receptor levels can account for the development of ICD in PD; however, we cannot rule out that differences in dopamine levels (particularly in ventral striatum) may be involved. © 2015 International Parkinson and Movement Disorder Society.

  14. Dopamine D3 receptor Ser9Gly variant is associated with impulse control disorders in Parkinson's disease patients.

    Science.gov (United States)

    Krishnamoorthy, Soumya; Rajan, Roopa; Banerjee, Moinak; Kumar, Hardeep; Sarma, Gangadhara; Krishnan, Syam; Sarma, Sankara; Kishore, Asha

    2016-09-01

    Impulse control disorders (ICD) are reported to occur at variable frequencies in different ethnic groups. Genetic vulnerability is suspected to underlie the individual risk for ICD. We investigated whether the allelic variants of dopamine (DRD3), glutamate (GRIN2B) and serotonin (HTR2A) receptors are linked to ICD in Indian Parkinson's disease (PD) patients. We conducted a prospective, case-control study which included PD patients (70 with ICD, 100 without ICD categorized after direct psychiatric interview of patient and caregiver) and 285 healthy controls. Single nucleotide polymorphism (SNP) variants of DRD3 p.S9G (rs6280), GRIN2B c.2664C>T (rs1806201) and HTR2A c.102T>C (rs6313) were genotyped. Multivariate regression analysis revealed that DRD3 p.Ser9Gly (rs6280) heterozygous variant CT (OR = 2.22, 95% CI: 1.03-4.86, p = 0.041), higher daily Levodopa equivalent doses (LED) of drugs (for 100 mg LED, OR = 1.14, 95% CI: 1.01-1.29, p = 0.041), current dopamine agonist but not Levodopa use (OR = 2.16, 95% CI: 1.03-4.55, p = 0.042) and age of onset of motor symptoms under 50 years (OR 2.09, 95% CI: 1.05-4.18, p = 0.035) were independently associated with ICD. DRD3 p.Ser9Gly (rs6280) CT genotype is associated with ICD in Indian PD patients and this association is novel. Enhanced D3 receptor affinity due to gain-of-function conferred by the glycine residues could impair reward-risk assessment in the mesolimbic system and contribute to development of impulsive behaviour, in carriers of this genotype. Copyright © 2016. Published by Elsevier Ltd.

  15. Adiponectin, a downstream target gene of peroxisome proliferator-activated receptor γ, controls hepatitis B virus replication

    International Nuclear Information System (INIS)

    Yoon, Sarah; Jung, Jaesung; Kim, Taeyeung; Park, Sun; Chwae, Yong-Joon; Shin, Ho-Joon; Kim, Kyongmin

    2011-01-01

    In this study, HepG2-hepatitis B virus (HBV)-stable cells that did not overexpress HBx and HBx-deficient mutant-transfected cells were analyzed for their expression of HBV-induced, upregulated adipogenic and lipogenic genes. The mRNAs of CCAAT enhancer binding protein α (C/EBPα), peroxisome proliferator-activated receptor γ (PPARγ), adiponectin, liver X receptor α (LXRα), sterol regulatory element binding protein 1c (SREBP1c), and fatty acid synthase (FAS) were expressed at higher levels in HepG2-HBV and lamivudine-treated stable cells and HBx-deficient mutant-transfected cells than in the HepG2 cells. Lamivudine treatment reduced the mRNA levels of PPARγ and C/EBPα. Conversely, HBV replication was upregulated by adiponectin and PPARγ agonist rosiglitazone treatments and was downregulated by adiponectin siRNAs. Collectively, our results demonstrate that HBV replication and/or protein expression, even in the absence of HBx, upregulated adipogenic or lipogenic genes, and that the control of adiponectin might prove useful as a therapeutic modality for the treatment of chronic hepatitis B.

  16. The Murine Natural Cytotoxic Receptor NKp46/NCR1 Controls TRAIL Protein Expression in NK Cells and ILC1s

    Directory of Open Access Journals (Sweden)

    Sam Sheppard

    2018-03-01

    Full Text Available Summary: TRAIL is an apoptosis-inducing ligand constitutively expressed on liver-resident type 1 innate lymphoid cells (ILC1s and a subset of natural killer (NK cells, where it contributes to NK cell anti-tumor, anti-viral, and immunoregulatory functions. However, the intrinsic pathways involved in TRAIL expression in ILCs remain unclear. Here, we demonstrate that the murine natural cytotoxic receptor mNKp46/NCR1, expressed on ILC1s and NK cells, controls TRAIL protein expression. Using NKp46-deficient mice, we show that ILC1s lack constitutive expression of TRAIL protein and that NK cells activated in vitro and in vivo fail to upregulate cell surface TRAIL in the absence of NKp46. We show that NKp46 regulates TRAIL expression in a dose-dependent manner and that the reintroduction of NKp46 in mature NK cells deficient for NKp46 is sufficient to restore TRAIL surface expression. These studies uncover a link between NKp46 and TRAIL expression in ILCs with potential implications in pathologies involving NKp46-expressing cells. : Sheppard et al. find that mice deficient in the activating receptor NCR1/NKp46 (Ncr1−/− fail to express the apoptosis-inducing ligand TRAIL at the surface of group 1 innate lymphoid cells (ILC1s. Keywords: NK cell, natural killer cell, NKp46, ILC1, TRAIL, IL-15, IL-2

  17. Investigating the association between polymorphism of follicle-stimulating hormone receptor gene and ovarian response in controlled ovarian hyperstimulation

    Directory of Open Access Journals (Sweden)

    Mohammad Hasan Sheikhha

    2011-01-01

    Full Text Available Aim : The aim of the study was to investigate the association between follicle-stimulating hormone receptor (FSHR gene polymorphism at Position 680 and the outcomes of controlled ovarian hyperstimulation for in vitro fertilization and embryo transfer (IVF-ET in infertile women. Materials and Methods : One hundred and eight patients under 35 years of age who underwent IVF-ET procedures were included in this study. The hormonal profile and treatment of all patients were analyzed and FSHR polymorphism was examined by polymerase chain reaction-restriction fragment length polymorphism. Women from all groups were classified based on polymorphisms at Position 680, occupied either by asparagines (Asn or serine (Ser as Asn/Asn, Asn/Ser, and Ser/Ser genotype. Result : Our study showed that all patients in the Asn/Asn group were normal responders and in the Asn/Ser group 64.8% were normal responders and 21.1% and 14.1% were poor and hyper responders respectively. In the Ser/Ser group we did not have normal responders and 46.7% of these patients were poor responders and 53.3% were hyper responders. Conclusion : FSH receptor polymorphism is correlated with response to ovarian stimulation.

  18. Gene structure and expression of serotonin receptor HTR2C in hypothalamic samples from infanticidal and control sows

    Directory of Open Access Journals (Sweden)

    Quilter Claire R

    2012-04-01

    Full Text Available Abstract Background The serotonin pathways have been implicated in behavioural phenotypes in a number of species, including human, rat, mouse, dog and chicken. Components of the pathways, including the receptors, are major targets for drugs used to treat a variety of physiological and psychiatric conditions in humans. In our previous studies we have identified genetic loci potentially contributing to maternal infanticide in pigs, which includes a locus on the porcine X chromosome long arm. The serotonin receptor HTR2C maps to this region, and is therefore an attractive candidate for further study based on its function and its position in the genome. Results In this paper we describe the structure of the major transcripts produced from the porcine HTR2C locus using cDNA prepared from porcine hypothalamic and pooled total brain samples. We have confirmed conservation of sites altered by RNA editing in other mammalian species, and identified polymorphisms in the gene sequence. Finally, we have analysed expression and editing of HTR2C in hypothalamus samples from infanticidal and control animals. Conclusions The results confirm that although the expression of the long transcriptional variant of HTR2C is raised in infanticidal animals, the overall patterns of editing in the hypothalamus are similar between the two states. Sequences associated with the cDNA and genomic structures of HTR2C reported in this paper are deposited in GenBank under accession numbers FR720593, FR720594 and FR744452.

  19. μ opioid receptor activation hyperpolarizes respiratory-controlling Kölliker-Fuse neurons and suppresses post-inspiratory drive.

    Science.gov (United States)

    Levitt, Erica S; Abdala, Ana P; Paton, Julian F R; Bissonnette, John M; Williams, John T

    2015-10-01

    In addition to reductions in respiratory rate, opioids also cause aspiration and difficulty swallowing, indicating impairment of the upper airways. The Kölliker-Fuse (KF) maintains upper airway patency and a normal respiratory pattern. In this study, activation of μ opioid receptors in the KF reduced respiratory frequency and tidal volume in anaesthetized rats. Nerve recordings in an in situ preparation showed that activation of μ opioid receptors in the KF eliminated the post-inspiration phase of the respiratory cycle. In brain slices, μ opioid agonists hyperpolarized a distinct population (61%) of KF neurons by activation of an inwardly rectifying potassium conductance. These results suggest that KF neurons that are hyperpolarized by opioids could contribute to opioid-induced respiratory disturbances, particularly the impairment of upper airways. Opioid-induced respiratory effects include aspiration and difficulty swallowing, suggesting impairment of the upper airways. The pontine Kölliker-Fuse nucleus (KF) controls upper airway patency and regulates respiration, in particular the inspiratory/expiratory phase transition. Given the importance of the KF in coordinating respiratory pattern, the mechanisms of μ opioid receptor activation in this nucleus were investigated at the systems and cellular level. In anaesthetized, vagi-intact rats, injection of opioid agonists DAMGO or [Met(5) ]enkephalin (ME) into the KF reduced respiratory frequency and amplitude. The μ opioid agonist DAMGO applied directly into the KF of the in situ arterially perfused working heart-brainstem preparation of rat resulted in robust apneusis (lengthened low amplitude inspiration due to loss of post-inspiratory drive) that was rapidly reversed by the opioid antagonist naloxone. In brain slice preparations, activation of μ opioid receptors on KF neurons hyperpolarized a distinct population (61%) of neurons. As expected, the opioid-induced hyperpolarization reduced the excitability of

  20. Receptor protein tyrosine phosphatase alpha activates Src-family kinases and controls integrin-mediated responses in fibroblasts

    DEFF Research Database (Denmark)

    Su, J; Muranjan, M; Sap, J

    1999-01-01

    of tyrosine kinases, the activity of which is tightly controlled by inhibitory phosphorylation of a carboxyterminal tyrosine residue (Tyr527 in chicken c-Src); this phosphorylation induces the kinases to form an inactive conformation. Whereas the identity of such inhibitory Tyr527 kinases has been well...... established, no corresponding phosphatases have been identified that, under physiological conditions, function as positive regulators of c-Src and Fyn in fibroblasts. RESULTS: Receptor protein tyrosine phosphatase alpha (RPTPalpha) was inactivated by homologous recombination. Fibroblasts derived from...... these RPTPalpha-/- mice had impaired tyrosine kinase activity of both c-Src and Fyn, and this was accompanied by a concomitant increase in c-Src Tyr527 phosphorylation. RPTPalpha-/- fibroblasts also showed a reduction in the rate of spreading on fibronectin substrates, a trait that is a phenocopy of the effect...

  1. The EGF receptor and notch signaling pathways control the initiation of the morphogenetic furrow during Drosophila eye development.

    Science.gov (United States)

    Kumar, J P; Moses, K

    2001-07-01

    The onset of pattern formation in the developing Drosophila retina begins with the initiation of the morphogenetic furrow, the leading edge of a wave of retinal development that transforms a uniform epithelium, the eye imaginal disc into a near crystalline array of ommatidial elements. The initiation of this wave of morphogenesis is under the control of the secreted morphogens Hedgehog (Hh), Decapentaplegic (Dpp) and Wingless (Wg). We show that the Epidermal Growth Factor Receptor and Notch signaling cascades are crucial components that are also required to initiate retinal development. We also show that the initiation of the morphogenetic furrow is the sum of two genetically separable processes: (1) the 'birth' of pattern formation at the posterior margin of the eye imaginal disc; and (2) the subsequent 'reincarnation' of retinal development across the epithelium.

  2. Mechanical stress regulates insulin sensitivity through integrin-dependent control of insulin receptor localization.

    Science.gov (United States)

    Kim, Jung; Bilder, David; Neufeld, Thomas P

    2018-01-15

    Insulin resistance, the failure to activate insulin signaling in the presence of ligand, leads to metabolic diseases, including type 2 diabetes. Physical activity and mechanical stress have been shown to protect against insulin resistance, but the molecular mechanisms remain unclear. Here, we address this relationship in the Drosophila larval fat body, an insulin-sensitive organ analogous to vertebrate adipose tissue and livers. We found that insulin signaling in Drosophila fat body cells is abolished in the absence of physical activity and mechanical stress even when excess insulin is present. Physical movement is required for insulin sensitivity in both intact larvae and fat bodies cultured ex vivo. Interestingly, the insulin receptor and other downstream components are recruited to the plasma membrane in response to mechanical stress, and this membrane localization is rapidly lost upon disruption of larval or tissue movement. Sensing of mechanical stimuli is mediated in part by integrins, whose activation is necessary and sufficient for mechanical stress-dependent insulin signaling. Insulin resistance develops naturally during the transition from the active larval stage to the immotile pupal stage, suggesting that regulation of insulin sensitivity by mechanical stress may help coordinate developmental programming with metabolism. © 2018 Kim et al.; Published by Cold Spring Harbor Laboratory Press.

  3. Ionotropic Receptor-dependent moist and dry cells control hygrosensation in Drosophila.

    Science.gov (United States)

    Knecht, Zachary A; Silbering, Ana F; Cruz, Joyner; Yang, Ludi; Croset, Vincent; Benton, Richard; Garrity, Paul A

    2017-06-16

    Insects use hygrosensation (humidity sensing) to avoid desiccation and, in vectors such as mosquitoes, to locate vertebrate hosts. Sensory neurons activated by either dry or moist air ('dry cells' and 'moist cells') have been described in many insects, but their behavioral roles and the molecular basis of their hygrosensitivity remain unclear. We recently reported that Drosophila hygrosensation relies on three Ionotropic Receptors (IRs) required for dry cell function: IR25a, IR93a and IR40a (Knecht et al., 2016). Here, we discover Drosophila moist cells and show that they require IR25a and IR93a together with IR68a, a conserved, but orphan IR. Both IR68a- and IR40a-dependent pathways drive hygrosensory behavior: each is important for dry-seeking by hydrated flies and together they underlie moist-seeking by dehydrated flies. These studies reveal that humidity sensing in Drosophila , and likely other insects, involves the combined activity of two molecularly related but neuronally distinct hygrosensing systems.

  4. Prostate stromal cells express the progesterone receptor to control cancer cell mobility.

    Science.gov (United States)

    Yu, Yue; Lee, Jennifer Suehyun; Xie, Ning; Li, Estelle; Hurtado-Coll, Antonio; Fazli, Ladan; Cox, Michael; Plymate, Stephen; Gleave, Martin; Dong, Xuesen

    2014-01-01

    Reciprocal interactions between epithelium and stroma play vital roles for prostate cancer development and progression. Enhanced secretions of cytokines and growth factors by cancer associated fibroblasts in prostate tumors create a favorable microenvironment for cancer cells to grow and metastasize. Our previous work showed that the progesterone receptor (PR) was expressed specifically in prostate stromal fibroblasts and smooth muscle cells. However, the expression levels of PR and its impact to tumor microenvironment in prostate tumors are poorly understood. Immunohistochemistry assays are applied to human prostate tissue biopsies. Cell migration, invasion and proliferation assays are performed using human prostate cells. Real-time PCR and ELISA are applied to measure gene expression at molecular levels. Immunohistochemistry assays showed that PR protein levels were decreased in cancer associated stroma when compared with paired normal prostate stroma. Using in vitro prostate stromal cell models, we showed that conditioned media collected from PR positive stromal cells inhibited prostate cancer cell migration and invasion, but had minor suppressive impacts on cancer cell proliferation. PR suppressed the secretion of stromal derived factor-1 (SDF-1) and interlukin-6 (IL-6) by stromal cells independent to PR ligands. Blocking PR expression by siRNA or supplementation of exogenous SDF-1 or IL-6 to conditioned media from PR positive stromal cells counteracted the inhibitory effects of PR to cancer cell migration and invasion. Decreased expression of the PR in cancer associated stroma may contribute to the elevated SDF-1 and IL-6 levels in prostate tumors and enhance prostate tumor progression.

  5. Action control is mediated by prefrontal BDNF and glucocorticoid receptor binding.

    Science.gov (United States)

    Gourley, Shannon L; Swanson, Andrew M; Jacobs, Andrea M; Howell, Jessica L; Mo, Michelle; Dileone, Ralph J; Koleske, Anthony J; Taylor, Jane R

    2012-12-11

    Stressor exposure biases decision-making strategies from those based on the relationship between actions and their consequences to others restricted by stimulus-response associations. Chronic stressor exposure also desensitizes glucocorticoid receptors (GR) and diminishes motivation to acquire food reinforcement, although causal relationships are largely not established. We show that a history of chronic exposure to the GR ligand corticosterone or acute posttraining GR blockade with RU38486 makes rodents less able to perform actions based on their consequences. Thus, optimal GR binding is necessary for the consolidation of new response-outcome learning. In contrast, medial prefrontal (but not striatal) BDNF can account for stress-related amotivation, in that selective medial prefrontal cortical Bdnf knockdown decreases break-point ratios in a progressive-ratio task. Knockdown also increases vulnerability to RU38486. Despite the role of BDNF in dendritic spine reorganization, deep-layer spine remodeling does not obviously parallel progressive-ratio response patterns, but treatment with the Na(+)-channel inhibitor riluzole reverses corticosteroid-induced motivational deficits and restores prefrontal BDNF expression after corticosterone. We argue that when prefrontal neurotrophin systems are compromised, and GR-mediated hypothalamic-pituitary-adrenal axis feedback is desensitized (as in the case of chronic stress hormone exposure), amotivation and inflexible maladaptive response strategies that contribute to stress-related mood disorders result.

  6. Enhanced odor discrimination and impaired olfactory memory by spatially controlled switch of AMPA receptors.

    Directory of Open Access Journals (Sweden)

    Derya R Shimshek

    2005-11-01

    Full Text Available Genetic perturbations of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPARs are widely used to dissect molecular mechanisms of sensory coding, learning, and memory. In this study, we investigated the role of Ca2+-permeable AMPARs in olfactory behavior. AMPAR modification was obtained by depletion of the GluR-B subunit or expression of unedited GluR-B(Q, both leading to increased Ca2+ permeability of AMPARs. Mice with this functional AMPAR switch, specifically in forebrain, showed enhanced olfactory discrimination and more rapid learning in a go/no-go operant conditioning task. Olfactory memory, however, was dramatically impaired. GluR-B depletion in forebrain was ectopically variable ("mosaic" among individuals and strongly correlated with decreased olfactory memory in hippocampus and cortex. Accordingly, memory was rescued by transgenic GluR-B expression restricted to piriform cortex and hippocampus, while enhanced odor discrimination was independent of both GluR-B variability and transgenic GluR-B expression. Thus, correlated differences in behavior and levels of GluR-B expression allowed a mechanistic and spatial dissection of olfactory learning, discrimination, and memory capabilities.

  7. Enhanced odor discrimination and impaired olfactory memory by spatially controlled switch of AMPA receptors.

    Science.gov (United States)

    Shimshek, Derya R; Bus, Thorsten; Kim, Jinhyun; Mihaljevic, Andre; Mack, Volker; Seeburg, Peter H; Sprengel, Rolf; Schaefer, Andreas T

    2005-11-01

    Genetic perturbations of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPARs) are widely used to dissect molecular mechanisms of sensory coding, learning, and memory. In this study, we investigated the role of Ca2+-permeable AMPARs in olfactory behavior. AMPAR modification was obtained by depletion of the GluR-B subunit or expression of unedited GluR-B(Q), both leading to increased Ca2+ permeability of AMPARs. Mice with this functional AMPAR switch, specifically in forebrain, showed enhanced olfactory discrimination and more rapid learning in a go/no-go operant conditioning task. Olfactory memory, however, was dramatically impaired. GluR-B depletion in forebrain was ectopically variable ("mosaic") among individuals and strongly correlated with decreased olfactory memory in hippocampus and cortex. Accordingly, memory was rescued by transgenic GluR-B expression restricted to piriform cortex and hippocampus, while enhanced odor discrimination was independent of both GluR-B variability and transgenic GluR-B expression. Thus, correlated differences in behavior and levels of GluR-B expression allowed a mechanistic and spatial dissection of olfactory learning, discrimination, and memory capabilities.

  8. The B-cell receptor controls fitness of MYC-driven lymphoma cells via GSK3β inhibition.

    Science.gov (United States)

    Varano, Gabriele; Raffel, Simon; Sormani, Martina; Zanardi, Federica; Lonardi, Silvia; Zasada, Christin; Perucho, Laura; Petrocelli, Valentina; Haake, Andrea; Lee, Albert K; Bugatti, Mattia; Paul, Ulrike; Van Anken, Eelco; Pasqualucci, Laura; Rabadan, Raul; Siebert, Reiner; Kempa, Stefan; Ponzoni, Maurilio; Facchetti, Fabio; Rajewsky, Klaus; Casola, Stefano

    2017-06-08

    Similar to resting mature B cells, where the B-cell antigen receptor (BCR) controls cellular survival, surface BCR expression is conserved in most mature B-cell lymphomas. The identification of activating BCR mutations and the growth disadvantage upon BCR knockdown of cells of certain lymphoma entities has led to the view that BCR signalling is required for tumour cell survival. Consequently, the BCR signalling machinery has become an established target in the therapy of B-cell malignancies. Here we study the effects of BCR ablation on MYC-driven mouse B-cell lymphomas and compare them with observations in human Burkitt lymphoma. Whereas BCR ablation does not, per se, significantly affect lymphoma growth, BCR-negative (BCR - ) tumour cells rapidly disappear in the presence of their BCR-expressing (BCR + ) counterparts in vitro and in vivo. This requires neither cellular contact nor factors released by BCR + tumour cells. Instead, BCR loss induces the rewiring of central carbon metabolism, increasing the sensitivity of receptor-less lymphoma cells to nutrient restriction. The BCR attenuates glycogen synthase kinase 3 beta (GSK3β) activity to support MYC-controlled gene expression. BCR - tumour cells exhibit increased GSK3β activity and are rescued from their competitive growth disadvantage by GSK3β inhibition. BCR - lymphoma variants that restore competitive fitness normalize GSK3β activity after constitutive activation of the MAPK pathway, commonly through Ras mutations. Similarly, in Burkitt lymphoma, activating RAS mutations may propagate immunoglobulin-crippled tumour cells, which usually represent a minority of the tumour bulk. Thus, while BCR expression enhances lymphoma cell fitness, BCR-targeted therapies may profit from combinations with drugs targeting BCR - tumour cells.

  9. Dietary approaches to stop hypertension influence on insulin receptor substrate-1gene expression: A randomized controlled clinical trial

    Directory of Open Access Journals (Sweden)

    Marzieh Kafeshani

    2015-01-01

    Full Text Available Background: Insulin receptor substrate (IRS Type 1 is a main substrate for the insulin receptor, controls insulin signaling in skeletal muscle, adipose tissue, and the vascular, so it is an important candidate gene for insulin resistance (IR. We aimed to compare the effects of the Dietary Approaches to Stop Hypertension (DASH and Usual Dietary Advices (UDA on IRS1 gene expression in women at risk for cardiovascular disease. Materials and Methods: A randomized controlled clinical trial was performed in 44 women at risk for cardiovascular disease. Participants were randomly assigned to a UDA diet or the DASH diet. The DASH diet was rich in fruits, vegetables, whole grains, and low-fat dairy products and low in saturated fat, total fat, cholesterol, refined grains, and sweets, with a total of 2400 mg/day sodium. The UDA diet was a regular diet with healthy dietary advice. Gene expression was assessed by the real-time polymerase chain reaction at the first of study and after 12 weeks. Independent sample t-test and paired-samples t-test were used to compare means of all variables within and between two groups respectively. Results: IRS1 gene expression was increased in DASH group compared with UDA diet (P = 0.00. Weight and waist circumference decreased in DASH group significantly compared to the UDA group (P < 0.05 but the results between the two groups showed no significant difference. Conclusion: DASH diet increased IRS1 gene expression and probably has beneficial effects on IR risks.

  10. Association of estrogen receptor beta variants and serum levels of estradiol with risk of colorectal cancer: a case control study

    Directory of Open Access Journals (Sweden)

    Wu Huanlei

    2012-07-01

    Full Text Available Abstract Background Endogenous estrogens may play a vital role in colorectal tumorigenesis. Estrogen receptor beta is the predominant subtype which mediates the biological effect of estrogens, while loss of expression of estrogen receptor beta has been indicated as a common step in the development of colorectal cancer (CRC. Epidemiological studies have revealed several functional polymorphisms of estrogen receptor beta (ESR2 for cancer risk, but relevant study in CRC is limited, particularly in men. This study aimed to investigate the association of circulating estradiol and variations of ESR2 with CRC risk in men. Methods We initiated a case–control study consisting of 390 patients with CRC and 445 healthy controls in men only. We genotyped ESR2 single nucleotide polymorphisms (SNPs rs1256049 and rs4986938 and measured serum estradiol concentration using chemilluminescence immunoassay. Multivariable logistic regression model was performed to evaluate the associations between these variables and CRC risk. Results ESR2 rs1256049 CT/TT genotypes were associated with reduced risk of CRC (odds ratio [OR], 0.7, 95% confidence interval [CI], 0.5–1.0, while rs4986938 CT/TT genotypes were associated with increased risk of CRC (OR, 1.5, 95% CI, 1.0–2.1. In addition, the CRC risk increased with the number of risk genotypes of these two SNPs in a dose–response manner (Ptrend, 0.003. Specifically, subjects carrying risk genotypes of both SNPs had the highest risk of CRC (OR, 2.0, 95% CI, 1.3–3.3.. Moreover, serum estradiol concentration alone was associated with risk of CRC in men (OR, 1.2, 95% CI, 1.0–1.3. However, individuals presenting both rs4986938 CT/TT genotypes and high level of serum estradiol had a high risk of CRC (OR, 2.3, 95% CI, 1.4–3.9, compared with those presenting CC genotype and low level of serum estradiol. The similar joint results were not observed for SNP rs1256049. Conclusions These results suggest that endogenous

  11. Night work and breast cancer risk defined by human epidermal growth factor receptor-2 (HER2) and hormone receptor status: A population-based case-control study in France.

    Science.gov (United States)

    Cordina-Duverger, Emilie; Koudou, Yves; Truong, Thérèse; Arveux, Patrick; Kerbrat, Pierre; Menegaux, Florence; Guénel, Pascal

    Night work has been associated with risk of breast cancer but this association needs to be confirmed. Because breast cancer is an etiologically heterogeneous disease, we explored the association of night work with breast cancer subtypes defined by tumor status (positive of negative) for estrogen-receptor (ER), progesterone-receptor (PR) and human epidermal growth factor-receptor 2 (HER2). Using the data from a case-control study in France including 975 cases and 1317 controls, we found that the odds ratios for ER+, PR+ or HER2+ breast cancers subtypes were significantly elevated, while no association with night shift work was observed for ER, PR or HER2-negative tumors. After stratification by menopausal status, the associations of night work with receptor-positive breast tumor subtypes were clearly seen in premenopausal women (odds ratios 2.04, 1.98 and 2.80, respectively) but did not appear in postmenopausal women. This study provides evidence that working at night may increase risk of ER, PR and HER2-positive subtypes of breast cancer particularly among premenopausal women.

  12. Insulin receptors

    International Nuclear Information System (INIS)

    Kahn, C.R.; Harrison, L.C.

    1988-01-01

    This book contains the proceedings on insulin receptors. Part A: Methods for the study of structure and function. Topics covered include: Method for purification and labeling of insulin receptors, the insulin receptor kinase, and insulin receptors on special tissues

  13. Gating characteristics control glutamate receptor distribution and trafficking in vivo.

    Science.gov (United States)

    Petzoldt, Astrid G; Lee, Yü-Hien; Khorramshahi, Omid; Reynolds, Eric; Plested, Andrew J R; Herzel, Hanspeter; Sigrist, Stephan J

    2014-09-08

    Glutamate-releasing synapses dominate excitatory release in the brain. Mechanisms governing their assembly are of major importance for circuit development and long-term plasticity underlying learning and memory. AMPA/Kainate-type glutamate receptors (GluRs) are tetrameric ligand-gated ion channels that open their ion-conducting pores in response to binding of the neurotransmitter. Changes in subunit composition of postsynaptic GluRs are highly relevant for plasticity and development of glutamatergic synapses [1-4]. To date, posttranslational modifications, mostly operating via the intracellular C-terminal domains (CTDs) of GluRs, are presumed to be the major regulator of trafficking [5]. In recent years, structural and electrophysiological analyses have improved our understanding of GluR gating mechanism [6-11]. However, whether conformational changes subsequent to glutamate binding may per se be able to influence GluR trafficking has remained an unaddressed question. Using a Drosophila system allowing for extended visualization of GluR trafficking in vivo, we here provide evidence that mutations changing the gating behavior alter GluR distribution and trafficking. GluR mutants associated with reduced charge transfer segregated from coexpressed wild-type GluRs on the level of individual postsynaptic densities. Segregation was lost upon blocking of evoked glutamate release. Photobleaching experiments suggested increased mobility of mutants with reduced charge transfer, which accumulated prematurely during early steps of synapse assembly, but failed to further increase their level in accordance with assembly of the presynaptic scaffold. In summary, gating characteristics seem to be a new variable for the understanding of GluR trafficking relevant to both development and plasticity. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. Ryanodine receptor gating controls generation of diastolic calcium waves in cardiac myocytes

    Science.gov (United States)

    Petrovič, Pavol; Valent, Ivan; Cocherová, Elena; Pavelková, Jana

    2015-01-01

    The role of cardiac ryanodine receptor (RyR) gating in the initiation and propagation of calcium waves was investigated using a mathematical model comprising a stochastic description of RyR gating and a deterministic description of calcium diffusion and sequestration. We used a one-dimensional array of equidistantly spaced RyR clusters, representing the confocal scanning line, to simulate the formation of calcium sparks. Our model provided an excellent description of the calcium dependence of the frequency of diastolic calcium sparks and of the increased tendency for the production of calcium waves after a decrease in cytosolic calcium buffering. We developed a hypothesis relating changes in the propensity to form calcium waves to changes of RyR gating and tested it by simulation. With a realistic RyR gating model, increased ability of RyR to be activated by Ca2+ strongly increased the propensity for generation of calcium waves at low (0.05–0.1-µM) calcium concentrations but only slightly at high (0.2–0.4-µM) calcium concentrations. Changes in RyR gating altered calcium wave formation by changing the calcium sensitivity of spontaneous calcium spark activation and/or the average number of open RyRs in spontaneous calcium sparks. Gating changes that did not affect RyR activation by Ca2+ had only a weak effect on the propensity to form calcium waves, even if they strongly increased calcium spark frequency. Calcium waves induced by modulating the properties of the RyR activation site could be suppressed by inhibiting the spontaneous opening of the RyR. These data can explain the increased tendency for production of calcium waves under conditions when RyR gating is altered in cardiac diseases. PMID:26009544

  15. Prostate stromal cells express the progesterone receptor to control cancer cell mobility.

    Directory of Open Access Journals (Sweden)

    Yue Yu

    Full Text Available Reciprocal interactions between epithelium and stroma play vital roles for prostate cancer development and progression. Enhanced secretions of cytokines and growth factors by cancer associated fibroblasts in prostate tumors create a favorable microenvironment for cancer cells to grow and metastasize. Our previous work showed that the progesterone receptor (PR was expressed specifically in prostate stromal fibroblasts and smooth muscle cells. However, the expression levels of PR and its impact to tumor microenvironment in prostate tumors are poorly understood.Immunohistochemistry assays are applied to human prostate tissue biopsies. Cell migration, invasion and proliferation assays are performed using human prostate cells. Real-time PCR and ELISA are applied to measure gene expression at molecular levels.Immunohistochemistry assays showed that PR protein levels were decreased in cancer associated stroma when compared with paired normal prostate stroma. Using in vitro prostate stromal cell models, we showed that conditioned media collected from PR positive stromal cells inhibited prostate cancer cell migration and invasion, but had minor suppressive impacts on cancer cell proliferation. PR suppressed the secretion of stromal derived factor-1 (SDF-1 and interlukin-6 (IL-6 by stromal cells independent to PR ligands. Blocking PR expression by siRNA or supplementation of exogenous SDF-1 or IL-6 to conditioned media from PR positive stromal cells counteracted the inhibitory effects of PR to cancer cell migration and invasion.Decreased expression of the PR in cancer associated stroma may contribute to the elevated SDF-1 and IL-6 levels in prostate tumors and enhance prostate tumor progression.

  16. Role of medial prefrontal cortex serotonin 2A receptors in the control of retrieval of recognition memory in rats.

    Science.gov (United States)

    Bekinschtein, Pedro; Renner, Maria Constanza; Gonzalez, Maria Carolina; Weisstaub, Noelia

    2013-10-02

    Often, retrieval cues are not uniquely related to one specific memory, which could lead to memory interference. Controlling interference is particularly important during episodic memory retrieval or when remembering specific events in a spatiotemporal context. Despite a clear involvement of prefrontal cortex (PFC) in episodic memory in human studies, information regarding the mechanisms and neurotransmitter systems in PFC involved in memory is scarce. Although the serotoninergic system has been linked to PFC functionality and modulation, its role in memory processing is poorly understood. We hypothesized that the serotoninergic system in PFC, in particular the 5-HT2A receptor (5-HT2AR) could have a role in the control of memory retrieval. In this work we used different versions of the object recognition task in rats to study the role of the serotoninergic modulation in the medial PFC (mPFC) in memory retrieval. We found that blockade of 5-HT2AR in mPFC affects retrieval of an object in context memory in a spontaneous novelty preference task, while sparing single-item recognition memory. We also determined that 5-HT2ARs in mPFC are required for hippocampal-mPFC interaction during retrieval of this type of memory, suggesting that the mPFC controls the expression of memory traces stored in the hippocampus biasing retrieval to the most relevant one.

  17. Adenosine A2A Receptors Control Glutamatergic Synaptic Plasticity in Fast Spiking Interneurons of the Prefrontal Cortex

    Directory of Open Access Journals (Sweden)

    Amber Kerkhofs

    2018-03-01

    Full Text Available Adenosine A2A receptors (A2AR are activated upon increased synaptic activity to assist in the implementation of long-term plastic changes at synapses. While it is reported that A2AR are involved in the control of prefrontal cortex (PFC-dependent behavior such as working memory, reversal learning and effort-based decision making, it is not known whether A2AR control glutamatergic synapse plasticity within the medial PFC (mPFC. To elucidate that, we tested whether A2AR blockade affects long-term plasticity (LTP of excitatory post-synaptic potentials in pyramidal neurons and fast spiking (FS interneurons in layer 5 of the mPFC and of population spikes. Our results show that A2AR are enriched at mPFC synapses, where their blockade reversed the direction of plasticity at excitatory synapses onto layer 5 FS interneurons from LTP to long-term depression, while their blockade had no effect on the induction of LTP at excitatory synapses onto layer 5 pyramidal neurons. At the network level, extracellularly induced LTP of population spikes was reduced by A2AR blockade. The interneuron-specificity of A2AR in controlling glutamatergic synapse LTP may ensure that during periods of high synaptic activity, a proper excitation/inhibition balance is maintained within the mPFC.

  18. Controle de qualidade interlaboratorial em imuno-histoquímica: citoceratinas e receptor de estrógeno como modelos Interlaboratorial quality-control in immunohistochemistry: cytokeratins and estrogen receptors as models

    Directory of Open Access Journals (Sweden)

    Venâncio Avancini Ferreira Alves

    2004-06-01

    Full Text Available INTRODUÇÃO: O grande incremento do uso da imuno-histoquímica (IHQ em numerosos laboratórios de anatomia patológica amplia o poder de resolução diagnóstica, mas traz certo grau de heterogeneidade de procedimentos e resultados. Seguindo recentes propostas da literatura internacional, participantes do Clube de IHQ da Sociedade Brasileira de Patologia desenvolvem ações de controle de qualidade, aplicando protocolos de sua rotina à pesquisa de antígenos que sirvam como indicadores de qualidade da reação. MATERIAL E MÉTODO: Um total de dez laboratórios participou das duas etapas deste estudo, cujos marcadores foram pancitoceratinas e receptores de estrógeno. Com lâminas controle recebidas dos laboratórios, cada participante efetuou a técnica de IHQ conforme sua prática diária, retornando as lâminas juntamente com o formulário de procedimento. A avaliação semiquantificada de 0 a 4 da intensidade da reação específica e de 0 a 3 da coloração de fundo e da qualidade da técnica histológica foram atribuídas individual e sigilosamente durante a projeção em data show em reunião do Clube de IHQ, gerando um escore final. RESULTADOS E DISCUSSÃO: As variações na imunocoloração de citoceratinas e receptor de estrógeno não comprometeram sua detecção nas lâminas preparadas nos diversos laboratórios. Tais variações associaram-se à diversidade de sistemas de recuperação antigênica e de amplificação, resultando ora em imunopositividade menos intensa, ora em maior fundo. Outros estudos devem abordar questões de interpretação, incluindo-se critérios para semiquantificação.BACKGROUND: The expansion of the use of immunohistochemistry (IHC in numerous laboratories extends the power of diagnostic resolution, but may impart heterogeneity in procedures and results. Following recent international proposals, participants of the Club of IHC of the Brazilian Society of Pathology developed actions of quality control

  19. The CNS glucagon-like peptide-2 receptor in the control of energy balance and glucose homeostasis

    Science.gov (United States)

    2014-01-01

    The gut-brain axis plays a key role in the control of energy balance and glucose homeostasis. In response to luminal stimulation of macronutrients and microbiota-derived metabolites (secondary bile acids and short chain fatty acids), glucagon-like peptides (GLP-1 and -2) are cosecreted from endocrine L cells in the gut and coreleased from preproglucagonergic neurons in the brain stem. Glucagon-like peptides are proposed as key mediators for bariatric surgery-improved glycemic control and energy balance. Little is known about the GLP-2 receptor (Glp2r)-mediated physiological roles in the control of food intake and glucose homeostasis, yet Glp1r has been studied extensively. This review will highlight the physiological relevance of the central nervous system (CNS) Glp2r in the control of energy balance and glucose homeostasis and focuses on cellular mechanisms underlying the CNS Glp2r-mediated neural circuitry and intracellular PI3K signaling pathway. New evidence (obtained from Glp2r tissue-specific KO mice) indicates that the Glp2r in POMC neurons is essential for suppressing feeding behavior, gastrointestinal motility, and hepatic glucose production. Mice with Glp2r deletion selectively in POMC neurons exhibit hyperphagic behavior, accelerated gastric emptying, glucose intolerance, and hepatic insulin resistance. GLP-2 differentially modulates postsynaptic membrane excitability of hypothalamic POMC neurons in Glp2r- and PI3K-dependent manners. GLP-2 activates the PI3K-Akt-FoxO1 signaling pathway in POMC neurons by Glp2r-p85α interaction. Intracerebroventricular GLP-2 augments glucose tolerance, suppresses glucose production, and enhances insulin sensitivity, which require PI3K (p110α) activation in POMC neurons. Thus, the CNS Glp2r plays a physiological role in the control of food intake and glucose homeostasis. This review will also discuss key questions for future studies. PMID:24990862

  20. The GPCR membrane receptor, DopEcR, mediates the actions of both dopamine and ecdysone to control sex pheromone perception in an insect

    Directory of Open Access Journals (Sweden)

    Antoine eAbrieux

    2014-09-01

    Full Text Available Olfactory information mediating sexual behavior is crucial for reproduction in many animals, including insects. In male moths, the macroglomerular complex of the primary olfactory center, the antennal lobe (AL is specialized in the treatment of information on the female-emitted sex pheromone. Evidence is accumulating that modulation of behavioral pheromone responses occurs through neuronal plasticity via the action of hormones and/or catecholamines. We recently showed that a G-protein-coupled receptor (GPCR, AipsDopEcR, with its homologue known in Drosophila for its double affinity to the main insect steroid hormone 20-hydroxyecdysone (20E, and dopamine (DA, present in the ALs, is involved in the behavioral response to pheromone in the moth, Agrotis ipsilon. Here we tested the role of AipsDopEcR as compared to nuclear 20E receptors in central pheromone processing combining receptor inhibition with intracellular recordings of AL neurons. We show that the sensitivity of AL neurons for the pheromone in males decreases strongly after AipsDopEcR-dsRNA injection but also after inhibition of nuclear 20E receptors. Moreover we tested the involvement of 20E and DA in the receptor-mediated behavioral modulation in wind tunnel experiments, using ligand applications and receptor inhibition treatments. We show that both ligands are necessary and act on AipsDopEcR-mediated behavior. Altogether these results indicate that the GPCR membrane receptor, AipsDopEcR, controls sex pheromone perception through the action of both 20E and DA in the central nervous system, probably in concert with 20E action through nuclear receptors.

  1. Role of ionotropic GABA, glutamate and glycine receptors in the tonic and reflex control of cardiac vagal outflow in the rat

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    Goodchild Ann K

    2010-10-01

    Full Text Available Abstract Background Cardiac vagal preganglionic neurons (CVPN are responsible for the tonic, reflex and respiratory modulation of heart rate (HR. Although CVPN receive GABAergic and glutamatergic inputs, likely involved in respiratory and reflex modulation of HR respectively, little else is known regarding the functions controlled by ionotropic inputs. Activation of g-protein coupled receptors (GPCR alters these inputs, but the functional consequence is largely unknown. The present study aimed to delineate how ionotropic GABAergic, glycinergic and glutamatergic inputs contribute to the tonic and reflex control of HR and in particular determine which receptor subtypes were involved. Furthermore, we wished to establish how activation of the 5-HT1A GPCR affects tonic and reflex control of HR and what ionotropic interactions this might involve. Results Microinjection of the GABAA antagonist picrotoxin into CVPN decreased HR but did not affect baroreflex bradycardia. The glycine antagonist strychnine did not alter HR or baroreflex bradycardia. Combined microinjection of the NMDA antagonist, MK801, and AMPA antagonist, CNQX, into CVPN evoked a small bradycardia and abolished baroreflex bradycardia. MK801 attenuated whereas CNQX abolished baroreceptor bradycardia. Control intravenous injections of the 5-HT1A agonist 8-OH-DPAT evoked a small bradycardia and potentiated baroreflex bradycardia. These effects were still observed following microinjection of picrotoxin but not strychnine into CVPN. Conclusions We conclude that activation of GABAA receptors set the level of HR whereas AMPA to a greater extent than NMDA receptors elicit baroreflex changes in HR. Furthermore, activation of 5-HT1A receptors evokes bradycardia and enhances baroreflex changes in HR due to interactions with glycinergic neurons involving strychnine receptors. This study provides reference for future studies investigating how diseases alter neurochemical inputs to CVPN.

  2. Role of adenosine A2A receptor signaling in the nicotine-evoked attenuation of reflex cardiac sympathetic control

    International Nuclear Information System (INIS)

    El-Mas, Mahmoud M.; El-gowilly, Sahar M.; Fouda, Mohamed A.; Saad, Evan I.

    2011-01-01

    Baroreflex dysfunction contributes to increased cardiovascular risk in cigarette smokers. Given the importance of adenosinergic pathways in baroreflex control, the hypothesis was tested that defective central adenosinergic modulation of cardiac autonomic activity mediates the nicotine-baroreflex interaction. Baroreflex curves relating changes in heart rate (HR) to increases or decreases in blood pressure (BP) evoked by i.v. doses (1-16 μg/kg) of phenylephrine (PE) and sodium nitroprusside (SNP), respectively, were constructed in conscious rats; slopes of the curves were taken as measures of baroreflex sensitivity (BRS). Nicotine (25 and 100 μg/kg i.v.) dose-dependently reduced BRS SNP in contrast to no effect on BRS PE . BRS SNP was also attenuated after intracisternal (i.c.) administration of nicotine. Similar reductions in BRS SNP were observed in rats pretreated with atropine or propranolol. The combined treatment with nicotine and atropine produced additive inhibitory effects on BRS, an effect that was not demonstrated upon concurrent exposure to nicotine and propranolol. BRS SNP was reduced in preparations treated with i.c. 8-phenyltheophylline (8-PT, nonselective adenosine receptor antagonist), 8-(3-Chlorostyryl) caffeine (CSC, A 2A antagonist), or VUF5574 (A 3 antagonist). In contrast, BRS SNP was preserved after blockade of A 1 (DPCPX) or A 2B (alloxazine) receptors or inhibition of adenosine uptake by dipyridamole. CSC or 8-PT abrogated the BRS SNP depressant effect of nicotine whereas other adenosinergic antagonists were without effect. Together, nicotine preferentially impairs reflex tachycardia via disruption of adenosine A 2A receptor-mediated facilitation of reflex cardiac sympathoexcitation. Clinically, the attenuation by nicotine of compensatory sympathoexcitation may be detrimental in conditions such as hypothalamic defense response, posture changes, and ventricular rhythms. - Research highlights: → The role of central adenosinergic sites in

  3. P2X7 receptor drives Th1 cell differentiation and controls the follicular helper T cell population to protect against Plasmodium chabaudi malaria.

    Directory of Open Access Journals (Sweden)

    Érika Machado de Salles

    2017-08-01

    Full Text Available A complete understanding of the mechanisms underlying the acquisition of protective immunity is crucial to improve vaccine strategies to eradicate malaria. However, it is still unclear whether recognition of damage signals influences the immune response to Plasmodium infection. Adenosine triphosphate (ATP accumulates in infected erythrocytes and is released into the extracellular milieu through ion channels in the erythrocyte membrane or upon erythrocyte rupture. The P2X7 receptor senses extracellular ATP and induces CD4 T cell activation and death. Here we show that P2X7 receptor promotes T helper 1 (Th1 cell differentiation to the detriment of follicular T helper (Tfh cells during blood-stage Plasmodium chabaudi malaria. The P2X7 receptor was activated in CD4 T cells following the rupture of infected erythrocytes and these cells became highly responsive to ATP during acute infection. Moreover, mice lacking the P2X7 receptor had increased susceptibility to infection, which correlated with impaired Th1 cell differentiation. Accordingly, IL-2 and IFNγ secretion, as well as T-bet expression, critically depended on P2X7 signaling in CD4 T cells. Additionally, P2X7 receptor controlled the splenic Tfh cell population in infected mice by promoting apoptotic-like cell death. Finally, the P2X7 receptor was required to generate a balanced Th1/Tfh cell population with an improved ability to transfer parasite protection to CD4-deficient mice. This study provides a new insight into malaria immunology by showing the importance of P2X7 receptor in controlling the fine-tuning between Th1 and Tfh cell differentiation during P. chabaudi infection and thus in disease outcome.

  4. Differences in the Control of Secondary Peristalsis in the Human Esophagus: Influence of the 5-HT4 Receptor versus the TRPV1 Receptor.

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    Chih-Hsun Yi

    Full Text Available Acute administration of 5-hydroxytryptamine4 (5-HT4 receptor agonist, mosapride or esophageal infusion of the transient receptor potential vanilloid receptor-1 (TRPV1 agonist capsaicin promotes secondary peristalsis. We aimed to investigate whether acute esophageal instillation of capsaicin-containing red pepper sauce or administration of mosapride has different effects on the physiological characteristics of secondary peristalsis.Secondary peristalsis was induced with mid-esophageal air injections in 14 healthy subjects. We compared the effects on secondary peristalsis subsequent to capsaicin-containing red pepper sauce (pure capsaicin, 0.84 mg or 40 mg oral mosapride.The threshold volume for generating secondary peristalsis during slow air distensions was significantly decreased with capsaicin infusion compared to mosapride (11.6 ± 1.0 vs. 14.1 ± 0.8 mL, P = 0.02. The threshold volume required to produce secondary peristalsis during rapid air distension was also significantly decreased with capsaicin infusion (4.6 ± 0.5 vs. 5.2 ± 0.6 mL, P = 0.02. Secondary peristalsis was noted more frequently in response to rapid air distension after capsaicin infusion than mosapride (80% [60-100%] vs. 65% [5-100%], P = 0.04. Infusion of capsaicin or mosapride administration didn't change any parameters of primary or secondary peristalsis.Esophageal infusion with capsaicin-containing red pepper sauce suspension does create greater mechanosensitivity as measured by secondary peristalsis than 5-HT4 receptor agonist mosapride. Capsaicin-sensitive afferents appear to be more involved in the sensory modulation of distension-induced secondary peristalsis.

  5. The progesterone receptor antagonist, onapristone has differential effects on the timing and control of the luteolytic mechanism depending on timing of administration in sheep.

    Science.gov (United States)

    Mann, G E; Wathes, D C; Robinson, R S

    2013-08-25

    Cyclic ewes were treated with control vehicle or progesterone receptor antagonist (onapristone; 100mg i.m. twice daily) during either early (day 3-5) or late (day 12-14) luteal phase and plasma samples collected for hormone analysis and to determine endogenous and oxytocin induced PGF2α release. On day 14 and 17, ewes were euthanised and reproductive tracts collected for ovarian morphology and endometrium for oxytoxin and steroid hormone receptor analysis. Early treatment increased LH, but not progesterone or oestradiol, while late treatment elevated all three hormones. Early treatment delayed the up-regulation of endometrial oxytocin receptors and responsiveness to oxytocin challenge, delaying luteolysis. Late treatment advanced development of oxytocin receptors and responsiveness to oxytocin though not timing of luteolysis. Patterns of hormone receptor mRNA were differentially disrupted by treatments. Results provide mechanistic insight into hormonal control of the oestrous cycle and identify the ability of the luteolytic mechanism to dissociate from functional luteolysis. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  6. The distribution of cerebral muscarinic acetylcholine receptors in vivo in patients with dementia. A controlled study with 123IQNB and single photon emission computed tomography

    International Nuclear Information System (INIS)

    Weinberger, D.R.; Gibson, R.; Coppola, R.; Jones, D.W.; Molchan, S.; Sunderland, T.; Berman, K.F.; Reba, R.C.

    1991-01-01

    A high-affinity muscarinic receptor antagonist, 123IQNB (3-quinuclidinyl-4-iodobenzilate labeled with iodine 123), was used with single photon emission computed tomography to image muscarinic acetylcholine receptors in 14 patients with dementia and in 11 healthy controls. High-resolution single photon emission computed tomographic scanning was performed 21 hours after the intravenous administration of approximately 5 mCi of IQNB. In normal subjects, the images of retained ligand showed a consistent regional pattern that correlated with postmortem studies of the relative distribution of muscarinic receptors in the normal human brain, having high radioactivity counts in the basal ganglia, occipital cortex, and insular cortex, low counts in the thalamus, and virtually no counts in the cerebellum. Eight of 12 patients with a clinical diagnosis of Alzheimer's disease had obvious focal cortical defects in either frontal or posterior temporal cortex. Both patients with a clinical diagnosis of Pick's disease had obvious frontal and anterior temporal defects. A region of interest statistical analysis of relative regional activity revealed a significant reduction bilaterally in the posterior temporal cortex of the patients with Alzheimer's disease compared with controls. This study demonstrates the practicability of acetylcholine receptor imaging with 123IQNB and single photon emission computed tomography. The data suggest that focal abnormalities in muscarinic binding in vivo may characterize some patients with Alzheimer's disease and Pick's disease, but further studies are needed to address questions about partial volume artifacts and receptor quantification

  7. Control of blood pressure, appetite, and glucose by leptin in mice lacking leptin receptors in proopiomelanocortin neurons.

    Science.gov (United States)

    do Carmo, Jussara M; da Silva, Alexandre A; Cai, Zhengwei; Lin, Shuying; Dubinion, John H; Hall, John E

    2011-05-01

    Although the central nervous system melanocortin system is an important regulator of energy balance, the role of proopiomelanocortin (POMC) neurons in mediating the chronic effects of leptin on appetite, blood pressure, and glucose regulation is unknown. Using Cre/loxP technology we tested whether leptin receptor deletion in POMC neurons (LepR(flox/flox)/POMC-Cre mice) attenuates the chronic effects of leptin to increase mean arterial pressure (MAP), enhance glucose use and oxygen consumption, and reduce appetite. LepR(flox/flox)/POMC-Cre, wild-type, LepR(flox/flox), and POMC-Cre mice were instrumented for MAP and heart rate measurement by telemetry and venous catheters for infusions. LepR(flox/flox)/POMC-Cre mice were heavier, hyperglycemic, hyperinsulinemic, and hyperleptinemic compared with wild-type, LepR(flox/flox), and POMC-Cre mice. Despite exhibiting features of metabolic syndrome, LepR(flox/flox)/POMC-Cre mice had normal MAP and heart rate compared with LepR(flox/flox) but lower MAP and heart rate compared with wild-type mice. After a 5-day control period, leptin was infused (2 μg/kg per minute, IV) for 7 days. In control mice, leptin increased MAP by ≈5 mm Hg despite decreasing food intake by ≈35%. In contrast, leptin infusion in LepR(flox/flox)/POMC-Cre mice reduced MAP by ≈3 mm Hg and food intake by ≈28%. Leptin significantly decreased insulin and glucose levels in control mice but not in LepR(flox/flox)/POMC-Cre mice. Leptin increased oxygen consumption in LepR(flox/flox)/POMC-Cre and wild-type mice. Activation of POMC neurons is necessary for the chronic effects of leptin to raise MAP and reduce insulin and glucose levels, whereas leptin receptors in other areas of the brain other than POMC neurons appear to play a key role in mediating the chronic effects of leptin on appetite and oxygen consumption.

  8. A randomized controlled trial of the efficacy and safety of CCX282-B, an orally-administered blocker of chemokine receptor CCR9, for patients with Crohn's disease

    DEFF Research Database (Denmark)

    Keshav, Satish; Vaňásek, Tomáš; Niv, Yaron

    2013-01-01

    CCX282-B, also called vercirnon, is a specific, orally-administered chemokine receptor CCR9 antagonist that regulates migration and activation of inflammatory cells in the intestine. This randomized, placebo-controlled trial was conducted to evaluate the safety and efficacy of CCX282-B in 436...

  9. Epidermal growth factor receptor-induced activato protein 1 activity controls density-dependent growht inhibition in normal rat kidney fibroblasts.

    NARCIS (Netherlands)

    Hornberg, J.J.; Dekker, H.; Peters, P.H.J.; Langerak, P.; Westerhoff, H.V.; Lankelma, J.; Zoelen, E.J.J.

    2006-01-01

    Density-dependent growth inhibition secures tissue homeostasis. Dysfunction of the mechanisms, which regulate this type of growth control is a major cause of neoplasia. In confluent normal rat kidney (NRK) fibroblasts, epidermal growth factor (EGF) receptor levels decline, ultimately rendering these

  10. The gene encoding the melanin-concentrating hormone receptor 1 is associated with schizophrenia in a Danish case-control sample

    DEFF Research Database (Denmark)

    Demontis, Ditte; Nyegaard, Mette; Christensen, Jane H

    2012-01-01

    OBJECTIVE: The MCHR1 gene encoding the melanin-concentrating hormone receptor 1 is located on chromosome 22q13.2 and has previously been associated with schizophrenia in a study of cases and controls from the Faroe Islands and Scotland. Herein we report an association between variations in the MCHR...

  11. Heart rate acceleration with GLP-1 receptor agonists in type 2 diabetes patients : an acute and 12-week randomised, double-blind, placebo-controlled trial

    NARCIS (Netherlands)

    Smits, Mark M; Tonneijck, Lennart; Muskiet, Marcel H A; Hoekstra, T.; Kramer, Mark H H; Diamant, Michaela; van Raalte, Daniël H

    OBJECTIVE: To examine mechanisms underlying resting heart rate (RHR) increments of GLP-1 receptor agonists in type 2 diabetes patients. DESIGN: Acute and 12-week randomised, placebo-controlled, double-blind, single-centre, parallel-group trial. METHODS: In total, 57 type 2 diabetes patients

  12. RECOMBINANT HUMAN INTERLEUKIN-1 RECEPTOR ANTAGONIST IN THE TREATMENT OF PATIENTS WITH SEPSIS SYNDROME - RESULTS FROM A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL

    NARCIS (Netherlands)

    FISHER, C. J.; DHAINAUT, J. F. A.; Opal, S. M.; Pribble, J. P.; BALK, R. A.; SLOTMAN, G. J.; IBERTI, T. J.; RACKOW, E. C.; SHAPIRO, M. J.; GREENMAN, R. L.; REINES, H. D.; SHELLY, M. P.; THOMPSON, B. W.; LABRECQUE, J. F.; Catalano, M. A.; KNAUS, W. A.; Sadoff, J. C.; ASTIZ, M.; CARPATI, C.; BONE, R. C.; FREIDMAN, B.; MURE, A. J.; BRATHWAITE, C.; SHAPIRO, E.; MELHORN, L.; TAYLOR, R.; KEEGAN, M.; OBRIEN, J.; SCHEIN, R.; PENA, M.; WASSERLOUF, M.; OROPELLO, J.; BENJAMIN, E.; DELGUIDICE, R.; EMMANUEL, G.; LIE, T.; Anderson, L.; Marshall, J.; DEMAJO, W.; ROTSTEIN, O.; FOSTER, D.; Abraham, E.; MIDDLETON, H.; Perry, C.; LEVY, H.; FRY, D. E.; SIMPSON, S. Q.; CROWELL, R. E.; Neidhart, M.; Stevens, D.; COFFMAN, T.; NARASIMHAM, N.; MERRICK, D. K.; BERGQUIST, W.; MATZEL, K. E.; HUEBLER, M.; Foulke, G. E.; ALBERTSON, T. E.; WALBY, W. F.; ALLEN, R. P.; Baughman, R.; HASSELGREN, P. O.; Fink, M. P.; FAVORITO, F.; THOMPSON, B. T.; CORBIN, R.; SHELLHORSE, G. Y.; FRAZIER, A.; White, S.; GARRARD, C.; ACOURT, C.; STORER, S.; GERVICH, D. H.; FOSHE, D.; BRASE, R.; BAGDAHN, A.; COONEY, R.; Smith, J. S.; MARTIN, L. F.; Vincent, J. L.; Friedman, G.; Berlot, G.; FLETCHER, J. R.; WILLIAMS, M. D.; WRIGHT, T. F.; Johnson, S.; FEILD, C.; WOLF, K.; MACINTYRE, N.; DUBIN, H. G.; DURKIN, M. R.; DUBIN, P. K.; STAUBACH, K. H.; FEIN, A. M.; SCHULMAN, D. B.; NIEDERMAN, M. S.; CHALFIN, D. B.; van Leeuwen, P. A. M.; Boermeester, M. A.; Schneider, A. J.; BANDER, J.; IMM, A.; BERNARD, G.; Nelson, L.; Stroud, M.; SAFCSAK, K.; CERRA, F.; RINDAL, J.; Mann, H.; HALPERN, N.; SILVERSTEIN, J.; ALICEA, M.; Sibbald, W. J.; MARTIN, C. M.; RUTLEDGE, F. S.; PETTI, K.; RUSSELL, J. A.; KRUGER, R.; DRUMMOND, A.; LANGE, P.; SEIFERT, T.; DUROCHER, A.; TENAILLON, A.; BOITEAU, R.; LHERM, T.; Lowry, S. F.; Coyle, S. M.; Barie, P. S.; DEMARIA, E.; SNYDMAN, D. R.; SCHWAITZBERG, S. D.; NASRAWAY, S. A.; GRINDLINGER, J.; SUMMER, W.; DEBOISBLANC, B.; WAHL, M.; ALESTIG, K.; GROSSMAN, J.; MAKI, D.; PAZ, H. L.; Weiner, M.; BIHARI, D.; Campbell, D.; BLEICHNER, G.; DAHN, M. S.; LANGE, M. P. A.; Hall, J.; POHLMAN, A.; WENZEL, R. P.; GROSSERODE, M.; COSTIGAN, M.; MILESKI, W.; WEIGELT, J.; YESTON, N.; IRIZARRY, C.; Ross, J.; ROBBINS, J.; NIGHTINGALE, P.; OWEN, K.; SANDSTEDT, S.; Berg, S.; SIMON, G. L.; SENEFF, M. G.; CONRY, K. M.; ZIMMERMAN, J. L.; Dellinger, R. P.; Johnston, R.; ALLEE, P.; GRANDE, P. O.; MYHRE, E.; DHAINAUT, J. F.; HAMY, I.; Mira, J. P.; HARMON, J.; White, J.; MCKIE, L.; SILVERMAN, H.; TUMA, P.; Bennett, D.; PORTER, J. C.; LAURELL, M. H.; Jacobs, S.; ASH, S.; Stiles, D. M.; PRIOR, M. J.; KNATTERUD, G.; TERRIN, M.; KUFERA, J.; WILKENS, P.; RA, K.; MONROE, L.; SPRUNG, C.; HAMILTON, C. M.; MATTHAY, R.; MCCABE, W.; TONASCIA, J.; WIEDEMAN, H.; Wittes, J.; CAMPION, G. V.; CROFT, C. R.; LUSTICK, R.; LOOKABAUGH, J.; GORDON, G. S.; NOE, L.; BLOEDOW, D.; SMITH, C. G.; BRANNON, D.; KUSH, R.; NG, D.; MOORE, E.; BAZEMORE, K.; GALVAN, M.; Wagner, D.; HARRELL, F.; STABLEIN, D.

    1994-01-01

    Objective.-To further define the safety and efficacy of recombinant human interleukin 1 receptor antagonist (rhlL-1ra) in the treatment of sepsis syndrome. Study Design.-Randomized, double-blind, placebo-controlled, multicenter, multinational clinical trial. Population.-A total of 893 patients with

  13. The autonomic nervous system and cardiac GLP-1 receptors control heart rate in mice

    Directory of Open Access Journals (Sweden)

    Laurie L. Baggio

    2017-11-01

    Conclusions: GLP-1R agonists increase HR through multiple mechanisms, including regulation of autonomic nervous system function, and activation of the atrial GLP-1R. Surprisingly, the isolated atrial GLP-1R does not transduce a direct chronotropic effect following exposure to GLP-1R agonists in the intact heart, or isolated atrium, ex vivo. Hence, cardiac GLP-1R circuits controlling HR require neural inputs and do not function in a heart-autonomous manner.

  14. Low serum vitamin D levels and anti-N-methyl-d-aspartate receptor encephalitis: A case-control study.

    Science.gov (United States)

    Shu, Yaqing; Su, Qingmei; Liao, Siyuan; Lu, Tingting; Li, Rui; Sun, Xiaobo; Qiu, Wei; Yang, Yu; Hu, Xueqiang; Lu, Zhengqi

    2017-01-01

    Low vitamin D levels are associated with autoimmunity, but the relationship with anti-N-Methyl-d-aspartate receptor (anti-NMDAR) encephalitis is unknown. 25(OH) D levels and clinical and cerebrospinal fluid parameters were evaluated in 30 patients with anti-NMDAR encephalitis and compared with 90 age-, sex-, and season-matched healthy controls. 25(OH)D levels were lower in patients with anti-NMDAR encephalitis compared to controls (43.89 ± 17.91 vs 64.24 ± 24.38 nmol/L, p  30 years, p = 0.002), severe impairment (mRS ≥ 5) (vs mRS D levels were associated with age (r = 0.393, p = 0.032), and mRS (r = -0.417, p = 0.022). Our data showed that serum 25(OH)D levels were reduced in patients with anti-NMDAR encephalitis. Copyright © 2016. Published by Elsevier Ltd.

  15. Toll-Like Receptors 2 and 4 Cooperate in the Control of the Emerging Pathogen Brucella microti.

    Science.gov (United States)

    Arias, Maykel A; Santiago, Llipsy; Costas-Ramon, Santiago; Jaime-Sánchez, Paula; Freudenberg, Marina; Jiménez De Bagüés, Maria P; Pardo, Julián

    2016-01-01

    Toll-like receptors (TLRs) recognize pathogen-derived molecules and play a critical role during the host innate and adaptive immune response. Brucella spp. are intracellular gram-negative bacteria including several virulent species, which cause a chronic zoonotic infection in a wide range of mammalian hosts known as brucellosis. A new Brucella species, Brucella microti , was recently isolated from wild rodents and found to be highly pathogenic in mice. Using this species-specific model, it was previously found that CD8 + T cells are required to control this infection. In order to find out the role of TLR-mediated responses in the control of this pathogen, the course of infection of B. microti was analyzed over 3 weeks in wild-type (WT) and TLR knock out (KO) mice including TLR2 -/- , TLR4 -/- , TLR9 -/- , TLR2×4 -/- and TLR2×4×9 -/- . WT and single TLR2, TLR4 and TLR9 KO mice similarly control infection in liver and spleen. In contrast, bacterial clearance was delayed in TLR2×4 -/- and TLR2×4×9 -/- mice at 7 and 14 days post-infection. This defect correlated with impaired maturation and pro-inflammatory cytokine production in B. microti -infected dendritic cells from TLR2×4 -/- and TLR2×4×9 -/- mice. Finally, it was found that Tc cells from TLR2×4 -/- and TLR2×4×9 -/- mice showed reduced ability to inhibit growth of B. microti in macrophages, suggesting the involvement of TLR2 and 4 in the generation of specific Tc cells. Our findings indicate that TLR2 and TLR4 are required to control B. microti infection in mice and that this effect could be related to its participation in the maturation of dendritic cells and the generation of specific CD8 + Tc cells.

  16. Enhanced Androgen Signaling with Androgen Receptor Overexpression in the Osteoblast Lineage Controls Skeletal Turnover, Matrix Quality and Bone Architecture

    Science.gov (United States)

    2009-12-01

    Fu , M. , and Pestell , R. ( 2006 ). Epigenetic regulation of nuclear steroid receptors . Biochem. Pharmacol. 72 , 1589 – 1596...2006;38:1289–1297. 21. Leader J, Wang C, Fu M, Pestell R. Epigenetic regulation of nuclear steroid receptors. Biochem Pharmacol 2006;72:1589–1596. 22...Nat Genet 2006;38:1289-97. 21. Leader J, Wang C, Fu M, Pestell R. Epigenetic regulation of nuclear steroid receptors. Biochem Pharmacol 2006;72

  17. PCA3 noncoding RNA is involved in the control of prostate-cancer cell survival and modulates androgen receptor signaling

    International Nuclear Information System (INIS)

    Ferreira, Luciana Bueno; Gimba, Etel Rodrigues Pereira; Palumbo, Antonio; Mello, Kivvi Duarte de; Sternberg, Cinthya; Caetano, Mauricio S; Oliveira, Felipe Leite de; Neves, Adriana Freitas; Nasciutti, Luiz Eurico; Goulart, Luiz Ricardo

    2012-01-01

    PCA3 is a non-coding RNA (ncRNA) that is highly expressed in prostate cancer (PCa) cells, but its functional role is unknown. To investigate its putative function in PCa biology, we used gene expression knockdown by small interference RNA, and also analyzed its involvement in androgen receptor (AR) signaling. LNCaP and PC3 cells were used as in vitro models for these functional assays, and three different siRNA sequences were specifically designed to target PCA3 exon 4. Transfected cells were analyzed by real-time qRT-PCR and cell growth, viability, and apoptosis assays. Associations between PCA3 and the androgen-receptor (AR) signaling pathway were investigated by treating LNCaP cells with 100 nM dihydrotestosterone (DHT) and with its antagonist (flutamide), and analyzing the expression of some AR-modulated genes (TMPRSS2, NDRG1, GREB1, PSA, AR, FGF8, CdK1, CdK2 and PMEPA1). PCA3 expression levels were investigated in different cell compartments by using differential centrifugation and qRT-PCR. LNCaP siPCA3-transfected cells significantly inhibited cell growth and viability, and increased the proportion of cells in the sub G0/G1 phase of the cell cycle and the percentage of pyknotic nuclei, compared to those transfected with scramble siRNA (siSCr)-transfected cells. DHT-treated LNCaP cells induced a significant upregulation of PCA3 expression, which was reversed by flutamide. In siPCA3/LNCaP-transfected cells, the expression of AR target genes was downregulated compared to siSCr-transfected cells. The siPCA3 transfection also counteracted DHT stimulatory effects on the AR signaling cascade, significantly downregulating expression of the AR target gene. Analysis of PCA3 expression in different cell compartments provided evidence that the main functional roles of PCA3 occur in the nuclei and microsomal cell fractions. Our findings suggest that the ncRNA PCA3 is involved in the control of PCa cell survival, in part through modulating AR signaling, which may raise new

  18. Alterations in the steroid hormone receptor co-chaperone FKBPL are associated with male infertility: a case-control study

    LENUS (Irish Health Repository)

    Sunnotel, Olaf

    2010-03-08

    Abstract Background Male infertility is a common cause of reproductive failure in humans. In mice, targeted deletions of the genes coding for FKBP6 or FKBP52, members of the FK506 binding protein family, can result in male infertility. In the case of FKBP52, this reflects an important role in potentiating Androgen Receptor (AR) signalling in the prostate and accessory glands, but not the testis. In infertile men, no mutations of FKBP52 or FKBP6 have been found so far, but the gene for FKBP-like (FKBPL) maps to chromosome 6p21.3, an area linked to azoospermia in a group of Japanese patients. Methods To determine whether mutations in FKBPL could contribute to the azoospermic phenotype, we examined expression in mouse and human tissues by RNA array blot, RT-PCR and immunohistochemistry and sequenced the complete gene from two azoospermic patient cohorts and matching control groups. FKBPL-AR interaction was assayed using reporter constructs in vitro. Results FKBPL is strongly expressed in mouse testis, with expression upregulated at puberty. The protein is expressed in human testis in a pattern similar to FKBP52 and also enhanced AR transcriptional activity in reporter assays. We examined sixty patients from the Japanese patient group and found one inactivating mutation and one coding change, as well as a number of non-coding changes, all absent in fifty-six controls. A second, Irish patient cohort of thirty showed another two coding changes not present in thirty proven fertile controls. Conclusions Our results describe the first alterations in the gene for FKBPL in azoospermic patients and indicate a potential role in AR-mediated signalling in the testis.

  19. Alterations in the steroid hormone receptor co-chaperone FKBPL are associated with male infertility: a case-control study

    Directory of Open Access Journals (Sweden)

    Barton David

    2010-03-01

    Full Text Available Abstract Background Male infertility is a common cause of reproductive failure in humans. In mice, targeted deletions of the genes coding for FKBP6 or FKBP52, members of the FK506 binding protein family, can result in male infertility. In the case of FKBP52, this reflects an important role in potentiating Androgen Receptor (AR signalling in the prostate and accessory glands, but not the testis. In infertile men, no mutations of FKBP52 or FKBP6 have been found so far, but the gene for FKBP-like (FKBPL maps to chromosome 6p21.3, an area linked to azoospermia in a group of Japanese patients. Methods To determine whether mutations in FKBPL could contribute to the azoospermic phenotype, we examined expression in mouse and human tissues by RNA array blot, RT-PCR and immunohistochemistry and sequenced the complete gene from two azoospermic patient cohorts and matching control groups. FKBPL-AR interaction was assayed using reporter constructs in vitro. Results FKBPL is strongly expressed in mouse testis, with expression upregulated at puberty. The protein is expressed in human testis in a pattern similar to FKBP52 and also enhanced AR transcriptional activity in reporter assays. We examined sixty patients from the Japanese patient group and found one inactivating mutation and one coding change, as well as a number of non-coding changes, all absent in fifty-six controls. A second, Irish patient cohort of thirty showed another two coding changes not present in thirty proven fertile controls. Conclusions Our results describe the first alterations in the gene for FKBPL in azoospermic patients and indicate a potential role in AR-mediated signalling in the testis.

  20. Genetic analysis of the vitamin D receptor gene in two epithelial cancers: melanoma and breast cancer case-control studies

    International Nuclear Information System (INIS)

    Barroso, Eva; Arias, Jose I; Zamora, Pilar; Blanco, Monserrat; Lazaro, Pablo; Benitez, Javier; Ribas, Gloria; Fernandez, Lara P; Milne, Roger L; Pita, Guillermo; Sendagorta, Elena; Floristan, Uxua; Feito, Marta; Aviles, Jose A; Martin-Gonzalez, Manuel

    2008-01-01

    Vitamin D serum levels have been found to be related to sun exposure and diet, together with cell differentiation, growth control and consequently, cancer risk. Vitamin D receptor (VDR) genotypes may influence cancer risk; however, no epidemiological studies in sporadic breast cancer (BC) or malignant melanoma (MM) have been performed in a southern European population. In this study, the VDR gene has been evaluated in two epithelial cancers BC and MM. We have conducted an analysis in 549 consecutive and non-related sporadic BC cases and 556 controls, all from the Spanish population, and 283 MM cases and 245 controls. Genotyping analyses were carried out on four putatively functional SNPs within the VDR gene. An association with the minor allele A of the non-synonymous SNP rs2228570 (rs10735810, FokI, Met1Thr) was observed for BC, with an estimated odds ratio (OR) of 1.26 (95% CI = 1.02–1.57; p = 0.036). The synonymous variant rs731236 (TaqI) appeared to be associated with protection from BC (OR = 0.80, 95%CI = 0.64–0.99; p = 0.047). No statistically significant associations with MM were observed for any SNP. Nevertheless, sub-group analyses revealed an association between rs2228570 (FokI) and absence of childhood sunburns (OR = 0.65, p = 0.003), between the 3'utr SNP rs739837 (BglI) and fair skin (OR = 1.31, p = 0.048), and between the promoter SNP rs4516035 and the more aggressive tumour location in head-neck and trunk (OR = 1.54, p = 0.020). In summary, we observed associations between SNPs in the VDR gene and BC risk, and a comprehensive analysis using clinical and tumour characteristics as outcome variables has revealed potential associations with MM. These associations required confirmation in independent studies

  1. Tumor necrosis factor (TNF) receptor shedding controls thresholds of innate immune activation that balance opposing TNF functions in infectious and inflammatory diseases

    DEFF Research Database (Denmark)

    Xanthoulea, Sofia; Pasparakis, Manolis; Kousteni, Stavroula

    2004-01-01

    Tumor necrosis factor (TNF) is a potent cytokine exerting critical functions in the activation and regulation of immune and inflammatory responses. Due to its pleiotropic activities, the amplitude and duration of TNF function must be tightly regulated. One of the mechanisms that may have evolved...... to modulate TNF function is the proteolytic cleavage of its cell surface receptors. In humans, mutations affecting shedding of the p55TNF receptor (R) have been linked with the development of the TNFR-associated periodic syndromes, disorders characterized by recurrent fever attacks and localized inflammation....... Here we show that knock-in mice expressing a mutated nonsheddable p55TNFR develop Toll-like receptor-dependent innate immune hyperreactivity, which renders their immune system more efficient at controlling intracellular bacterial infections. Notably, gain of function for antibacterial host defenses...

  2. Significance of ACTH4-10 in the control of hippocampal corticosterone receptor capacity of hypophysectomized rats

    NARCIS (Netherlands)

    Veldhuis, H D; De Kloet, E R

    1982-01-01

    The effect of hypophysectomy on the number of corticosterone receptor sites was investigated in three rat brain regions and was compared with the effect of long-term adrenalectomy. Subsequently, the effect on receptor capacity was measured after the hypophysectomized rats had received as

  3. Autonomous control of phosphatidylinositol turnover by histamine and acetylcholine receptors in the NIE-115 neuron-like cell line

    International Nuclear Information System (INIS)

    Large, T.H.; Lambert, M.P.; Cohen, N.M.; Klein, W.L.

    1986-01-01

    Histamine was found to stimulate the turnover of phosphatidylinositol (PI) in cultures of neuron-like NE-115 cells. Turnover was measured by increased production of ( 3 H)inositol phosphates (breakdown) and by accelerated incorporation of 32 P into PI (resynthesis). Data were consistent with hydrolysis of polyphosphoinositides being the initial event in receptor-stimulated PI turnover. This response to histamine desensitized within 10 min. Receptor systems for histamine and acetylcholine were tested for possible interactions: PI turnover in response to dual stimulation was approximately equal to the sum of the individual responses while prior desensitization of the acetylcholine receptor system had no effect on subsequent stimulation of the histamine receptor system. These results are consistent with the hypothesis that components of acetylcholine and histamine receptor systems responsible for PI turnover are autonomously organised and regulated. (author)

  4. Sexual dimorphism in the volume of song control nuclei in European starlings: assessment by a Nissl stain and autoradiography for muscarinic cholinergic receptors.

    Science.gov (United States)

    Bernard, D J; Casto, J M; Ball, G F

    1993-08-22

    Previous studies have found that the volume of several song control nuclei is larger in male songbirds than in female songbirds. The degree of this volumetric sex difference within a given species appears to be systematically related to the degree of the behavioral sex difference. The largest volumetric differences have been reported in species in which the male sings and the female sings little, if at all, and the smallest sex differences in volume have been reported in species in which males and females both sing in nearly equal amounts. We compared the volume of three song control nuclei in male and female European starlings (Sturnus vulgaris), a species in which females are known to sing, though at a much lower rate than males. We investigated the volume of hyperstriatum ventrale, pars caudale, nucleus robustus archistriatalis, and area X of the lobus parolfactorius as defined with the use of a Nissl stain. In addition, we measured the volume of area X as defined by the density of muscarinic cholinergic receptors visualized by in vitro receptor autoradiographic methods. The volumes of all three of the song nuclei, as defined by Nissl staining, are significantly larger in males than in females. For area X, Nissl staining and receptor autoradiography indicate the same significant volumetric sex difference. The three nuclei are approximately one and one half to two times larger in males than in females, a degree of dimorphism that is intermediate to those reported for other species. Previous investigations of sex differences in the avian vocal control system have used only Nissl stains to define nuclear volumes. We demonstrate in this paper that receptor autoradiography can be used to assess dimorphisms in nuclear volume. Broad application of this approach to a number of neurotransmitter receptor systems will better characterize the dimorphisms in the song system, and therefore will provide greater insight into the neuroanatomical and neurochemical control of

  5. A Novel Mechanism of Androgen Receptor Action

    National Research Council Canada - National Science Library

    Roberts, Jr, Charles T

    2006-01-01

    .... Specifically, the authors had determined that the androgen receptor controls the expression of the cell-surface receptor for the hormone IGF-1 at the level of translation of the IGF-1 receptor mRNA...

  6. Artery Tertiary Lymphoid Organs Control Aorta Immunity and Protect against Atherosclerosis via Vascular Smooth Muscle Cell Lymphotoxin β Receptors

    Science.gov (United States)

    Hu, Desheng; Mohanta, Sarajo K.; Yin, Changjun; Peng, Li; Ma, Zhe; Srikakulapu, Prasad; Grassia, Gianluca; MacRitchie, Neil; Dever, Gary; Gordon, Peter; Burton, Francis L.; Ialenti, Armando; Sabir, Suleman R.; McInnes, Iain B.; Brewer, James M.; Garside, Paul; Weber, Christian; Lehmann, Thomas; Teupser, Daniel; Habenicht, Livia; Beer, Michael; Grabner, Rolf; Maffia, Pasquale; Weih, Falk; Habenicht, Andreas J.R.

    2015-01-01

    Summary Tertiary lymphoid organs (TLOs) emerge during nonresolving peripheral inflammation, but their impact on disease progression remains unknown. We have found in aged Apoe−/− mice that artery TLOs (ATLOs) controlled highly territorialized aorta T cell responses. ATLOs promoted T cell recruitment, primed CD4+ T cells, generated CD4+, CD8+, T regulatory (Treg) effector and central memory cells, converted naive CD4+ T cells into induced Treg cells, and presented antigen by an unusual set of dendritic cells and B cells. Meanwhile, vascular smooth muscle cell lymphotoxin β receptors (VSMC-LTβRs) protected against atherosclerosis by maintaining structure, cellularity, and size of ATLOs though VSMC-LTβRs did not affect secondary lymphoid organs: Atherosclerosis was markedly exacerbated in Apoe−/−Ltbr−/− and to a similar extent in aged Apoe−/−Ltbrfl/flTagln-cre mice. These data support the conclusion that the immune system employs ATLOs to organize aorta T cell homeostasis during aging and that VSMC-LTβRs participate in atherosclerosis protection via ATLOs. PMID:26084025

  7. Lithocholic acid controls adaptive immune responses by inhibition of Th1 activation through the Vitamin D receptor.

    Science.gov (United States)

    Pols, Thijs W H; Puchner, Teresa; Korkmaz, H Inci; Vos, Mariska; Soeters, Maarten R; de Vries, Carlie J M

    2017-01-01

    Bile acids are established signaling molecules next to their role in the intestinal emulsification and uptake of lipids. We here aimed to identify a potential interaction between bile acids and CD4+ Th cells, which are central in adaptive immune responses. We screened distinct bile acid species for their potency to affect T cell function. Primary human and mouse CD4+ Th cells as well as Jurkat T cells were used to gain insight into the mechanism underlying these effects. We found that unconjugated lithocholic acid (LCA) impedes Th1 activation as measured by i) decreased production of the Th1 cytokines IFNγ and TNFαα, ii) decreased expression of the Th1 genes T-box protein expressed in T cells (T-bet), Stat-1 and Stat4, and iii) decreased STAT1α/β phosphorylation. Importantly, we observed that LCA impairs Th1 activation at physiological relevant concentrations. Profiling of MAPK signaling pathways in Jurkat T cells uncovered an inhibition of ERK-1/2 phosphorylation upon LCA exposure, which could provide an explanation for the impaired Th1 activation. LCA induces these effects via Vitamin D receptor (VDR) signaling since VDR RNA silencing abrogated these effects. These data reveal for the first time that LCA controls adaptive immunity via inhibition of Th1 activation. Many factors influence LCA levels, including bile acid-based drugs and gut microbiota. Our data may suggest that these factors also impact on adaptive immunity via a yet unrecognized LCA-Th cell axis.

  8. Polymorphisms of genes coding for ghrelin and its receptor in relation to colorectal cancer risk: a two-step gene-wide case-control study.

    Science.gov (United States)

    Campa, Daniele; Pardini, Barbara; Naccarati, Alessio; Vodickova, Ludmila; Novotny, Jan; Steinke, Verena; Rahner, Nils; Holinski-Feder, Elke; Morak, Monika; Schackert, Hans K; Görgens, Heike; Kötting, Judith; Betz, Beate; Kloor, Matthias; Engel, Christoph; Büttner, Reinhard; Propping, Peter; Försti, Asta; Hemminki, Kari; Barale, Roberto; Vodicka, Pavel; Canzian, Federico

    2010-09-28

    Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor (GHSR), has two major functions: the stimulation of the growth hormone production and the stimulation of food intake. Accumulating evidence also indicates a role of ghrelin in cancer development. We conducted a case-control study to examine the association of common genetic variants in the genes coding for ghrelin (GHRL) and its receptor (GHSR) with colorectal cancer risk. Pairwise tagging was used to select the 11 polymorphisms included in the study. The selected polymorphisms were genotyped in 680 cases and 593 controls from the Czech Republic. We found two SNPs associated with lower risk of colorectal cancer, namely SNPs rs27647 and rs35683. We replicated the two hits, in additional 569 cases and 726 controls from Germany. A joint analysis of the two populations indicated that the T allele of rs27647 SNP exerted a protective borderline effect (Ptrend = 0.004).

  9. mRNA expression of 5-hydroxytryptamine 1B, 1D, and 1F receptors and their role in controlling the release of calcitonin gene-related peptide in the rat trigeminovascular system

    DEFF Research Database (Denmark)

    Amrutkar, Dipak V; Ploug, Kenneth B; Hay-Schmidt, Anders

    2012-01-01

    Triptans, a family of 5-hydroxytryptamine (5-HT) 1B, 1D, and 1F receptor agonists, are used in the acute treatment of migraine attacks. The site of action and subtypes of the 5-HT(1) receptor that mediate the antimigraine effect have still to be identified. This study investigated the mRNA expres......Triptans, a family of 5-hydroxytryptamine (5-HT) 1B, 1D, and 1F receptor agonists, are used in the acute treatment of migraine attacks. The site of action and subtypes of the 5-HT(1) receptor that mediate the antimigraine effect have still to be identified. This study investigated the m......RNA expression of these receptors and the role of 5-HT(1) receptor subtypes in controlling the release of calcitonin gene-related peptide (CGRP) in rat dura mater, trigeminal ganglion (TG), and trigeminal nucleus caudalis (TNC). The mRNA for each receptor subtype was quantified by quantitative real...

  10. Association of nicotinic acetylcholine receptors with central respiratory control in isolated brainstem-spinal cord preparation of neonatal rats

    Directory of Open Access Journals (Sweden)

    EIKI HATORI

    2006-01-01

    Full Text Available Nicotine exposure is a risk factor in several breathing disorders Nicotinic acetylcholine receptors (nAChRs exist in the ventrolateral medulla, an important site for respiratory control. We examined the effects of nicotinic acetylcholine neurotransmission on central respiratory control by addition of a nAChR agonist or one of various antagonists into superfusion medium in the isolated brainstem-spinal cord from neonatal rats. Ventral C4 neuronal activity was monitored as central respiratory output, and activities of respiratory neurons in the ventrolateral medulla were recorded in whole-cell configuration. RJR-2403 (0.1-10mM, alpha4beta2 nAChR agonist induced dose-dependent increases in respiratory frequency. Non-selective nAChR antagonist mecamylamine (0.1-100mM, alpha4beta2 antagonist dihydro-beta-erythroidine (0.1-100mM, alpha7 antagonist methyllycaconitine (0.1-100mM, and a-bungarotoxin (0.01-10mM all induced dose-dependent reductions in C4 respiratory rate. We next examined effects of 20mM dihydro-beta-erythroidine and 20mM methyllycaconitine on respiratory neurons. Dihydro-beta-erythroidine induces hyperpolarization and decreases intraburst firing frequency of inspiratory and preinspiratory neurons. In contrast, methyllycaconitine has no effect on the membrane potential of inspiratory neurons, but does decrease their intraburst firing frequency while inducing hyperpolarization and decreasing intraburst firing frequency in preinspiratory neurons. These findings indicate that alpha4beta2 nAChR is involved in both inspiratory and preinspiratory neurons, whereas alpha7 nAChR functions only in preinspiratory neurons to modulate C4 respiratory rate

  11. Lateral hypothalamic GLP-1 receptors are critical for the control of food reinforcement, ingestive behavior and body weight.

    Science.gov (United States)

    López-Ferreras, L; Richard, J E; Noble, E E; Eerola, K; Anderberg, R H; Olandersson, K; Taing, L; Kanoski, S E; Hayes, M R; Skibicka, K P

    2017-09-12

    Increased motivation for highly rewarding food is a major contributing factor to obesity. Most of the literature focuses on the mesolimbic nuclei as the core of reward behavior regulation. However, the lateral hypothalamus (LH) is also a key reward-control locus in the brain. Here we hypothesize that manipulating glucagon-like peptide-1 receptor (GLP-1R) activity selectively in the LH can profoundly affect food reward behavior, ultimately leading to obesity. Progressive ratio operant responding for sucrose was examined in male and female rats, following GLP-1R activation and pharmacological or genetic GLP-1R blockade in the LH. Ingestive behavior and metabolic parameters, as well as molecular and efferent targets, of the LH GLP-1R activation were also evaluated. Food motivation was reduced by activation of LH GLP-1R. Conversely, acute pharmacological blockade of LH GLP-1R increased food motivation but only in male rats. GLP-1R activation also induced a robust reduction in food intake and body weight. Chronic knockdown of LH GLP-1R induced by intraparenchymal delivery of an adeno-associated virus-short hairpin RNA construct was sufficient to markedly and persistently elevate ingestive behavior and body weight and ultimately resulted in a doubling of fat mass in males and females. Interestingly, increased food reinforcement was again found only in males. Our data identify the LH GLP-1R as an indispensable element of normal food reinforcement, food intake and body weight regulation. These findings also show, for we believe the first time, that brain GLP-1R manipulation can result in a robust and chronic body weight gain. The broader implications of these findings are that the LH differs between females and males in its ability to control motivated and ingestive behaviors.Molecular Psychiatry advance online publication, 12 September 2017; doi:10.1038/mp.2017.187.

  12. Role of the multichain IL-2 receptor complex in the control of normal and malignant T-cell proliferation

    International Nuclear Information System (INIS)

    Waldmann, T.A.

    1987-01-01

    Antigen-induced activation of resting T-cells induces the synthesis of interleukin-2 (IL-2), as well as the expression of specific cell surface receptors for this lymphokine. There are at least two forms of the cellular receptors for IL-2, one with a very high affinity and the other with a lower affinity. The authors have identified two IL-2 binding peptides, a 55-kd peptide reactive with the anti-Tac monoclonal antibody, and a novel 75-kd non-Tac IL-2 binding peptide. Cell lines bearing either the p55, Tac, or the p75 peptide along manifested low-affinity IL-2 binding, whereas cell lines bearing both peptides manifested both high- and low-affinity receptors. Fusion of cell membranes from low-affinity IL-2 binding cells bearing the Tac peptide alone with membranes from a cell line bearing the p75 peptide alone generates hybrid membranes bearing high-affinity receptors. They propose a multichain model for the high-affinity IL-2 receptor in which both the Tac and the p75 IL-2 binding peptides are associated in a receptor complex. In contrast to resting T-cells, human T-cell lymphotropic virus I-associated adult T-cell leukemia cells constitutively express large numbers of IL-2 receptors. Because IL-2 receptors are present on the malignant T-cells but not on normal resting cells, clinical trials have been initiated in which patients with adult T-cell leukemia are being treated with either unmodified or toxin-conjugated forms of anti-Tac monoclonal antibody directed toward this growth factor receptor. Cross-linking studies were done using [ 125 I] IL-2

  13. Anandamide Revisited: How Cholesterol and Ceramides Control Receptor-Dependent and Receptor-Independent Signal Transmission Pathways of a Lipid Neurotransmitter.

    Science.gov (United States)

    Di Scala, Coralie; Fantini, Jacques; Yahi, Nouara; Barrantes, Francisco J; Chahinian, Henri

    2018-05-22

    Anandamide is a lipid neurotransmitter derived from arachidonic acid, a polyunsaturated fatty acid. The chemical differences between anandamide and arachidonic acid result in a slightly enhanced solubility in water and absence of an ionisable group for the neurotransmitter compared with the fatty acid. In this review, we first analyze the conformational flexibility of anandamide in aqueous and membrane phases. We next study the interaction of the neurotransmitter with membrane lipids and discuss the molecular basis of the unexpected selectivity of anandamide for cholesterol and ceramide from among other membrane lipids. We show that cholesterol behaves as a binding partner for anandamide, and that following an initial interaction mediated by the establishment of a hydrogen bond, anandamide is attracted towards the membrane interior, where it forms a molecular complex with cholesterol after a functional conformation adaptation to the apolar membrane milieu. The complex is then directed to the anandamide cannabinoid receptor (CB1) which displays a high affinity binding pocket for anandamide. We propose that cholesterol may regulate the entry and exit of anandamide in and out of CB1 by interacting with low affinity cholesterol recognition sites (CARC and CRAC) located in transmembrane helices. The mirror topology of cholesterol binding sites in the seventh transmembrane domain is consistent with the delivery, extraction and flip-flop of anandamide through a coordinated cholesterol-dependent mechanism. The binding of anandamide to ceramide illustrates another key function of membrane lipids which may occur independently of protein receptors. Interestingly, ceramide forms a tight complex with anandamide which blocks the degradation pathway of both lipids and could be exploited for anti-cancer therapies.

  14. Testosterone treatment increases androgen receptor and aromatase gene expression in myotubes from patients with PCOS and controls, but does not induce insulin resistance.

    Science.gov (United States)

    Eriksen, Mette Brandt; Glintborg, Dorte; Nielsen, Michael Friberg Bruun; Jakobsen, Marianne Antonius; Brusgaard, Klaus; Tan, Qihua; Gaster, Michael

    2014-09-05

    Polycystic ovary syndrome (PCOS) is associated with insulin resistance and increased risk of type 2 diabetes. Skeletal muscle is the major site of insulin mediated glucose disposal and the skeletal muscle tissue is capable to synthesize, convert and degrade androgens. Insulin sensitivity is conserved in cultured myotubes (in vitro) from patients with PCOS, but the effect of testosterone on this insulin sensitivity is unknown. We investigated the effect of 7days testosterone treatment (100nmol/l) on glucose transport and gene expression levels of hormone receptors and enzymes involved in the synthesis and conversion of testosterone (HSD17B1, HSD17B2, CYP19A1, SRD5A1-2, AR, ER-α, HSD17B6 and AKR1-3) in myotubes from ten patients with PCOS and ten matched controls. Testosterone treatment significantly increased aromatase and androgen receptor gene expression levels in patients and controls. Glucose transport in myotubes was comparable in patients with PCOS vs. controls and was unchanged by testosterone treatment (p=0.21 PCOS vs. controls). These results suggest that testosterone treatment of myotubes increases the aromatase and androgen receptor gene expression without affecting insulin sensitivity and if testosterone is implicated in muscular insulin resistance in PCOS, this is by and indirect mechanism. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. Cannabinoid transmission in the prelimbic cortex bidirectionally controls opiate reward and aversion signaling through dissociable kappa versus μ-opiate receptor dependent mechanisms.

    Science.gov (United States)

    Ahmad, Tasha; Lauzon, Nicole M; de Jaeger, Xavier; Laviolette, Steven R

    2013-09-25

    Cannabinoid, dopamine (DA), and opiate receptor pathways play integrative roles in emotional learning, associative memory, and sensory perception. Modulation of cannabinoid CB1 receptor transmission within the medial prefrontal cortex (mPFC) regulates the emotional valence of both rewarding and aversive experiences. Furthermore, CB1 receptor substrates functionally interact with opiate-related motivational processing circuits, particularly in the context of reward-related learning and memory. Considerable evidence demonstrates functional interactions between CB1 and DA signaling pathways during the processing of motivationally salient information. However, the role of mPFC CB1 receptor transmission in the modulation of behavioral opiate-reward processing is not currently known. Using an unbiased conditioned place preference paradigm with rats, we examined the role of intra-mPFC CB1 transmission during opiate reward learning. We report that activation or inhibition of CB1 transmission within the prelimbic cortical (PLC) division of the mPFC bidirectionally regulates the motivational valence of opiates; whereas CB1 activation switched morphine reward signaling into an aversive stimulus, blockade of CB1 transmission potentiated the rewarding properties of normally sub-reward threshold conditioning doses of morphine. Both of these effects were dependent upon DA transmission as systemic blockade of DAergic transmission prevented CB1-dependent modulation of morphine reward and aversion behaviors. We further report that CB1-mediated intra-PLC opiate motivational signaling is mediated through a μ-opiate receptor-dependent reward pathway, or a κ-opiate receptor-dependent aversion pathway, directly within the ventral tegmental area. Our results provide evidence for a novel CB1-mediated motivational valence switching mechanism within the PLC, controlling dissociable subcortical reward and aversion pathways.

  16. Enhanced Androgen Signaling With Androgen Receptor Overexpression in the Osteoblast Lineage Controls Skeletal Turnover, Matrix Quality and Bone Architecture

    National Research Council Canada - National Science Library

    Wiren, Kristine M; Jepsen, Karl

    2006-01-01

    .... We genetically engineered transgenic mice in which androgen receptor (AR) overexpression is skeletally targeted in two separate models to better understand the role of androgen signaling directly in bone...

  17. ERK controls epithelial cell death receptor signalling and cellular FLICE-like inhibitory protein (c-FLIP) in ulcerative colitis

    DEFF Research Database (Denmark)

    Seidelin, Jakob Benedict; Coskun, Mehmet; Vainer, Ben

    2013-01-01

    Intestinal epithelial cell (IEC) death signalling through the Fas receptor is impaired in active ulcerative colitis (UC). This is possibly due to the activation of cytoprotective pathways resulting in limitation of the tissue injury secondary to inflammation. We hypothesized that inflammatory...... the resistance to receptor mediated epithelial apoptosis in active UC. Oncogenic c-FLIP could promote propagation of DNA-damaged IECs and contribute to cancer development in UC....

  18. Effects of the antitumor drug OSI-906, a dual inhibitor of IGF-1 receptor and insulin receptor, on the glycemic control, β-cell functions, and β-cell proliferation in male mice.

    Science.gov (United States)

    Shirakawa, Jun; Okuyama, Tomoko; Yoshida, Eiko; Shimizu, Mari; Horigome, Yuka; Tuno, Takayuki; Hayasaka, Moe; Abe, Shiori; Fuse, Masahiro; Togashi, Yu; Terauchi, Yasuo

    2014-06-01

    The IGF-1 receptor has become a therapeutic target for the treatment of cancer. The efficacy of OSI-906 (linstinib), a dual inhibitor of IGF-1 receptor and insulin receptor, for solid cancers has been examined in clinical trials. The effects of OSI-906, however, on the blood glucose levels and pancreatic β-cell functions have not yet been reported. We investigated the impact of OSI-906 on glycemic control, insulin secretion, β-cell mass, and β-cell proliferation in male mice. Oral administration of OSI-906 worsened glucose tolerance in a dose-dependent manner in the wild-type mice. OSI-906 at a dose equivalent to the clinical daily dose (7.5 mg/kg) transiently evoked glucose intolerance and hyperinsulinemia. Insulin receptor substrate (IRS)-2-deficient mice and mice with diet-induced obesity, both models of peripheral insulin resistance, exhibited more severe glucose intolerance after OSI-906 administration than glucokinase-haploinsufficient mice, a model of impaired insulin secretion. Phloridzin improved the hyperglycemia induced by OSI-906 in mice. In vitro, OSI-906 showed no effect on insulin secretion from isolated islets. After daily administration of OSI-906 for a week to mice, the β-cell mass and β-cell proliferation rate were significantly increased. The insulin signals in the β-cells were apparently unaffected in those mice. Taken together, the results suggest that OSI-906 could exacerbate diabetes, especially in patients with insulin resistance. On the other hand, the results suggest that the β-cell mass may expand in response to chemotherapy with this drug.

  19. Association of Estrogen Receptor Gene Polymorphisms and Primary Biliary Cirrhosis in a Chinese Population: A Case-Control Study

    Directory of Open Access Journals (Sweden)

    Liu Yang

    2015-01-01

    Full Text Available Background: Primary biliary cirrhosis (PBC is a chronic and slowly progressive cholestatic liver disease characterized by destruction of the interlobular bile ducts and a striking female predominance. The aim of this study was to identify associations between estrogen receptor (ESR gene polymorphisms with the risk of developing PBC and abnormal serum liver tests in a Chinese population. Methods: Thirty-six patients with PBC (case group and 35 healthy individuals (control group from the First Hospital of Jilin University were studied. Whole genomic DNA was extracted from all the participants. Three single-nucleotide polymorphisms (rs2234693, rs2228480, and rs3798577 from ESR1 and two (rs1256030 and rs1048315 from ESR2 were analyzed by a pyrosequencing method. Demographic data and liver biochemical data were collected. Results: Subjects with the T allele at ESR2 rs1256030 had 1.5 times higher risk of developing PBC than those with the C allele (odds ratio [OR] = 2.1277, 95% confidence interval [CI] = 1.1872-4.5517. Haplotypes TGC of ESR1 rs2234693, rs2228480, and rs3798577 were risk factors for having PBC. The C allele at ESR1 rs2234693 was associated with abnormal alkaline phosphatase (OR = 5.2469, 95% CI = 1.3704-20.0895 and gamma-glutamyl transferase (OR = 3.4286, 95% CI = 1.0083-13.6578 levels in PBC patients. Conclusions: ESR2 rs1256030 T allele may be a significant risk factor for the development of PBC. Screening for patients with gene polymorphisms may help to make early diagnoses in patients with PBC.

  20. Receptor for advanced glycation end products involved in lung ischemia reperfusion injury in cardiopulmonary bypass attenuated by controlled oxygen reperfusion in a canine model.

    Science.gov (United States)

    Rong, Jian; Ye, Sheng; Liang, Meng-ya; Chen, Guang-xian; Liu, Hai; Zhang, Jin-Xin; Wu, Zhong-kai

    2013-01-01

    Controlled oxygen reperfusion could protect the lung against ischemia-reperfusion injury in cardiopulmonary bypass (CPB) by downregulating high mobility group box 1 (HMGB1), a high affinity receptor of HMGB1. This study investigated the effect of controlled oxygen reperfusion on receptor for advanced glycation end products (RAGE) expression and its downstream effects on lung ischemia-reperfusion injury. Fourteen canines received CPB with 60 minutes of aortic clamping and cardioplegic arrest followed by 90 minutes of reperfusion. Animals were randomized to receive 80% FiO2 during the entire procedure (control group) or to a test group receiving a controlled oxygen reperfusion protocol. Pathologic changes in lung tissues, RAGE expression, serum interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were evaluated. The lung pathologic scores after 25 and 90 minutes of reperfusion were significantly lower in the test group compared with the control group (p RAGE expression, TNF-α, and IL-6 were downregulated by controlled oxygen treatment (p RAGE might be involved in the lung ischemia-reperfusion injury in canine model of CPB, which was downregulated by controlled oxygen reperfusion.

  1. Somatostatin receptors

    DEFF Research Database (Denmark)

    Møller, Lars Neisig; Stidsen, Carsten Enggaard; Hartmann, Bolette

    2003-01-01

    functional units, receptors co-operate. The total receptor apparatus of individual cell types is composed of different-ligand receptors (e.g. SRIF and non-SRIF receptors) and co-expressed receptor subtypes (e.g. sst(2) and sst(5) receptors) in characteristic proportions. In other words, levels of individual......-peptides, receptor agonists and antagonists. Relatively long half lives, as compared to those of the endogenous ligands, have been paramount from the outset. Motivated by theoretical puzzles or the shortcomings of present-day diagnostics and therapy, investigators have also aimed to produce subtype...

  2. Phytoestrogens/insoluble fibers and colonic estrogen receptor β: Randomized, double-blind, placebo-controlled study

    Science.gov (United States)

    Principi, Mariabeatrice; Di Leo, Alfredo; Pricci, Maria; Scavo, Maria Principia; Guido, Raffaella; Tanzi, Sabina; Piscitelli, Domenico; Pisani, Antonio; Ierardi, Enzo; Comelli, Maria Cristina; Barone, Michele

    2013-01-01

    AIM: To assess the safety and effect of the supplementation of a patented blend of dietary phytoestrogens and insoluble fibers on estrogen receptor (ER)-β and biological parameters in sporadic colonic adenomas. METHODS: A randomized, double-blind placebo-controlled trial was performed. Patients scheduled to undergo surveillance colonoscopy for previous sporadic colonic adenomas were identified, and 60 eligible patients were randomized to placebo or active dietary intervention (ADI) twice a day, for 60 d before surveillance colonoscopy. ADI was a mixture of 175 mg milk thistle extract, 20 mg secoisolariciresinol and 750 mg oat fiber extract. ER-β and ER-α expression, apoptosis and proliferation (Ki-67 LI) were assessed in colon samples. RESULTS: No adverse event related to ADI was recorded. ADI administration showed a significant increases in ER-β protein (0.822 ± 0.08 vs 0.768 ± 0.10, P = 0.04) and a general trend to an increase in ER-β LI (39.222 ± 2.69 vs 37.708 ± 5.31, P = 0.06), ER-β/ER-α LI ratio (6.564 ± 10.04 vs 2.437 ± 1.53, P = 0.06), terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (35.592 ± 14.97 vs 31.541 ± 11.54, P = 0.07) and Ki-67 (53.923 ± 20.91 vs 44.833 ± 10.38, P = 0.07) approximating statistical significance. A significant increase of ER-β protein (0.805 ± 0.13 vs 0.773 ± 0.13, P = 0.04), mRNA (2.278 ± 1.19 vs 1.105 ± 1.07, P < 0.02) and LI (47.533 ± 15.47 vs 34.875 ± 16.67, P < 0.05) and a decrease of ER-α protein (0.423 ± 0.06 vs 0.532 ± 0.11, P < 0.02) as well as a trend to increase of ER-β/ER-α protein in ADI vs placebo group were observed in patients without polyps (1.734 ± 0.20 vs 1.571 ± 0.42, P = 0.07). CONCLUSION: The role of ER-β on the control of apoptosis, and its amenability to dietary intervention, are supported in our study. PMID:23885143

  3. A Transcriptional Regulatory Network Containing Nuclear Receptors and Long Noncoding RNAs Controls Basal and Drug-Induced Expression of Cytochrome P450s in HepaRG Cells.

    Science.gov (United States)

    Chen, Liming; Bao, Yifan; Piekos, Stephanie C; Zhu, Kexin; Zhang, Lirong; Zhong, Xiao-Bo

    2018-07-01

    Cytochrome P450 (P450) enzymes are responsible for metabolizing drugs. Expression of P450s can directly affect drug metabolism, resulting in various outcomes in therapeutic efficacy and adverse effects. Several nuclear receptors are transcription factors that can regulate expression of P450s at both basal and drug-induced levels. Some long noncoding RNAs (lncRNAs) near a transcription factor are found to participate in the regulatory functions of the transcription factors. The aim of this study is to determine whether there is a transcriptional regulatory network containing nuclear receptors and lncRNAs controlling both basal and drug-induced expression of P450s in HepaRG cells. Small interfering RNAs or small hairpin RNAs were applied to knock down four nuclear receptors [hepatocyte nuclear factor 1 α (HNF1 α ), hepatocyte nuclear factor 4 α (HNF4 α ), pregnane X receptor (PXR), and constitutive androstane receptor (CAR)] as well as two lncRNAs [HNF1 α antisense RNA 1 (HNF1 α -AS1) and HNF4 α antisense RNA 1 (HNF4 α -AS1)] in HepaRG cells with or without treatment of phenobarbital or rifampicin. Expression of eight P450 enzymes was examined in both basal and drug-induced levels. CAR and PXR mainly regulated expression of specific P450s. HNF1 α and HNF4 α affected expression of a wide range of P450s as well as other transcription factors. HNF1 α and HNF4 α controlled the expression of their neighborhood lncRNAs, HNF1 α -AS1 and HNF4 α -AS1, respectively. HNF1 α -AS1 and HNF4 α -AS1 was also involved in the regulation of P450s and transcription factors in diverse manners. Altogether, our study concludes that a transcription regulatory network containing the nuclear receptors and lncRNAs controls both basal and drug-induced expression of P450s in HepaRG cells. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

  4. Reduced type II interleukin-4 receptor signalling drives initiation, but not progression, of colorectal carcinogenesis: evidence from transgenic mouse models and human case?control epidemiological observations

    OpenAIRE

    Ingram, Nicola; Northwood, Emma L.; Perry, Sarah L.; Marston, Gemma; Snowden, Helen; Taylor, John C.; Scott, Nigel; Bishop, D. Timothy; Coletta, P. Louise; Hull, Mark A.

    2013-01-01

    We investigated the role of interleukin (IL)-4 receptor (IL-4R) signalling during mouse carcinogen-induced colorectal carcinogenesis and in a case-control genetic epidemiological study of IL-4Rα single nucleotide polymorphisms (SNPs). Azoxymethane-induced aberrant crypt focus (ACF; 6 weeks) and tumours (32 weeks) were analysed in wild-type (WT) BALB/c mice, as well as in IL-4Rα (-) (/-) , IL-13 (-/-) and 'double-knockout' (DKO) animals. Colorectal cancer (CRC) cases (1502) and controls (584) ...

  5. Control of the subthalamic innervation of substantia nigra pars reticulata by D1 and D2 dopamine receptors.

    Science.gov (United States)

    Ibañez-Sandoval, Osvaldo; Hernández, Adán; Florán, Benjamin; Galarraga, Elvira; Tapia, Dagoberto; Valdiosera, Rene; Erlij, David; Aceves, Jorge; Bargas, José

    2006-03-01

    The effects of activating dopaminergic D1 and D2 class receptors of the subthalamic projections that innervate the pars reticulata of the subtantia nigra (SNr) were explored in slices of the rat brain using the whole cell patch-clamp technique. Excitatory postsynaptic currents (EPSCs) that could be blocked by 6-cyano-7-nitroquinoxalene-2,3-dione and D-(-)-2-amino-5-phosphonopentanoic acid were evoked onto reticulata GABAergic projection neurons by local field stimulation inside the subthalamic nucleus in the presence of bicuculline. Bath application of (RS)-2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine hydrochloride (SKF-38393), a dopaminergic D1-class receptor agonist, increased evoked EPSCs by approximately 30% whereas the D2-class receptor agonist, trans-(-)-4aR-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo(3,4-g)quinoline (quinpirole), reduced EPSCs by approximately 25%. These apparently opposing actions were blocked by the specific D1- and D2-class receptor antagonists: R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetra-hydro-1H-3-benzazepinehydrochloride (SCH 23390) and S-(-)-5-amino-sulfonyl-N-[(1-ethyl-2-pyrrolidinyl)-methyl]-2-methoxybenzamide (sulpiride), respectively. Both effects were accompanied by changes in the paired-pulse ratio, indicative of a presynaptic site of action. The presynaptic location of dopamine receptors at the subthalamonigral projections was confirmed by mean-variance analysis. The effects of both SKF-38393 and quinpirole could be observed on terminals contacting the same postsynaptic neuron. Sulpiride and SCH 23390 enhanced and reduced the evoked EPSC, respectively, suggesting a constitutive receptor activation probably arising from endogenous dopamine. These data suggest that dopamine presynaptically modulates the subthalamic projection that targets GABAergic neurons of the SNr. Implications of this modulation for basal ganglia function are discussed.

  6. Aryl hydrocarbon receptor-dependent regulation of miR-196a expression controls lung fibroblast apoptosis but not proliferation

    International Nuclear Information System (INIS)

    Hecht, Emelia; Zago, Michela; Sarill, Miles; Rico de Souza, Angela; Gomez, Alvin; Matthews, Jason; Hamid, Qutayba; Eidelman, David H.; Baglole, Carolyn J.

    2014-01-01

    The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor implicated in the regulation of apoptosis and proliferation. Although activation of the AhR by xenobiotics such as dioxin inhibits the cell cycle and control apoptosis, paradoxically, AhR expression also promotes cell proliferation and survival independent of exogenous ligands. The microRNA (miRNA) miR-196a has also emerged as a regulator of proliferation and apoptosis but a relationship between the AhR and miR-196a is not known. Therefore, we hypothesized that AhR-dependent regulation of endogenous miR-196a expression would promote cell survival and proliferation. Utilizing lung fibroblasts from AhR deficient (AhR −/− ) and wild-type (AhR +/+ ) mice, we show that there is ligand-independent regulation of miRNA, including low miR-196a in AhR −/− cells. Validation by qRT-PCR revealed a significant decrease in basal expression of miR-196a in AhR −/− compared to AhR +/+ cells. Exposure to AhR agonists benzo[a]pyrene (B[a]P) and FICZ as well as AhR antagonist CH-223191 decreased miR-196a expression in AhR +/+ fibroblasts concomitant with decreased AhR protein levels. There was increased proliferation only in AhR +/+ lung fibroblasts in response to serum, corresponding to a decrease in p27 KIP1 protein, a cyclin-dependent kinase inhibitor. Increasing the cellular levels of miR-196a had no effect on proliferation or expression of p27 KIP1 in AhR −/− fibroblasts but attenuated cigarette smoke-induced apoptosis. This study provides the first evidence that AhR expression is essential for the physiological regulation of cellular miRNA levels- including miR-196a. Future experiments designed to elucidate the functional relationship between the AhR and miR-196a may delineate additional novel ligand-independent roles for the AhR. - Highlights: • The AhR controls proliferation and apoptosis in lung cells. • The AhR regulates the expression of the microRNA miR-196a independent of

  7. Aryl hydrocarbon receptor-dependent regulation of miR-196a expression controls lung fibroblast apoptosis but not proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Hecht, Emelia [Department of Medicine, McGill University, Montreal, Quebec (Canada); Zago, Michela [Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec (Canada); Sarill, Miles [Department of Medicine, McGill University, Montreal, Quebec (Canada); Rico de Souza, Angela [Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec (Canada); Gomez, Alvin; Matthews, Jason [Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON (Canada); Hamid, Qutayba; Eidelman, David H. [Department of Medicine, McGill University, Montreal, Quebec (Canada); Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec (Canada); Baglole, Carolyn J., E-mail: Carolyn.baglole@McGill.ca [Department of Medicine, McGill University, Montreal, Quebec (Canada); Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec (Canada)

    2014-11-01

    The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor implicated in the regulation of apoptosis and proliferation. Although activation of the AhR by xenobiotics such as dioxin inhibits the cell cycle and control apoptosis, paradoxically, AhR expression also promotes cell proliferation and survival independent of exogenous ligands. The microRNA (miRNA) miR-196a has also emerged as a regulator of proliferation and apoptosis but a relationship between the AhR and miR-196a is not known. Therefore, we hypothesized that AhR-dependent regulation of endogenous miR-196a expression would promote cell survival and proliferation. Utilizing lung fibroblasts from AhR deficient (AhR{sup −/−}) and wild-type (AhR{sup +/+}) mice, we show that there is ligand-independent regulation of miRNA, including low miR-196a in AhR{sup −/−} cells. Validation by qRT-PCR revealed a significant decrease in basal expression of miR-196a in AhR{sup −/−} compared to AhR{sup +/+} cells. Exposure to AhR agonists benzo[a]pyrene (B[a]P) and FICZ as well as AhR antagonist CH-223191 decreased miR-196a expression in AhR{sup +/+} fibroblasts concomitant with decreased AhR protein levels. There was increased proliferation only in AhR{sup +/+} lung fibroblasts in response to serum, corresponding to a decrease in p27{sup KIP1} protein, a cyclin-dependent kinase inhibitor. Increasing the cellular levels of miR-196a had no effect on proliferation or expression of p27{sup KIP1} in AhR{sup −/−} fibroblasts but attenuated cigarette smoke-induced apoptosis. This study provides the first evidence that AhR expression is essential for the physiological regulation of cellular miRNA levels- including miR-196a. Future experiments designed to elucidate the functional relationship between the AhR and miR-196a may delineate additional novel ligand-independent roles for the AhR. - Highlights: • The AhR controls proliferation and apoptosis in lung cells. • The AhR regulates the

  8. Co-ordinate regulation of growth factor receptors and lipid phosphate phosphatase-1 controls cell activation by exogenous lysophosphatidate.

    Science.gov (United States)

    Pilquil, C; Ling, Z C; Singh, I; Buri, K; Zhang, Q X; Brindley, D N

    2001-11-01

    The serum-derived lipid growth factors, lysophosphatidate (LPA) and sphingosine 1-phosphate (S1P), activate cells selectively through different members of a family of endothelial differentiation gene (EDG) receptors. Activation of EDG receptors by LPA and S1P provides a variety of signalling cascades depending upon the G-protein coupling of the different EDG receptors. This leads to chemotactic and mitogenic responses, which are important in wound healing. For example, LPA stimulates fibroblast division and S1P stimulates the chemotaxis and division of endothelial cells leading to angiogenesis. Counteracting these effects of LPA and S1P, are the actions of lipid phosphate phosphatases (LPP, or phosphatidate phosphohydrolases, Type 2). The isoform LPP-1 is expressed in the plasma membrane with its active site outside the cell. This enzyme is responsible for 'ecto-phosphatase' activity leading to the degradation of exogenous lipid phosphate mediators, particularly LPA. Expression of LPP-1 decreases cell activation by exogenous LPA. The mechanism for this is controversial and several mechanisms have been proposed. Evidence will be presented that the LPPs cross-talk with EDG and other growth factor receptors, thus, regulating the responses of the cells to lipid phosphate mediators of signal transduction.

  9. Heterogeneous expression of melatonin receptor MT1 mRNA in the rat intestine under control and fasting conditions

    Czech Academy of Sciences Publication Activity Database

    Soták, Matúš; Mrnka, Libor; Pácha, Jiří

    2006-01-01

    Roč. 41, č. 2 (2006), s. 183-188 ISSN 0742-3098 R&D Projects: GA ČR(CZ) GP305/03/D140 Institutional research plan: CEZ:AV0Z5011922 Keywords : melatonin receptor, * malnutrition * intestine Subject RIV: ED - Physiology Impact factor: 4.228, year: 2006

  10. Pre-diabetes augments neuropeptide Y1- and α1-receptor control of basal hindlimb vascular tone in young ZDF rats.

    Directory of Open Access Journals (Sweden)

    Nicole M Novielli

    Full Text Available Peripheral vascular disease in pre-diabetes may involve altered sympathetically-mediated vascular control. Thus, we investigated if pre-diabetes modifies baseline sympathetic Y(1-receptor (Y(1R and α(1-receptor (α(1R control of hindlimb blood flow (Q(fem and vascular conductance (VC.Q(fem and VC were measured in pre-diabetic ZDF rats (PD and lean controls (CTRL under infusion of BIBP3226 (Y(1R antagonist, prazosin (α(1R antagonist and BIBP3226+prazosin. Neuropeptide Y (NPY concentration and Y(1R and α(1R expression were determined from hindlimb skeletal muscle samples.Baseline Q(fem and VC were similar between groups. Independent infusions of BIBP3226 and prazosin led to increases in Q(fem and VC in CTRL and PD, where responses were greater in PD (p<0.05. The percent change in VC following both drugs was also greater in PD compared to CTRL (p<0.05. As well, Q(fem and VC responses to combined blockade (BIBP3226+prazosin were greater in PD compared to CTRL (p<0.05. Interestingly, an absence of synergistic effects was observed within groups, as the sum of the VC responses to independent drug infusions was similar to responses following combined blockade. Finally, white and red vastus skeletal muscle NPY concentration, Y(1R expression and α(1R expression were greater in PD compared to CTRL.For the first time, we report heightened baseline Y(1R and α(1R sympathetic control of Q(fem and VC in pre-diabetic ZDF rats. In support, our data suggest that augmented sympathetic ligand and receptor expression in pre-diabetes may contribute to vascular dysregulation.

  11. Effects of interleukin-1 receptor antagonist (IL-1Ra) gene 86 bp VNTR polymorphism on recurrent pregnancy loss: a case-control study.

    Science.gov (United States)

    Hajizadeh, Yasamin Sayed; Emami, Elina; Nottagh, Marina; Amini, Zahra; Maroufi, Nazila Fathi; Azimian, Saba Haj; Isazadeh, Alireza

    2017-05-26

    Objective Recurrent pregnancy loss (RPL) is a heterogeneous disease which is defined as two or more consecutive fetal losses during early pregnancy. Interleukin-1 receptor antagonist (IL-1Ra) is a anti-inflammatory cytokine, which inhibits IL-1 activity by binding to its receptors. The aim of this study was to investigate the association between RPL and IL-1Ra intron 2 polymorphism (86 bp VNTR) in Iranian women. Materials and methods In this case control study, genetic polymorphism was studied in 140 RPL patients and 140 healthy women as controls. Genomic DNA was extracted from the blood samples and polymorphism analysis was performed using the polymerase chain reaction (PCR) method. Finally, the data obtained were analyzed by statistical software. Results We found an increased frequency of the IL-1Ra 1/1 genotype in the case group compared to the control group. Whereas, the frequency of IL-1Ra genotype 1/2 was higher in control group than in the case group. However, we did not observe an association between IL-1Ra 86 bp VNTR polymorphism in intron 2 and RPL patients (p > 0.05). Conclusion IL-1Ra VNTR polymorphism may not be a genetic factor for RPL. However, investigation of IL-1Ra polymorphism was recommended in other populations and patients with recurrent pregnancy loss.

  12. Role of the ERC motif in the proximal part of the second intracellular loop and the C-terminal domain of the human prostaglandin F2alpha receptor (hFP-R) in G-protein coupling control.

    Science.gov (United States)

    Pathe-Neuschäfer-Rube, Andrea; Neuschäfer-Rube, Frank; Püschel, Gerhard P

    2005-05-15

    The human FP-R (F2alpha prostaglandin receptor) is a Gq-coupled heptahelical ectoreceptor, which is of significant medical interest, since it is a potential target for the treatment of glaucoma and preterm labour. On agonist exposure, it mediates an increase in intracellular inositol phosphate formation. Little is known about the structures that govern the agonist-dependent receptor activation. In other prostanoid receptors, the C-terminal domain has been inferred in the control of agonist-dependent receptor activation. A DRY motif at the beginning of the second intracellular loop is highly conserved throughout the G-protein-coupled receptor family and appears to be crucial for controlling agonist-dependent receptor activation. It is replaced by an ERC motif in the FP-R and no evidence for the relevance of this motif in ligand-dependent activation of prostanoid receptors has been provided so far. The aim of the present study was to elucidate the potential role of the C-terminal domain and the ERC motif in agonist-controlled intracellular signalling in FP-R mutants generated by site-directed mutagenesis. It was found that substitution of the acidic Glu(132) in the ERC motif by a threonine residue led to full constitutive activation, whereas truncation of the receptor's C-terminal domain led to partial constitutive activation of all three intracellular signal pathways that had previously been shown to be activated by the FP-R, i.e. inositol trisphosphate formation, focal adhesion kinase activation and T-cell factor signalling. Inositol trisphosphate formation and focal adhesion kinase phosphorylation were further enhanced by ligand binding in cells expressing the truncation mutant but not the E132T (Glu132-->Thr) mutant. Thus C-terminal truncation appeared to result in a receptor with partial constitutive activation, whereas substitution of Glu132 by threonine apparently resulted in a receptor with full constitutive activity.

  13. The Size of Activating and Inhibitory Killer Ig-like Receptor Nanoclusters Is Controlled by the Transmembrane Sequence and Affects Signaling

    Directory of Open Access Journals (Sweden)

    Anna Oszmiana

    2016-05-01

    Full Text Available Super-resolution microscopy has revealed that immune cell receptors are organized in nanoscale clusters at cell surfaces and immune synapses. However, mechanisms and functions for this nanoscale organization remain unclear. Here, we used super-resolution microscopy to compare the surface organization of paired killer Ig-like receptors (KIR, KIR2DL1 and KIR2DS1, on human primary natural killer cells and cell lines. Activating KIR2DS1 assembled in clusters two-fold larger than its inhibitory counterpart KIR2DL1. Site-directed mutagenesis established that the size of nanoclusters is controlled by transmembrane amino acid 233, a lysine in KIR2DS1. Super-resolution microscopy also revealed two ways in which the nanoscale clustering of KIR affects signaling. First, KIR2DS1 and DAP12 nanoclusters are juxtaposed in the resting cell state but coalesce upon receptor ligation. Second, quantitative super-resolution microscopy revealed that phosphorylation of the kinase ZAP-70 or phosphatase SHP-1 is favored in larger KIR nanoclusters. Thus, the size of KIR nanoclusters depends on the transmembrane sequence and affects downstream signaling.

  14. The phosphorylation state of CD3gamma influences T cell responsiveness and controls T cell receptor cycling

    DEFF Research Database (Denmark)

    Dietrich, J; Bäckström, T; Lauritsen, J P

    1998-01-01

    The T cell receptor (TCR) is internalized following activation of protein kinase C (PKC) via a leucine (Leu)-based motif in CD3gamma. Some studies have indicated that the TCR is recycled back to the cell surface following PKC-mediated internalization. The functional state of recycled TCR and the ......The T cell receptor (TCR) is internalized following activation of protein kinase C (PKC) via a leucine (Leu)-based motif in CD3gamma. Some studies have indicated that the TCR is recycled back to the cell surface following PKC-mediated internalization. The functional state of recycled TCR...... the phosphorylation state of CD3gamma and T cell responsiveness. Based on these observations a physiological role of CD3gamma and TCR cycling is proposed....

  15. Polyunsaturated fatty acid receptors, GPR40 and GPR120, are expressed in the hypothalamus and control energy homeostasis and inflammation

    DEFF Research Database (Denmark)

    Dragano, Nathalia R V; Solon, Carina; Ramalho, Albina F

    2017-01-01

    BACKGROUND: The consumption of large amounts of dietary fats is one of the most important environmental factors contributing to the development of obesity and metabolic disorders. GPR120 and GPR40 are polyunsaturated fatty acid receptors that exert a number of systemic effects that are beneficial...... for metabolic and inflammatory diseases. Here, we evaluate the expression and potential role of hypothalamic GPR120 and GPR40 as targets for the treatment of obesity. METHODS: Male Swiss (6-weeks old), were fed with a high fat diet (HFD, 60% of kcal from fat) for 4 weeks. Next, mice underwent stereotaxic...... the treatment period. At the end of the experiment, the hypothalamus was collected for real-time PCR analysis. RESULTS: We show that both receptors are expressed in the hypothalamus; GPR120 is primarily present in microglia, whereas GPR40 is expressed in neurons. Upon intracerebroventricular treatment, GW9508...

  16. The scaffold protein calcium/calmodulin-dependent serine protein kinase controls ATP release in sensory ganglia upon P2X3 receptor activation and is part of an ATP keeper complex.

    Science.gov (United States)

    Bele, Tanja; Fabbretti, Elsa

    2016-08-01

    P2X3 receptors, gated by extracellular ATP, are expressed by sensory neurons and are involved in peripheral nociception and pain sensitization. The ability of P2X3 receptors to transduce extracellular stimuli into neuronal signals critically depends on the dynamic molecular partnership with the calcium/calmodulin-dependent serine protein kinase (CASK). The present work used trigeminal sensory neurons to study the impact that activation of P2X3 receptors (evoked by the agonist α,β-meATP) has on the release of endogenous ATP and how CASK modulates this phenomenon. P2X3 receptor function was followed by ATP efflux via Pannexin1 (Panx1) hemichannels, a mechanism that was blocked by the P2X3 receptor antagonist A-317491, and by P2X3 silencing. ATP efflux was enhanced by nerve growth factor, a treatment known to potentiate P2X3 receptor function. Basal ATP efflux was not controlled by CASK, and carbenoxolone or Pannexin silencing reduced ATP release upon P2X3 receptor function. CASK-controlled ATP efflux followed P2X3 receptor activity, but not depolarization-evoked ATP release. Molecular biology experiments showed that CASK was essential for the transactivation of Panx1 upon P2X3 receptor activation. These data suggest that P2X3 receptor function controls a new type of feed-forward purinergic signaling on surrounding cells, with consequences at peripheral and spinal cord level. Thus, P2X3 receptor-mediated ATP efflux may be considered for the future development of pharmacological strategies aimed at containing neuronal sensitization. P2X3 receptors are involved in sensory transduction and associate to CASK. We have studied in primary sensory neurons the molecular mechanisms downstream P2X3 receptor activation, namely ATP release and partnership with CASK or Panx1. Our data suggest that CASK and P2X3 receptors are part of an ATP keeper complex, with important feed-forward consequences at peripheral and central level. © 2016 International Society for Neurochemistry.

  17. The autism associated MET receptor tyrosine kinase engages early neuronal growth mechanism and controls glutamatergic circuits development in the forebrain

    OpenAIRE

    Peng, Yun; Lu, Zhongming; Li, Guohui; Piechowicz, Mariel; Anderson, Miranda; Uddin, Yasin; Wu, Jie; Qiu, Shenfeng

    2016-01-01

    The human MET gene imparts a replicated risk for autism spectrum disorder (ASD), and is implicated in the structural and functional integrity of brain. MET encodes a receptor tyrosine kinase, MET, which plays a pleiotropic role in embryogenesis and modifies a large number of neurodevelopmental events. Very little is known, however, on how MET signaling engages distinct cellular events to collectively affect brain development in ASD-relevant disease domains. Here, we show that MET protein expr...

  18. Brain purine metabolism and xanthine dehydrogenase/oxidase conversion in hyperammonemia are under control of NMDA receptors and nitric oxide.

    Science.gov (United States)

    Kaminsky, Yury; Kosenko, Elena

    2009-10-19

    In hyperammonemia, a decrease in brain ATP can be a result of adenine nucleotide catabolism. Xanthine dehydrogenase (XD) and xanthine oxidase (XO) are the end steps in the purine catabolic pathway and directly involved in depletion of the adenylate pool in the cell. Besides, XD can easily be converted to XO to produce reactive oxygen species in the cell. In this study, the effects of acute ammonia intoxication in vivo on brain adenine nucleotide pool and xanthine and hypoxanthine, the end degradation products of adenine nucleotides, during the conversion of XD to XO were studied. Injection of rats with ammonium acetate was shown to lead to the dramatic decrease in the ATP level, adenine nucleotide pool size and adenylate energy charge and to the great increase in hypoxanthine and xanthine 11 min after the lethal dose indicating rapid degradation of adenylates. Conversion of XD to XO in hyperammonemic rat brain was evidenced by elevated XO/XD activity ratio. Injection of MK-801, a NMDA receptor blocker, prevented ammonia-induced catabolism of adenine nucleotides and conversion of XD to XO suggesting that in vivo these processes are mediated by activation of NMDA receptors. The in vitro dose-dependent effects of sodium nitroprusside, a NO donor, on XD and XO activities are indicative of the direct modification of the enzymes by nitric oxide. This is the first report evidencing the increase in brain xanthine and hypoxanthine levels and adenine nucleotide breakdown in acute ammonia intoxication and NMDA receptor-mediated prevention of these alterations.

  19. Retinoic Acid Receptors Control Spermatogonia Cell-Fate and Induce Expression of the SALL4A Transcription Factor.

    Directory of Open Access Journals (Sweden)

    Aurore Gely-Pernot

    2015-10-01

    Full Text Available All-trans retinoic acid (ATRA is instrumental to male germ cell differentiation, but its mechanism of action remains elusive. To address this question, we have analyzed the phenotypes of mice lacking, in spermatogonia, all rexinoid receptors (RXRA, RXRB and RXRG or all ATRA receptors (RARA, RARB and RARG. We demonstrate that the combined ablation of RXRA and RXRB in spermatogonia recapitulates the set of defects observed both upon ablation of RAR in spermatogonia. We also show that ATRA activates RAR and RXR bound to a conserved regulatory region to increase expression of the SALL4A transcription factor in spermatogonia. Our results reveal that this major pluripotency gene is a target of ATRA signaling and that RAR/RXR heterodimers are the functional units driving its expression in spermatogonia. They add to the mechanisms through which ATRA promote expression of the KIT tyrosine kinase receptor to trigger a critical step in spermatogonia differentiation. Importantly, they indicate also that meiosis eventually occurs in the absence of a RAR/RXR pathway within germ cells and suggest that instructing this process is either ATRA-independent or requires an ATRA signal originating from Sertoli cells.

  20. Transforming growth factor-β1 and its receptor soluble endoglin are altered in polycystic ovary syndrome during controlled ovarian stimulation.

    Science.gov (United States)

    Tal, Reshef; Seifer, David B; Shohat-Tal, Aya; Grazi, Richard V; Malter, Henry E

    2013-08-01

    To evaluate the relationship between transforming growth factor (TGF)-β1 and its receptor, soluble endoglin (sENG), in the serum and follicular fluid of women with polycystic ovarian syndrome (PCOS) compared with that of non-PCOS normal ovulating women during controlled ovarian stimulation (COS). Prospective case-control study. Academic-affiliated assisted reproductive technology unit. Fourteen PCOS and 14 matched non-PCOS control women undergoing COS. Serum was collected on day 3 (baseline), day of hCG, and day of retrieval. Follicular fluid (FF) was collected on day of oocyte retrieval. ELISA was performed to determine TGF-β1 and sENG protein levels. Serum and FF levels of TGF-β1 and sENG. Serum TGF-β1 did not change significantly during COS but was increased in PCOS compared with non-PCOS women on day 3 and days of hCG administration and oocyte retrieval. Serum sENG increased after hCG administration only in the non-PCOS control group. In addition, serum sENG was decreased in PCOS compared with non-PCOS control women on the days of hCG and retrieval. Accordingly, the bioavailability of TGF-β1 (TGF-β1/sENG ratio) was increased in women with PCOS compared with non-PCOS controls at all three time points. No differences in either factor were noted in FF between groups. The increased TGF-β1 bioavailability in PCOS is not only due to increased TGF-β1 levels but also to decreased levels of its receptor, sENG. These data suggest that increased TGF-β1 bioavailability may contribute to the pathogenesis of PCOS and its increased risk for ovarian hyperstimulation. Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  1. Organochlorine exposures influence on breast cancer risk and survival according to estrogen receptor status: a Danish cohort-nested case-control study

    International Nuclear Information System (INIS)

    Høyer, Annette P; Jørgensen, Torben; Rank, Fritz; Grandjean, Philippe

    2001-01-01

    The relationship between breast cancer and organochlorine exposure is controversial and complex. As estrogen receptor positive and negative breast cancer may represent different entities of the disease, this study was undertaken to evaluate organochlorines influence on breast cancer risk and survival according to receptor status. The background material stems from the Copenhagen City Heart Study (Denmark 1976-78). The breast cancer risk was investigated in a cohort nested case-control design including 161 cases and twice as many breast cancer free controls. The cases served as a cohort in the survival analysis. Serum organochlorine concentrations were determined by gaschromotography. The observed increased breast cancer risk associated with exposure to dieldrin derived from women who developed an estrogen receptor negative (ERN) tumor (Odds ratio [OR] I vs. IV quartile, 7.6, 95% confidence interval [95% CI] 1.4-46.1, p-value for linear trend 0.01). Tumors in women with the highest dieldrin serum level were larger and more often spread at the time of diagnosis than ERP tumors. The risk of dying was for the remaining evaluated compounds higher among patients with ERP breast cancer when compared to those with ERN. In the highest quartile of polychlorinated biphenyls (ΣPCB) it was more than 2-fold increased (Relative risk [RR] I vs. IV quartile, 2.5, 95% CI 1.1-5.7), but no dose-response relation was apparent. The results do not suggest that exposure to potential estrogenic organochlorines leads to development of an ERP breast cancer. A possible adverse effect on prognosis of hormone-responsive breast cancers needs to be clarified

  2. Poly(ADP-ribose) polymerase as a novel regulator of 17β-estradiol-induced cell growth through a control of the estrogen receptor/IGF-1 receptor/PDZK1 axis.

    Science.gov (United States)

    Kim, Hogyoung; Tarhuni, Abdelmetalab; Abd Elmageed, Zakaria Y; Boulares, A Hamid

    2015-07-17

    We and others have extensively investigated the role of PARP-1 in cell growth and demise in response to pathophysiological cues. Most of the clinical trials on PARP inhibitors are targeting primarily estrogen receptor (ER) negative cancers with BRCA-deficiency. It is surprising that the role of the enzyme has yet to be investigated in ER-mediated cell growth. It is noteworthy that ER is expressed in the majority of breast cancers. We recently showed that the scaffolding protein PDZK1 is critical for 17β-estradiol (E2)-induced growth of breast cancer cells. We demonstrated that E2-induced PDZK1 expression is indirectly regulated by ER and requires IGF-1 receptor (IGF-1R). The breast cancer cell lines MCF-7 and BT474 were used as ER(+) cell culture models. Thieno[2,3-c]isoquinolin-5-one (TIQ-A) and olaparib (AZD2281) were used as potent inhibitors of PARP. PARP-1 knockdown by shRNA was used to show specificity of the effects to PARP-1. In this study, we aimed to determine the effect of PARP inhibition on estrogen-induced growth of breast cancer cells and examine whether the potential effect is linked to PDZK1 and IGF-1R expression. Our results show that PARP inhibition pharmacologically by TIQ-A or olaparib or by PARP-1 knockdown blocked E2-dependent growth of MCF-7 cells. Such inhibitory effect was also observed in olaparib-treated BT474 cells. The effect of PARP inhibition on cell growth coincided with an efficient reduction in E2-induced PDZK1 expression. This effect was accompanied by a similar decrease in the cell cycle protein cyclin D1. PARP appeared to regulate E2-induced PDZK1 at the mRNA level. Such regulation may be linked to a modulation of IGF-1R as PARP inhibition pharmacologically or by PARP-1 knockdown efficiently reduced E2-induced expression of the receptor at the protein and mRNA levels. Overall, our results show for the first time that PARP regulates E2-mediated cell growth by controlling the ER/IGF-1R/PDZK1 axis. These findings suggest that the

  3. Testosterone treatment increases androgen receptor and aromatase gene expression in myotubes from patients with PCOS and controls, but does not induce insulin resistance

    DEFF Research Database (Denmark)

    Eriksen, Mette Brandt; Glintborg, Dorte; Nielsen, Michael Friberg Bruun

    2014-01-01

    Polycystic ovary syndrome (PCOS) is associated with insulin resistance and increased risk of type 2 diabetes. Skeletal muscle is the major site of insulin mediated glucose disposal and the skeletal muscle tissue is capable to synthesize, convert and degrade androgens. Insulin sensitivity is conse......Polycystic ovary syndrome (PCOS) is associated with insulin resistance and increased risk of type 2 diabetes. Skeletal muscle is the major site of insulin mediated glucose disposal and the skeletal muscle tissue is capable to synthesize, convert and degrade androgens. Insulin sensitivity...... is conserved in cultured myotubes (in vitro) from patients with PCOS, but the effect of testosterone on this insulin sensitivity is unknown. We investigated the effect of 7days testosterone treatment (100nmol/l) on glucose transport and gene expression levels of hormone receptors and enzymes involved...... in the synthesis and conversion of testosterone (HSD17B1, HSD17B2, CYP19A1, SRD5A1-2, AR, ER-α, HSD17B6 and AKR1-3) in myotubes from ten patients with PCOS and ten matched controls. Testosterone treatment significantly increased aromatase and androgen receptor gene expression levels in patients and controls...

  4. Liver X receptor β controls thyroid hormone feedback in the brain and regulates browning of subcutaneous white adipose tissue.

    Science.gov (United States)

    Miao, Yifei; Wu, Wanfu; Dai, Yubing; Maneix, Laure; Huang, Bo; Warner, Margaret; Gustafsson, Jan-Åke

    2015-11-10

    The recent discovery of browning of white adipose tissue (WAT) has raised great research interest because of its significant potential in counteracting obesity and type 2 diabetes. Browning is the result of the induction in WAT of a newly discovered type of adipocyte, the beige cell. When mice are exposed to cold or several kinds of hormones or treatments with chemicals, specific depots of WAT undergo a browning process, characterized by highly activated mitochondria and increased heat production and energy expenditure. However, the mechanisms underlying browning are still poorly understood. Liver X receptors (LXRs) are one class of nuclear receptors, which play a vital role in regulating cholesterol, triglyceride, and glucose metabolism. Following our previous finding that LXRs serve as repressors of uncoupling protein-1 (UCP1) in classic brown adipose tissue in female mice, we found that LXRs, especially LXRβ, also repress the browning process of subcutaneous adipose tissue (SAT) in male rodents fed a normal diet. Depletion of LXRs activated thyroid-stimulating hormone (TSH)-releasing hormone (TRH)-positive neurons in the paraventricular nucleus area of the hypothalamus and thus stimulated secretion of TSH from the pituitary. Consequently, production of thyroid hormones in the thyroid gland and circulating thyroid hormone level were increased. Moreover, the activity of thyroid signaling in SAT was markedly increased. Together, our findings have uncovered the basis of increased energy expenditure in male LXR knockout mice and provided support for targeting LXRs in treatment of obesity.

  5. G protein-coupled receptor 84 controls osteoclastogenesis through inhibition of NF-κB and MAPK signaling pathways.

    Science.gov (United States)

    Park, Ji-Wan; Yoon, Hye-Jin; Kang, Woo Youl; Cho, Seungil; Seong, Sook Jin; Lee, Hae Won; Yoon, Young-Ran; Kim, Hyun-Ju

    2018-02-01

    GPR84, a member of the G protein-coupled receptor family, is found predominantly in immune cells, such as macrophages, and functions as a pivotal modulator of inflammatory responses. In this study, we investigated the role of GPR84 in receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation. Our microarray data showed that GPR84 was significantly downregulated in osteoclasts compared to in their precursors, macrophages. The overexpression of GPR84 in bone marrow-derived macrophages suppressed the formation of multinucleated osteoclasts without affecting precursor proliferation. In addition, GPR84 overexpression attenuated the induction of c-Fos and nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), which are transcription factors that are critical for osteoclastogenesis. Furthermore, knockdown of GPR84 using a small hairpin RNA promoted RANKL-mediated osteoclast differentiation and gene expression of osteoclastogenic markers. Mechanistically, GPR84 overexpression blocked RANKL-stimulated phosphorylation of IκBα and three MAPKs, JNK, ERK, and p38. GPR84 also suppressed NF-κB transcriptional activity mediated by RANKL. Conversely, GPR84 knockdown enhanced RANKL-induced activation of IκBα and the three MAPKs. Collectively, our results revealed that GPR84 functions as a negative regulator of osteoclastogenesis, suggesting that it may be a potential therapeutic target for osteoclast-mediated bone-destructive diseases. © 2017 Wiley Periodicals, Inc.

  6. The selectivity of receptor tyrosine kinase signaling is controlled by a secondary SH2 domain binding site.

    Science.gov (United States)

    Bae, Jae Hyun; Lew, Erin Denise; Yuzawa, Satoru; Tomé, Francisco; Lax, Irit; Schlessinger, Joseph

    2009-08-07

    SH2 domain-mediated interactions represent a crucial step in transmembrane signaling by receptor tyrosine kinases. SH2 domains recognize phosphotyrosine (pY) in the context of particular sequence motifs in receptor phosphorylation sites. However, the modest binding affinity of SH2 domains to pY containing peptides may not account for and likely represents an oversimplified mechanism for regulation of selectivity of signaling pathways in living cells. Here we describe the crystal structure of the activated tyrosine kinase domain of FGFR1 in complex with a phospholipase Cgamma fragment. The structural and biochemical data and experiments with cultured cells show that the selectivity of phospholipase Cgamma binding and signaling via activated FGFR1 are determined by interactions between a secondary binding site on an SH2 domain and a region in FGFR1 kinase domain in a phosphorylation independent manner. These experiments reveal a mechanism for how SH2 domain selectivity is regulated in vivo to mediate a specific cellular process.

  7. The role of calcium in the receptor mediated control of potassium permeability in the rat lacrimal gland

    International Nuclear Information System (INIS)

    Parod, R.J.; Putney, J.W. Jr.

    1978-01-01

    In the presence of extracellular Ca, adrenaline stimulated by a large increase in the rate of K ( 86 Rb) release from rat lacrimal slices, followed by a lower, more sustained rate. In the absence of extracellular Ca, adrenaline elicited only a transient release of 86 Rb. The artificial introduction of Ca into the cytosol by the ionophore A-23187 could also initiate the release of 86 Rb. In a zero-Ca medium, if either adrenaline or carbachol produced a transient release of 86 Rb, the tissue could not respond to the other agonist with a transient release unless Ca was momentarily reintroduced to the medium. If Ca was present in a limiting concentration, the Ca-dependent rate of 86 Rb release elicited from a lacrimal slice exposed simultaneously to carbachol and adrenaline was not significantly different from the release seen with carbachol alone. It is concluded that the agonist-induced release of K from the lacrimal gland consists of both a Ca-independent phase which is initiated by the release of a limited pool of Ca, and a Ca-dependent phase which is mediated by the influx of extracellular Ca. It is also concluded that both α-adrenergic and muscarinic receptors occupation activate a common, post-receptor mechanism which may be responsible for both phases of K release. (author)

  8. CDKL5 controls postsynaptic localization of GluN2B-containing NMDA receptors in the hippocampus and regulates seizure susceptibility.

    Science.gov (United States)

    Okuda, Kosuke; Kobayashi, Shizuka; Fukaya, Masahiro; Watanabe, Aya; Murakami, Takuto; Hagiwara, Mai; Sato, Tempei; Ueno, Hiroe; Ogonuki, Narumi; Komano-Inoue, Sayaka; Manabe, Hiroyuki; Yamaguchi, Masahiro; Ogura, Atsuo; Asahara, Hiroshi; Sakagami, Hiroyuki; Mizuguchi, Masashi; Manabe, Toshiya; Tanaka, Teruyuki

    2017-10-01

    Mutations in the Cyclin-dependent kinase-like 5 (CDKL5) gene cause severe neurodevelopmental disorders accompanied by intractable epilepsies, i.e. West syndrome or atypical Rett syndrome. Here we report generation of the Cdkl5 knockout mouse and show that CDKL5 controls postsynaptic localization of GluN2B-containing N-methyl-d-aspartate (NMDA) receptors in the hippocampus and regulates seizure susceptibility. Cdkl5 -/Y mice showed normal sensitivity to kainic acid; however, they displayed significant hyperexcitability to NMDA. In concordance with this result, electrophysiological analysis in the hippocampal CA1 region disclosed an increased ratio of NMDA/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated excitatory postsynaptic currents (EPSCs) and a significantly larger decay time constant of NMDA receptor-mediated EPSCs (NMDA-EPSCs) as well as a stronger inhibition of the NMDA-EPSCs by the GluN2B-selective antagonist ifenprodil in Cdkl5 -/Y mice. Subcellular fractionation of the hippocampus from Cdkl5 -/Y mice revealed a significant increase of GluN2B and SAP102 in the PSD (postsynaptic density)-1T fraction, without changes in the S1 (post-nuclear) fraction or mRNA transcripts, indicating an intracellular distribution shift of these proteins to the PSD. Immunoelectron microscopic analysis of the hippocampal CA1 region further confirmed postsynaptic overaccumulation of GluN2B and SAP102 in Cdkl5 -/Y mice. Furthermore, ifenprodil abrogated the NMDA-induced hyperexcitability in Cdkl5 -/Y mice, suggesting that upregulation of GluN2B accounts for the enhanced seizure susceptibility. These data indicate that CDKL5 plays an important role in controlling postsynaptic localization of the GluN2B-SAP102 complex in the hippocampus and thereby regulates seizure susceptibility, and that aberrant NMDA receptor-mediated synaptic transmission underlies the pathological mechanisms of the CDKL5 loss-of-function. Copyright © 2017 Elsevier Inc. All rights

  9. Receptor assay

    Energy Technology Data Exchange (ETDEWEB)

    Kato, K; Ibayashi, H [Kyushu Univ., Fukuoka (Japan). Faculty of Medicine

    1975-05-01

    This paper summarized present status and problems of analysis of hormone receptor and a few considerations on clinical significance of receptor abnormalities. It was pointed that in future clinical field quantitative and qualitative analysis of receptor did not remain only in the etiological discussion, but that it was an epoch-making field of investigation which contained the possiblity of artificial change of sensitivity of living body on drugs and the development connected directly with treatment of various diseases.

  10. FGFR antagonist induces protective autophagy in FGFR1-amplified breast cancer cell

    International Nuclear Information System (INIS)

    Chen, Yi; Xie, Xiaoyan; Li, Xinyi; Wang, Peiqi; Jing, Qian; Yue, Jiaqi; Liu, Yang; Cheng, Zhong; Li, Jingyi; Song, Haixing; Li, Guoyu; Liu, Rui; Wang, Jinhui

    2016-01-01

    Breast cancer, representing approximately 30% of all gynecological cancer cases diagnosed yearly, is a leading cause of cancer-related mortality for women. Amplification of FGFR1 is frequently observed in breast cancers and is associated with poor prognosis. Though FGFRs have long been considered as anti-cancer drug targets, and a cluster of FGFR antagonists are currently under clinical trials, the precise cellular responses under the treatment of FGFR antagonists remains unclear. Here, we show that PD166866, an FGFR1-selective inhibitor, inhibits proliferation and triggers anoikis in FGFR1-amplified breast cancer cell lines. Notably, we demonstrate that PD166866 induces autophagy in FGFR1-amplified breast cancer cell lines, while blockage of autophagy by Atg5 knockdown further enhances the anti-proliferative activities of PD166866. Moreover, mechanistic study reveals that PD166866 induces autophagy through repressing Akt/mTOR signaling pathway. Together, the present study provides new insights into the molecular mechanisms underlying the anti-tumor activities of FGFR antagonists, and may further assist the FGFRs-based drug discovery. -- Highlights: •FGFR1 antagonist inhibits cell viability in FGFR1-amplified breast cancer cells. •FGFR1 antagonist induces autophagy in FGFR1-amplified breast cancer cells. •FGFR1 antagonist-induced autophagy is protective. •FGFR1 antagonist induces autophagy by inhibiting Akt/mTOR pathway.

  11. FGFR antagonist induces protective autophagy in FGFR1-amplified breast cancer cell

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Yi [The School of Biomedical Sciences, Chengdu Medical College, Chengdu 610083 (China); Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu (China); Xie, Xiaoyan; Li, Xinyi; Wang, Peiqi [State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University (China); Jing, Qian; Yue, Jiaqi; Liu, Yang [The School of Biomedical Sciences, Chengdu Medical College, Chengdu 610083 (China); Cheng, Zhong [Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu (China); Li, Jingyi, E-mail: li--jingyi@hotmail.com [The School of Biomedical Sciences, Chengdu Medical College, Chengdu 610083 (China); Song, Haixing [The School of Biomedical Sciences, Chengdu Medical College, Chengdu 610083 (China); Li, Guoyu, E-mail: liguoyulisa@163.com [School of Pharmacy, Shihezi University, Shihezi 832003 (China); Liu, Rui, E-mail: liurui_scu@hotmail.com [State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University (China); Wang, Jinhui [School of Pharmacy, Shihezi University, Shihezi 832003 (China)

    2016-05-20

    Breast cancer, representing approximately 30% of all gynecological cancer cases diagnosed yearly, is a leading cause of cancer-related mortality for women. Amplification of FGFR1 is frequently observed in breast cancers and is associated with poor prognosis. Though FGFRs have long been considered as anti-cancer drug targets, and a cluster of FGFR antagonists are currently under clinical trials, the precise cellular responses under the treatment of FGFR antagonists remains unclear. Here, we show that PD166866, an FGFR1-selective inhibitor, inhibits proliferation and triggers anoikis in FGFR1-amplified breast cancer cell lines. Notably, we demonstrate that PD166866 induces autophagy in FGFR1-amplified breast cancer cell lines, while blockage of autophagy by Atg5 knockdown further enhances the anti-proliferative activities of PD166866. Moreover, mechanistic study reveals that PD166866 induces autophagy through repressing Akt/mTOR signaling pathway. Together, the present study provides new insights into the molecular mechanisms underlying the anti-tumor activities of FGFR antagonists, and may further assist the FGFRs-based drug discovery. -- Highlights: •FGFR1 antagonist inhibits cell viability in FGFR1-amplified breast cancer cells. •FGFR1 antagonist induces autophagy in FGFR1-amplified breast cancer cells. •FGFR1 antagonist-induced autophagy is protective. •FGFR1 antagonist induces autophagy by inhibiting Akt/mTOR pathway.

  12. The Use of Benzodiazepine Receptor Agonists and Risk of Respiratory Failure in Patients with Chronic Obstructive Pulmonary Disease: A Nationwide Population-Based Case-Control Study

    Science.gov (United States)

    Chen, Su-Jung; Yeh, Chiu-Mei; Chao, Tze-Fan; Liu, Chia-Jen; Wang, Kang-Ling; Chen, Tzeng-Ji; Chou, Pesus; Wang, Fu-Der

    2015-01-01

    Study Objectives: Insomnia is prevalent in patients with chronic obstructive pulmonary disease (COPD), and benzodiazepine receptor agonists (BZRAs) are the most commonly used drugs despite their adverse effects on respiratory function. The aim of this study was to investigate whether the use of BZRAs was associated with an increased risk of respiratory failure (RF) in COPD patients. Design: Matched case-control study. Setting: National Health Insurance Research Database (NHIRD) in Taiwan. Participants: The case group consisted of 2,434 COPD patients with RF, and the control group consisted of 2,434 COPD patients without RF, matched for age, sex, and date of enrollment. Measurements and Results: Exposure to BZRAs during the 180-day period preceding the index date was analyzed and compared in the case and control groups. Conditional logistic regression was performed, and the use of BZRAs was associated with an increased risk of RF (adjusted odds ratio [aOR] 1.56, 95% confidence interval [CI] 1.14–2.13). In subgroup analysis, we found that the benzodiazepine (BZD) users had a higher risk of RF (aOR 1.58, 95% CI 1.14–2.20), whereas the risk in non-benzodiazepine (non-BZD) users was insignificant (aOR 0.85, 95% CI 0.51–1.44). A greater than 2-fold increase in risk was found in those who received two or more kinds of BZRAs and those using a combination of BZD and non-BZD medications. Conclusions: The use of benzodiazepine receptor agonists was a significant risk factor for respiratory failure in patients with chronic obstructive pulmonary disease (COPD). Compared to benzodiazepine, the prescription of non-benzodiazepine may be safer for the management of insomnia in COPD patients. Citation: Chen SJ, Yeh CM, Chao TF, Liu CJ, Wang KL, Chen TJ, Chou P, Wang FD. The use of benzodiazepine receptor agonists and risk of respiratory failure in patients with chronic obstructive pulmonary disease: a nationwide population-based case-control study. SLEEP 2015;38(7):1045–1050

  13. Common selective serotonin reuptake inhibitor side effects in older adults associated with genetic polymorphisms in the serotonin transporter and receptors: data from a randomized controlled trial.

    Science.gov (United States)

    Garfield, Lauren D; Dixon, David; Nowotny, Petra; Lotrich, Francis E; Pollock, Bruce G; Kristjansson, Sean D; Doré, Peter M; Lenze, Eric J

    2014-10-01

    Antidepressant side effects are a significant public health issue, associated with poor adherence, premature treatment discontinuation, and, rarely, significant harm. Older adults assume the largest and most serious burden of medication side effects. We investigated the association between antidepressant side effects and genetic variation in the serotonin system in anxious, older adults participating in a randomized, placebo-controlled trial of the selective serotonin reuptake inhibitor (SSRI) escitalopram. Adults (N = 177) aged ≥ 60 years were randomized to active treatment or placebo for 12 weeks. Side effects were assessed using the Udvalg fur Kliniske Undersøgelser side-effect rating scale. Genetic polymorphisms were putative functional variants in the promoters of the serotonin transporter and 1A and 2A receptors (5-HTTLPR [L/S + rs25531], HTR1A rs6295, HTR2A rs6311, respectively). Four significant drug-placebo side-effect differences were found: increased duration of sleep, dry mouth, diarrhea, and diminished sexual desire. Analyses using putative high- versus low-transcription genotype groupings revealed six pharmacogenetic effects: greater dry mouth and decreased sexual desire for the low- and high-expressing serotonin transporter genotypes, respectively, and greater diarrhea with the 1A receptor low-transcription genotype. Diminished sexual desire was experienced significantly more by high-expressing genotypes in the serotonin transporter, 1A, or 2A receptors. There was not a significant relationship between drug concentration and side effects nor a mean difference in drug concentration between low- and high-expressing genotypes. Genetic variation in the serotonin system may predict who develops common SSRI side effects and why. More work is needed to further characterize this genetic modulation and to translate research findings into strategies useful for more personalized patient care. Published by Elsevier Inc.

  14. Common SSRI side-effects in older adults associated with genetic polymorphisms in the serotonin transporter and receptors: Data from a randomized controlled trial

    Science.gov (United States)

    Garfield, Lauren D.; Dixon, David; Nowotny, Petra; Lotrich, Francis E.; Pollock, Bruce G.; Kristjansson, Sean D.; Doré, Peter M.; Lenze, Eric J.

    2013-01-01

    Objective Antidepressant side-effects are a significant public health issue, associated with poor adherence, premature treatment discontinuation and in rare cases significant harm. This is especially relevant for older adults, who assume the largest and most serious burden of medication side-effects. We investigated the association between antidepressant side-effects and genetic variation in the serotonin system in anxious, older adults participating in a randomized, placebo-controlled trial of the SSRI escitalopram. Method Adults (n=177) aged ≥ 60 years were randomized to active treatment or placebo for 12-weeks. Side-effects were assessed using the UKU side effect rating scale. Genetic polymorphisms were putative functional variants in the promoters of the serotonin transporter and 1A and 2A receptors (5-HTTLPR (L/S + rs25531), HTR1A rs6295, HTR2A rs6311, respectively). Results Four significant drug-placebo side-effect differences were found, including increased duration of sleep, dry mouth, diarrhea and diminished sexual desire. Analyses using putative high- vs low-transcription genotype groupings revealed 6 pharmacogenetic effects: greater dry mouth and decreased sexual desire for the low- and high-expressing genotypes of the serotonin transporter, respectively, and greater diarrhea with the low-transcription genotype of the 1A receptor. Diminished sexual desire was experienced significantly more in those with high-expressing genotype and either the serotonin transporter, 1A or 2A receptors. There was not a significant relationship between drug concentration and side-effects nor a mean difference in drug concentration between low- and high-expressing genotypes. Conclusion Genetic variation in the 5HT system may predict who develops common SSRI side-effects and why. More work is needed to further characterize this genetic modulation and to translate research findings into strategies useful for more personalized patient care. PMID:24021217

  15. The phosphorylation state of CD3gamma influences T cell responsiveness and controls T cell receptor cycling

    DEFF Research Database (Denmark)

    Dietrich, J; Backstrom, T; Lauritsen, JP

    1998-01-01

    The T cell receptor (TCR) is internalized following activation of protein kinase C (PKC) via a leucine (Leu)-based motif in CD3gamma. Some studies have indicated that the TCR is recycled back to the cell surface following PKC-mediated internalization. The functional state of recycled TCR...... the phosphorylation state of CD3gamma and T cell responsiveness. Based on these observations a physiological role of CD3gamma and TCR cycling is proposed....... and the mechanisms involved in the sorting events following PKC-induced internalization are not known. In this study, we demonstrated that following PKC-induced internalization, the TCR is recycled back to the cell surface in a functional state. TCR recycling was dependent on dephosphorylation of CD3gamma, probably...

  16. Improving the prognosis of diabetic patients: evaluating the role of intensive versus moderate blood pressure control with selective angiotensin II receptor blocker (ARB therapy

    Directory of Open Access Journals (Sweden)

    Martin P Bedigian

    2000-06-01

    Full Text Available The ABCD (Appropriate Blood Pressure Control in Diabetes and ABCD-2V (Part 2 with Valsartan are prospective, randomised clinical trials which will provide important data on the impact of intensive vs. moderate blood pressure (BP control on microvascular and macrovascular complications in normotensive and hypertensive patients with type 2 diabetes mellitus (DM. The ABCD trial was a five-year study that compared the effects of intensive vs. moderate BP control on the endpoints of nephropathy, retinopathy, neuropathy, and cardiovascular disease events using a calcium channel blocker (CCB and an angiotensin-converting enzyme (ACE inhibitor as the primary antihypertensive agents. The recently published results of the hypertensive cohort of ABCD are reviewed herein. The follow-up study, ABCD-2V, is ongoing and was designed to compare intensive vs. moderate BP control on the same endpoints as the ABCD study, using the highly selective angiotensin II receptor blocker (ARB valsartan as the primary antihypertensive agent. First results of ABCD-2V are expected in 2004. The baseline characteristics for the patients enrolled thus far in the hypertensive cohort of ABCD-2V are reviewed. These studies will provide insight into the role of intensive vs. moderate BP control in the management of normotensive and hypertensive patients with type 2 DM.

  17. The Use of Benzodiazepine Receptor Agonists and Risk of Respiratory Failure in Patients with Chronic Obstructive Pulmonary Disease: A Nationwide Population-Based Case-Control Study.

    Science.gov (United States)

    Chen, Su-Jung; Yeh, Chiu-Mei; Chao, Tze-Fan; Liu, Chia-Jen; Wang, Kang-Ling; Chen, Tzeng-Ji; Chou, Pesus; Wang, Fu-Der

    2015-07-01

    Insomnia is prevalent in patients with chronic obstructive pulmonary disease (COPD), and benzodiazepine receptor agonists (BZRAs) are the most commonly used drugs despite their adverse effects on respiratory function. The aim of this study was to investigate whether the use of BZRAs was associated with an increased risk of respiratory failure (RF) in COPD patients. Matched case-control study. National Health Insurance Research Database (NHIRD) in Taiwan. The case group consisted of 2,434 COPD patients with RF, and the control group consisted of 2,434 COPD patients without RF, matched for age, sex, and date of enrollment. Exposure to BZRAs during the 180-day period preceding the index date was analyzed and compared in the case and control groups. Conditional logistic regression was performed, and the use of BZRAs was associated with an increased risk of RF (adjusted odds ratio [aOR] 1.56, 95% confidence interval [CI] 1.14-2.13). In subgroup analysis, we found that the benzodiazepine (BZD) users had a higher risk of RF (aOR 1.58, 95% CI 1.14-2.20), whereas the risk in non-benzodiazepine (non-BZD) users was insignificant (aOR 0.85, 95% CI 0.51-1.44). A greater than 2-fold increase in risk was found in those who received two or more kinds of BZRAs and those using a combination of BZD and non-BZD medications. The use of benzodiazepine receptor agonists was a significant risk factor for respiratory failure in patients with chronic obstructive pulmonary disease (COPD). Compared to benzodiazepine, the prescription of non-benzodiazepine may be safer for the management of insomnia in COPD patients. © 2015 Associated Professional Sleep Societies, LLC.

  18. Periodic variation in bile acids controls circadian changes in uric acid via regulation of xanthine oxidase by the orphan nuclear receptor PPARα.

    Science.gov (United States)

    Kanemitsu, Takumi; Tsurudome, Yuya; Kusunose, Naoki; Oda, Masayuki; Matsunaga, Naoya; Koyanagi, Satoru; Ohdo, Shigehiro

    2017-12-29

    Xanthine oxidase (XOD), also known as xanthine dehydrogenase, is a rate-limiting enzyme in purine nucleotide degradation, which produces uric acid. Uric acid concentrations in the blood and liver exhibit circadian oscillations in both humans and rodents; however, the underlying mechanisms remain unclear. Here, we demonstrate that XOD expression and enzymatic activity exhibit circadian oscillations in the mouse liver. We found that the orphan nuclear receptor peroxisome proliferator-activated receptor-α (PPARα) transcriptionally activated the mouse XOD gene and that bile acids suppressed XOD transactivation. The synthesis of bile acids is known to be under the control of the circadian clock, and we observed that the time-dependent accumulation of bile acids in hepatic cells interfered with the recruitment of the co-transcriptional activator p300 to PPARα, thereby repressing XOD expression. This time-dependent suppression of PPARα-mediated transactivation by bile acids caused an oscillation in the hepatic expression of XOD, which, in turn, led to circadian alterations in uric acid production. Finally, we also demonstrated that the anti-hyperuricemic effect of the XOD inhibitor febuxostat was enhanced by administering it at the time of day before hepatic XOD activity increased. These results suggest an underlying mechanism for the circadian alterations in uric acid production and also underscore the importance of selecting an appropriate time of day for administering XOD inhibitors. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  19. The Use of an IL-1 Receptor Antagonist Peptide to Control Inflammation in the Treatment of Corneal Limbal Epithelial Stem Cell Deficiency

    Directory of Open Access Journals (Sweden)

    E. Fok

    2015-01-01

    Full Text Available Corneal limbal stem cell deficiency (LSCD may be treated using ex vivo limbal epithelial stem cells (LESCs derived from cadaveric donor tissue. However, continuing challenges exist around tissue availability, inflammation, and transplant rejection. Lipopolysaccharide (LPS or recombinant human IL-1β stimulated primary human keratocyte and LESC models were used to investigate the anti-inflammatory properties of a short chain, IL-1 receptor antagonist peptide for use in LESC sheet growth to control inflammation. The peptide was characterized using mass spectroscopy and high performance liquid chromatography. Peptide cytotoxicity, patterns of cell cytokine expression in response to LPS or IL-1β stimulation, and peptide suppression of this response were investigated by MTS/LDH assays, ELISA, and q-PCR. Cell differences in LPS stimulated toll-like receptor 4 expression were investigated using immunocytochemistry. A significant reduction in rIL-1β stimulated inflammatory cytokine production occurred following LESC and keratocyte incubation with anti-inflammatory peptide and in LPS stimulated IL-6 and IL-8 production following keratocyte incubation with peptide (1 mg/mL P<0.05. LESCs produced no cytokine response to LPS stimulation and showed no TLR4 expression. The peptide supported LESC growth when adhered to a silicone hydrogel contact lens indicating potential use in improved LESC grafting through suppression of inflammation.

  20. The Secreted Protein C1QL1 and Its Receptor BAI3 Control the Synaptic Connectivity of Excitatory Inputs Converging on Cerebellar Purkinje Cells

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    Séverine M. Sigoillot

    2015-02-01

    Full Text Available Precise patterns of connectivity are established by different types of afferents on a given target neuron, leading to well-defined and non-overlapping synaptic territories. What regulates the specific characteristics of each type of synapse, in terms of number, morphology, and subcellular localization, remains to be understood. Here, we show that the signaling pathway formed by the secreted complement C1Q-related protein C1QL1 and its receptor, the adhesion-GPCR brain angiogenesis inhibitor 3 (BAI3, controls the stereotyped pattern of connectivity established by excitatory afferents on cerebellar Purkinje cells. The BAI3 receptor modulates synaptogenesis of both parallel fiber and climbing fiber afferents. The restricted and timely expression of its ligand C1QL1 in inferior olivary neurons ensures the establishment of the proper synaptic territory for climbing fibers. Given the broad expression of C1QL and BAI proteins in the developing mouse brain, our study reveals a general mechanism contributing to the formation of a functional brain.

  1. G-protein-coupled receptors for free fatty acids

    DEFF Research Database (Denmark)

    Milligan, Graeme; Ulven, Trond; Murdoch, Hannah

    2014-01-01

    of these receptors. However, ongoing clinical trials of agonists of free fatty acid receptor 1 suggest that this receptor and other receptors for free fatty acids may provide a successful strategy for controlling hyperglycaemia and providing novel approaches to treat diabetes. Receptors responsive to free fatty acid...

  2. Evidence for cholinergic participation in the control of bird song; acetylcholinesterase distribution and muscarinic receptor autoradiography in the zebra finch brain

    International Nuclear Information System (INIS)

    Ryan, S.M.; Arnold, A.P.

    1981-01-01

    Brain regions thought to be involved in the control of song in the zebra finch (Poephila guttata), were examined histochemically using the Karnovsky and Roots direct-coloring method for the detection of acetylcholinesterase (AChE) and the autoradiographic method for the localization of muscarinic cholinergic receptors following injection of tritiated quinuclidinyl benzilate (3H QNB). All presently identified vocal control nuclei in both males and females contain AChE. These nuclei include Area X, magnocellular nucleus of the anterior neostriatum (MAN), nucleus interface (NIF), caudal nucleus of the hyperstriatum ventrale (HVc), intercollicular nucleus (ICo), nucleus uva, robust nucleus of the archistriatum (RA), and tracheosyringeal portion of the hypoglossal nerve nucleus (nXIIts). All nuclei except Area X contain mostly AChE-synthesizing cell bodies. All of these nuclei contain some AChE in the neuropil, with particularly intense staining in Area X, the surrounding LPO, and the dorsomedial portion of ICo. In agreement with this description are very high concentrations of 3H QNB in both Area X and the dorsomedial ICo. HVc also appears specifically labeled. Evidence from these two histological technique suggests that efferent projections of most vocal control area may utilize acetylcholine, and that several of the vocal control nuclei may themselves receive muscarinic cholinergic projection. In Area X, there are sex differences of AChE neuropil staining. This evidence suggesting that sexually dimorphic projections to or within Area X are cholinergic or cholinoceptive

  3. Additive Effect of Qidan Dihuang Grain, a Traditional Chinese Medicine, and Angiotensin Receptor Blockers on Albuminuria Levels in Patients with Diabetic Nephropathy: A Randomized, Parallel-Controlled Trial

    Science.gov (United States)

    Xiang, Lei; Jiang, Pingping; Zhou, Lin; Sun, Xiaomin; Bi, Jianlu; Cui, Lijuan; Nie, Xiaoli; Luo, Ren; Liu, Yanyan

    2016-01-01

    Albuminuria is characteristic of early-stage diabetic nephropathy (DN). The conventional treatments with angiotensin receptor blockers (ARB) are unable to prevent the development of albuminuria in normotensive individuals with type 2 diabetes mellitus (T2DM). Purpose. The present study aimed to evaluate the effect of ARB combined with a Chinese formula Qidan Dihuang grain (QDDHG) in improving albuminuria and Traditional Chinese Medicine Symptom (TCMS) scores in normotensive individuals with T2DM. Methods. Eligible patients were randomized to the treatment group and the control group. Results. Compared with baseline (week 0), both treatment and control groups markedly improved the 24-hour albuminuria, total proteinuria (TPU), and urinary albumin to creatinine ratio (A/C) at 4, 8, and 12 weeks. Between treatment and the control group, the levels of albuminuria in the treatment group were significantly lower than in the control group at 8 and 12 weeks (p < 0.05). In addition, treatment group markedly decreased the scores of TCMS after treatment. Conclusion. This trial suggests that QDDHG combined with ARB administration decreases the levels of albuminuria and the scores for TCMS in normotensive individuals with T2DM. PMID:27375762

  4. Expression of feeding-related peptide receptors mRNA in GT1-7 cell line and roles of leptin and orexins in control of GnRH secretion.

    Science.gov (United States)

    Yang, Ying; Zhou, Li-bin; Liu, Shang-quan; Tang, Jing-feng; Li, Feng-yin; Li, Rong-ying; Song, Huai-dong; Chen, Ming-dao

    2005-08-01

    To investigate the expression of feeding-related peptide receptors mRNA in GT1-7 cell line and roles of leptin and orexins in the control of GnRH secretion. Receptors of bombesin3, cholecystokinin (CCK)-A, CCK-B, glucagon-like peptide (GLP)1, melanin-concentrating hormone (MCH)1, orexin1, orexin2, neuromedin-B, neuropeptide Y (NPY)1 and NPY5, neurotensin (NT)1, NT2, NT3, and leptin receptor long form mRNA in GT1-7 cells were detected by reversed transcriptase-polymerase chain reaction. GT1-7 cells were treated with leptin, orexin A and orexin B at a cohort of concentrations for different lengths of time, and GnRH in medium was determined by radioimmunoassay (RIA). Receptors of bombesin 3, CCK-B, GLP1, MCH1, orexin1, neuromedin-B, NPY1, NPY5, NT1, NT3, and leptin receptor long form mRNA were expressed in GT1-7 cells, of which, receptors of GLP1, neuromedin-B, NPY1, and NT3 were highly expressed. No amplified fragments of orexin2, NT2, and CCK-A receptor cDNA were generated with GT1-7 RNA, indicating that the GT1-7 cells did not express mRNA of them. Leptin induced a significant stimulation of GnRH release, the results being most significant at 0.1 nmol/L for 15 min. In contrast to other studies in hypothalamic explants, neither orexin A nor orexin B affected basal GnRH secretion over a wide range of concentrations ranging from 1 nmol/L to 500 nmol/Lat 15, 30, and 60 min. Feeding and reproductive function are closely linked. Many orexigenic and anorexigenic signals may control feeding behavior as well as alter GnRH secretion through their receptors on GnRH neurons.

  5. Thyroid hormone and adrenergic signaling interact to control pineal expression of the dopamine receptor D4 gene (Drd4)

    DEFF Research Database (Denmark)

    Kim, Jong-So; Bailey, Michael J; Weller, Joan L

    2009-01-01

    is circadian in nature and under photoneural control. Whereas most rhythmically expressed genes in the pineal are controlled by adrenergic/cAMP signaling, Drd4 expression also requires thyroid hormone. This advance raises the questions of whether Drd4 expression is regulated by this mechanism in other systems...

  6. α1B-Adrenergic receptor signaling controls circadian expression of Tnfrsf11b by regulating clock genes in osteoblasts

    Directory of Open Access Journals (Sweden)

    Takao Hirai

    2015-11-01

    Full Text Available Circadian clocks are endogenous and biological oscillations that occur with a period of <24 h. In mammals, the central circadian pacemaker is localized in the suprachiasmatic nucleus (SCN and is linked to peripheral tissues through neural and hormonal signals. In the present study, we investigated the physiological function of the molecular clock on bone remodeling. The results of loss-of-function and gain-of-function experiments both indicated that the rhythmic expression of Tnfrsf11b, which encodes osteoprotegerin (OPG, was regulated by Bmal1 in MC3T3-E1 cells. We also showed that REV-ERBα negatively regulated Tnfrsf11b as well as Bmal1 in MC3T3-E1 cells. We systematically investigated the relationship between the sympathetic nervous system and the circadian clock in osteoblasts. The administration of phenylephrine, a nonspecific α1-adrenergic receptor (AR agonist, stimulated the expression of Tnfrsf11b, whereas the genetic ablation of α1B-AR signaling led to the alteration of Tnfrsf11b expression concomitant with Bmal1 and Per2 in bone. Thus, this study demonstrated that the circadian regulation of Tnfrsf11b was regulated by the clock genes encoding REV-ERBα (Nr1d1 and Bmal1 (Bmal1, also known as Arntl, which are components of the core loop of the circadian clock in osteoblasts.

  7. A Tumor Suppressor Gene Product, Platelet-Derived Growth Factor Receptor-Like Protein Controls Chondrocyte Proliferation and Differentiation.

    Science.gov (United States)

    Kawata, Kazumi; Kubota, Satoshi; Eguchi, Takanori; Aoyama, Eriko; Moritani, Norifumi H; Oka, Morihiko; Kawaki, Harumi; Takigawa, Masaharu

    2017-11-01

    The platelet-derived growth factor receptor-like (PDGFRL) gene is regarded as a tumor suppressor gene. However, nothing is known about the molecular function of PDGFRL. In this study, we initially clarified its function in chondrocytes. Among all cell lines examined, the PDGFRL mRNA level was the highest in chondrocytic HCS-2/8 cells. Interestingly, the proliferation of chondrocytic HCS-2/8 cells was promoted by PDGFRL overexpression, whereas that of the breast cancer-derived MDA-MB-231 cells was inhibited. Of note, in PDGFRL-overexpressing HCS-2/8 cells, the expression of chondrocyte differentiation marker genes, SOX9, ACAN, COL2A1, COL10A1, and ALP, was decreased. Moreover, we confirmed the expression of PDGFRL mRNA in normal cartilage tissue and chondrocytes. Eventually, the expression of PDGFRL mRNA in condrocytes except in the case of hypertrophic chondrocytes was demonstrated in vivo and in vitro. These findings suggest that PDGFRL plays the different roles, depending upon cell types. Particularly, in chondrocytes, PDGFRL may play a new and important role which is distinct from the function previously reported. J. Cell. Biochem. 118: 4033-4044, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  8. Son of sevenless directly links the Robo receptor to rac activation to control axon repulsion at the midline.

    Science.gov (United States)

    Yang, Long; Bashaw, Greg J

    2006-11-22

    Son of sevenless (Sos) is a dual specificity guanine nucleotide exchange factor (GEF) that regulates both Ras and Rho family GTPases and thus is uniquely poised to integrate signals that affect both gene expression and cytoskeletal reorganization. Here, using genetics, biochemistry, and cell biology, we demonstrate that Sos is recruited to the plasma membrane, where it forms a ternary complex with the Roundabout receptor and the SH3-SH2 adaptor protein Dreadlocks (Dock) to regulate Rac-dependent cytoskeletal rearrangement in response to the Slit ligand. Intriguingly, the Ras and Rac-GEF activities of Sos can be uncoupled during Robo-mediated axon repulsion; Sos axon guidance function depends on its Rac-GEF activity, but not its Ras-GEF activity. These results provide in vivo evidence that the Ras and RhoGEF domains of Sos are separable signaling modules and support a model in which Robo recruits Sos to the membrane via Dock to activate Rac during midline repulsion.

  9. Functional variation of the dopamine D2 receptor gene is associated with emotional control as well as brain activity and connectivity during emotion processing in humans.

    Science.gov (United States)

    Blasi, Giuseppe; Lo Bianco, Luciana; Taurisano, Paolo; Gelao, Barbara; Romano, Raffaella; Fazio, Leonardo; Papazacharias, Apostolos; Di Giorgio, Annabella; Caforio, Grazia; Rampino, Antonio; Masellis, Rita; Papp, Audrey; Ursini, Gianluca; Sinibaldi, Lorenzo; Popolizio, Teresa; Sadee, Wolfgang; Bertolino, Alessandro

    2009-11-25

    Personality traits related to emotion processing are, at least in part, heritable and genetically determined. Dopamine D(2) receptor signaling is involved in modulation of emotional behavior and activity of associated brain regions such as the amygdala and the prefrontal cortex. An intronic single nucleotide polymorphism within the D(2) receptor gene (DRD2) (rs1076560, guanine > thymine or G > T) shifts splicing of the two protein isoforms (D(2) short, mainly presynaptic, and D(2) long) and has been associated with modulation of memory performance and brain activity. Here, our aim was to investigate the association of DRD2 rs1076560 genotype with personality traits of emotional stability and with brain physiology during processing of emotionally relevant stimuli. DRD2 genotype and Big Five Questionnaire scores were evaluated in 134 healthy subjects demonstrating that GG subjects have reduced "emotion control" compared with GT subjects. Functional magnetic resonance imaging in a sample of 24 individuals indicated greater amygdala activity during implicit processing and greater dorsolateral prefrontal cortex (DLPFC) response during explicit processing of facial emotional stimuli in GG subjects compared with GT. Other results also demonstrate an interaction between DRD2 genotype and facial emotional expression on functional connectivity of both amygdala and dorsolateral prefrontal regions with overlapping medial prefrontal areas. Moreover, rs1076560 genotype is associated with differential relationships between amygdala/DLPFC functional connectivity and emotion control scores. These results suggest that genetically determined D(2) signaling may explain part of personality traits related to emotion processing and individual variability in specific brain responses to emotionally relevant inputs.

  10. Polymorphisms of VEGF and VEGF receptors are associated with the occurrence of ovarian hyperstimulation syndrome (OHSS)-a retrospective case-control study.

    Science.gov (United States)

    Nouri, Kazem; Haslinger, Peter; Szabo, Ladislaus; Sator, Michael; Schreiber, Martin; Schneeberger, Christian; Pietrowski, Detlef

    2014-01-01

    Ovarian hyperstimulation syndrome (OHSS) is the most serious complication of IVF/ICSI therapy. The pathophysiology and etiology of the disease is still not fully clarified. To assess whether polymorphisms of the VEGF/VEGF-receptor system contribute to the occurrence of ovarian hyperstimulation syndrome (OHSS), we performed a retrospective analysis of 116 OHSS patients, and 124 female controls. The following SNPs were genotyped: Rs2071559 (VEGFR2-604); rs2305948 (VEGFR2-1192); rs1870377 (VEGFR2-1719); rs2010963 (VEGF-405); and rs111458691 (VEGFR1-519). Odds ratios (ORs) were estimated with a 95% confidence interval (CI). Linkage disequilibrium (LD) analysis was performed in the three loci of the VEGFR2 gene. We found an overrepresentation of the T allele of the VEGFR1-519 polymorphism in OHSS patients (P = 0.02, OR: 3.62, CI: 1.16 - 11.27). By genotype modeling, we found that polymorphism of VEGFR1-519 and VEGF-405 showed significant differences in patients and controls (p = 0.02, OR: 3.79 CI: 1.98 - 11.97 and p = 0.000005, OR: 0.29, CI: 0.17 - 0.50). LD analysis revealed significant linkage disequilibrium in VEGFR2. Polymorphisms in the VEGFR2 gene and in the VEGF gene are associated with the occurrence of OHSS. This strengthens the evidence for an important role of the VEGF/VEGF- receptor system in the occurrence of OHSS.

  11. Direct control of peripheral lipid deposition by CNS GLP-1 receptor signaling is mediated by the sympathetic nervous system and blunted in diet-induced obesity.

    Science.gov (United States)

    Nogueiras, Ruben; Pérez-Tilve, Diego; Veyrat-Durebex, Christelle; Morgan, Donald A; Varela, Luis; Haynes, William G; Patterson, James T; Disse, Emmanuel; Pfluger, Paul T; López, Miguel; Woods, Stephen C; DiMarchi, Richard; Diéguez, Carlos; Rahmouni, Kamal; Rohner-Jeanrenaud, Françoise; Tschöp, Matthias H

    2009-05-06

    We investigated a possible role of the central glucagon-like peptide (GLP-1) receptor system as an essential brain circuit regulating adiposity through effects on nutrient partitioning and lipid metabolism independent from feeding behavior. Both lean and diet-induced obesity mice were used for our experiments. GLP-1 (7-36) amide was infused in the brain for 2 or 7 d. The expression of key enzymes involved in lipid metabolism was measured by real-time PCR or Western blot. To test the hypothesis that the sympathetic nervous system may be responsible for informing adipocytes about changes in CNS GLP-1 tone, we have performed direct recording of sympathetic nerve activity combined with experiments in genetically manipulated mice lacking beta-adrenergic receptors. Intracerebroventricular infusion of GLP-1 in mice directly and potently decreases lipid storage in white adipose tissue. These effects are independent from nutrient intake. Such CNS control of adipocyte metabolism was found to depend partially on a functional sympathetic nervous system. Furthermore, the effects of CNS GLP-1 on adipocyte metabolism were blunted in diet-induced obese mice. The CNS GLP-1 system decreases fat storage via direct modulation of adipocyte metabolism. This CNS GLP-1 control of adipocyte lipid metabolism appears to be mediated at least in part by the sympathetic nervous system and is independent of parallel changes in food intake and body weight. Importantly, the CNS GLP-1 system loses the capacity to modulate adipocyte metabolism in obese states, suggesting an obesity-induced adipocyte resistance to CNS GLP-1.

  12. Control of Anther Cell Differentiation by the Small Protein Ligand TPD1 and Its Receptor EMS1 in Arabidopsis.

    Directory of Open Access Journals (Sweden)

    Jian Huang

    2016-08-01

    Full Text Available A fundamental feature of sexual reproduction in plants and animals is the specification of reproductive cells that conduct meiosis to form gametes, and the associated somatic cells that provide nutrition and developmental cues to ensure successful gamete production. The anther, which is the male reproductive organ in seed plants, produces reproductive microsporocytes (pollen mother cells and surrounding somatic cells. The microsporocytes yield pollen via meiosis, and the somatic cells, particularly the tapetum, are required for the normal development of pollen. It is not known how the reproductive cells affect the differentiation of these somatic cells, and vice versa. Here, we use molecular genetics, cell biological, and biochemical approaches to demonstrate that TPD1 (TAPETUM DETERMINANT1 is a small secreted cysteine-rich protein ligand that interacts with the LRR (Leucine-Rich Repeat domain of the EMS1 (EXCESS MICROSPOROCYTES1 receptor kinase at two sites. Analyses of the expressions and localizations of TPD1 and EMS1, ectopic expression of TPD1, experimental missorting of TPD1, and ablation of microsporocytes yielded results suggesting that the precursors of microsporocyte/microsporocyte-derived TPD1 and pre-tapetal-cell-localized EMS1 initially promote the periclinal division of secondary parietal cells and then determine one of the two daughter cells as a functional tapetal cell. Our results also indicate that tapetal cells suppress microsporocyte proliferation. Collectively, our findings show that tapetal cell differentiation requires reproductive-cell-secreted TPD1, illuminating a novel mechanism whereby signals from reproductive cells determine somatic cell fate in plant sexual reproduction.

  13. Presynaptic D2 dopamine receptors control long-term depression expression and memory processes in the temporal hippocampus.

    Science.gov (United States)

    Rocchetti, Jill; Isingrini, Elsa; Dal Bo, Gregory; Sagheby, Sara; Menegaux, Aurore; Tronche, François; Levesque, Daniel; Moquin, Luc; Gratton, Alain; Wong, Tak Pan; Rubinstein, Marcelo; Giros, Bruno

    2015-03-15

    Dysfunctional mesocorticolimbic dopamine signaling has been linked to alterations in motor and reward-based functions associated with psychiatric disorders. Converging evidence from patients with psychiatric disorders and use of antipsychotics suggests that imbalance of dopamine signaling deeply alters hippocampal functions. However, given the lack of full characterization of a functional mesohippocampal pathway, the precise role of dopamine transmission in memory deficits associated with these disorders and their dedicated therapies is unknown. In particular, the positive outcome of antipsychotic treatments, commonly antagonizing D2 dopamine receptors (D2Rs), on cognitive deficits and memory impairments remains questionable. Following pharmacologic and genetic manipulation of dopamine transmission, we performed anatomic, neurochemical, electrophysiologic, and behavioral investigations to uncover the role of D2Rs in hippocampal-dependent plasticity and learning. Naïve mice (n = 4-21) were used in the different procedures. Dopamine modulated both long-term potentiation and long-term depression in the temporal hippocampus as well as spatial and recognition learning and memory in mice through D2Rs. Although genetic deletion or pharmacologic blockade of D2Rs led to the loss of long-term potentiation expression, the specific genetic removal of presynaptic D2Rs impaired long-term depression and performances on spatial memory tasks. Presynaptic D2Rs in dopamine fibers of the temporal hippocampus tightly modulate long-term depression expression and play a major role in the regulation of hippocampal learning and memory. This direct role of mesohippocampal dopamine input as uncovered here adds a new dimension to dopamine involvement in the physiology underlying deficits associated with neuropsychiatric disorders. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  14. Cis-regulatory control of the nuclear receptor Coup-TF gene in the sea urchin Paracentrotus lividus embryo.

    Directory of Open Access Journals (Sweden)

    Lamprini G Kalampoki

    Full Text Available Coup-TF, an orphan member of the nuclear receptor super family, has a fundamental role in the development of metazoan embryos. The study of the gene's regulatory circuit in the sea urchin embryo will facilitate the placement of this transcription factor in the well-studied embryonic Gene Regulatory Network (GRN. The Paracentrotus lividus Coup-TF gene (PlCoup-TF is expressed throughout embryonic development preferentially in the oral ectoderm of the gastrula and the ciliary band of the pluteus stage. Two overlapping λ genomic clones, containing three exons and upstream sequences of PlCoup-TF, were isolated from a genomic library. The transcription initiation site was determined and 5' deletions and individual segments of a 1930 bp upstream region were placed ahead of a GFP reporter cassette and injected into fertilized P.lividus eggs. Module a (-532 to -232, was necessary and sufficient to confer ciliary band expression to the reporter. Comparison of P.lividus and Strongylocentrotus purpuratus upstream Coup-TF sequences, revealed considerable conservation, but none within module a. 5' and internal deletions into module a, defined a smaller region that confers ciliary band specific expression. Putative regulatory cis-acting elements (RE1, RE2 and RE3 within module a, were specifically bound by proteins in sea urchin embryonic nuclear extracts. Site-specific mutagenesis of these elements resulted in loss of reporter activity (RE1 or ectopic expression (RE2, RE3. It is proposed that sea urchin transcription factors, which bind these three regulatory sites, are necessary for spatial and quantitative regulation of the PlCoup-TF gene at pluteus stage sea urchin embryos. These findings lead to the future identification of these factors and to the hierarchical positioning of PlCoup-TF within the embryonic GRN.

  15. Experimental pain ratings and reactivity of cortisol and soluble tumor necrosis factor-α receptor II following a trial of hypnosis: Results of a randomized controlled pilot study

    Science.gov (United States)

    Goodin, Burel R.; Quinn, Noel B.; Kronfli, Tarek; King, Christopher D.; Page, Gayle G.; Haythornthwaite, Jennifer A.; Edwards, Robert R.; Stapleton, Laura M.; McGuire, Lynanne

    2011-01-01

    Objective Current evidence supports the efficacy of hypnosis for reducing the pain associated with experimental stimulation and various acute and chronic conditions; however, the mechanisms explaining how hypnosis exerts its effects remain less clear. The hypothalamic-pituitary-adrenal (HPA) axis and pro-inflammatory cytokines represent potential targets for investigation given their purported roles in the perpetuation of painful conditions; yet, no clinical trials have thus far examined the influence of hypnosis on these mechanisms. Design Healthy participants, highly susceptible to the effects of hypnosis, were randomized to either a hypnosis intervention or a no-intervention control. Using a cold pressor task, assessments of pain intensity and pain unpleasantness were collected prior to the intervention (Pre) and following the intervention (Post) along with pain-provoked changes in salivary cortisol and the soluble receptor of tumor necrosis factor-α (sTNFαRII). Results Compared to the no-intervention control, data analyses revealed that hypnosis significantly reduced pain intensity and pain unpleasantness. Hypnosis was not significantly associated with suppression of cortisol or sTNFαRII reactivity to acute pain from Pre to Post; however, the effect sizes for these associations were medium-sized. Conclusions Overall, the findings from this randomized controlled pilot study support the importance of a future large-scale study on the effects of hypnosis for modulating pain-related changes of the HPA axis and pro-inflammatory cytokines. PMID:22233394

  16. Transgenic Adipose-specific Expression of the Nuclear Receptor RORα Drives a Striking Shift in Fat Distribution and Impairs Glycemic Control

    Directory of Open Access Journals (Sweden)

    Zewen Kelvin Tuong

    2016-09-01

    Full Text Available RORα is a member of the nuclear receptor (NR superfamily and analysis of the (global RORα-deficient mouse model revealed this NR has a role in glycemic control and fat deposition. Therefore, we generated an adipose-specific RORα ‘gain of function’ mouse model under the control of the fatty acid binding protein 4 (FABP4 promoter to elucidate the function of RORα in adipose tissue. The Tg-FABP4-RORα4 mice demonstrated a shift in fat distribution to non-adipose tissues when challenged with a high fat diet (HFD. Specifically, we observed a subcutaneous lipodystrophy, accompanied by hepatomegaly (fatty liver/mild portal fibrosis and splenomegaly; in a background of decreased weight gain and total body fat after HFD. Moreover, we observed significantly higher fasting blood glucose and impaired clearance of glucose in Tg-FABP4-RORα4 mice. Genome wide expression and qPCR profiling analysis identified: (i subcutaneous adipose specific decreases in the expression of genes involved in fatty acid biosynthesis, lipid droplet expansion and glycemic control, and (ii the fibrosis pathway as the most significant pathway [including dysregulation of the collagen/extracellular matrix (ECM pathways] in subcutaneous adipose and liver. The pathology presented in the Tg-FABP4-RORα4 mice is reminiscent of human metabolic disease (associated with aberrant ECM expression highlighting the therapeutic potential of this NR.

  17. Supraphysiologic control over HIV-1 replication mediated by CD8 T cells expressing a re-engineered CD4-based chimeric antigen receptor.

    Directory of Open Access Journals (Sweden)

    Rachel S Leibman

    2017-10-01

    Full Text Available HIV is adept at avoiding naturally generated T cell responses; therefore, there is a need to develop HIV-specific T cells with greater potency for use in HIV cure strategies. Starting with a CD4-based chimeric antigen receptor (CAR that was previously used without toxicity in clinical trials, we optimized the vector backbone, promoter, HIV targeting moiety, and transmembrane and signaling domains to determine which components augmented the ability of T cells to control HIV replication. This re-engineered CAR was at least 50-fold more potent in vitro at controlling HIV replication than the original CD4 CAR, or a TCR-based approach, and substantially better than broadly neutralizing antibody-based CARs. A humanized mouse model of HIV infection demonstrated that T cells expressing optimized CARs were superior at expanding in response to antigen, protecting CD4 T cells from infection, and reducing viral loads compared to T cells expressing the original, clinical trial CAR. Moreover, in a humanized mouse model of HIV treatment, CD4 CAR T cells containing the 4-1BB costimulatory domain controlled HIV spread after ART removal better than analogous CAR T cells containing the CD28 costimulatory domain. Together, these data indicate that potent HIV-specific T cells can be generated using improved CAR design and that CAR T cells could be important components of an HIV cure strategy.

  18. Insulin growth factor-1 receptor (IGF-1R) expression as a prognostic indicator of local recurrence in conservatively treated breast cancer: a case-control study

    International Nuclear Information System (INIS)

    Turner, B.C.; Haffty, B.G.; Carter, D.; Gumbs, A.A.; Naryanan, L.; Baserga, R.; Glazer, P.M.

    1996-01-01

    Purpose: The IGF-1R is a glycoprotein receptor that consists of a heterodimer of two alpha and two beta subunits which are processed from a single precursor transmembrane polypeptide and has been found to be overexpressed in a variety of tumors. IGF-1R has been shown to play a critical role in malignant transformation and to influence apoptosis. We have recently shown in gene transfer studies that overexpression of the IGF-1R confers relative radioresistance on mouse fibroblasts in culture. To test the significance of this finding in a clinical setting, we have sought to determine the prognostic significance of overexpression of IGF-1R with respect to ipsilateral breast tumor recurrence (IBTR) in the conservatively treated breast cancer patient. Materials and Methods: Over 1,000 breast cancer patients treated with conservative surgery followed by radiation therapy to the intact breast served as the patient population for this study. Twenty-five patients with a diagnosis of invasive ductal carcinoma who had an IBTR as the first site of failure comprised the index case population base of this study. Following the identification of 25 patients with IBTR, the breast database was searched for 25 matching control patients who did not have an IBTR. The control patients were matched to the index case with respect to age (within 5 years), menopausal status, approximate date of radiation therapy, primary histology, axillary dissection, nodal status, primary tumor size, estrogen/progesterone receptor (ER/PR) status, and adjuvant chemotherapy/hormonal therapy. Both index cases and the matched control group received radiation therapy to a total dose of 64 Gy to the tumor bed. Following identification of index and control cases, the individual paraffin-embedded blocks (PEB) were evaluated for invasive ductal carcinoma with H and E staining by the pathologist. All PEB were then processed for immunohistochemical staining with a polyclonal antibody to the beta-chain of IGF-1R

  19. Mechanism for iron control of the Vibrio fischeri luminescence system: involvement of cyclic AMP and cyclic AMP receptor protein and modulation of DNA level.

    Science.gov (United States)

    Dunlap, P V

    1992-07-01

    Iron controls luminescence in Vibrio fischeri by an indirect but undefined mechanism. To gain insight into that mechanism, the involvement of cyclic AMP (cAMP) and cAMP receptor protein (CRP) and of modulation of DNA levels in iron control of luminescence were examined in V. fischeri and in Escherichia coli containing the cloned V. fischeri lux genes on plasmids. For V. fischeri and E. coli adenylate cyclase (cya) and CRP (crp) mutants containing intact lux genes (luxR luxICDABEG), presence of the iron chelator ethylenediamine-di(o-hydroxyphenyl acetic acid) (EDDHA) increased expression of the luminescence system like in the parent strains only in the cya mutants in the presence of added cAMP. In the E. coli strains containing a plasmid with a Mu dl(lacZ) fusion in luxR, levels of beta-galactosidase activity (expression from the luxR promoter) and luciferase activity (expression from the lux operon promoter) were both 2-3-fold higher in the presence of EDDHA in the parent strain, and for the mutants this response to EDDHA was observed only in the cya mutant in the presence of added cAMP. Therefore, cAMP and CRP are required for the iron restriction effect on luminescence, and their involvement in iron control apparently is distinct from the known differential control of transcription from the luxR and luxICDABEG promoters by cAMP-CRP. Furthermore, plasmid and chromosomal DNA levels were higher in E. coli and V. fischeri in the presence of EDDHA. The higher DNA levels correlated with an increase in expression of chromosomally encoded beta-galactosidase in E. coli and with a higher level of autoinducer in cultures of V. fischeri. These results implicate cAMP-CRP and modulation of DNA levels in the mechanism of iron control of the V. fischeri luminescence system.

  20. Platelet-activating factor receptor (PAF-R)-dependent pathways control tumour growth and tumour response to chemotherapy

    International Nuclear Information System (INIS)

    Oliveira, Soraya I de; Andrade, Luciana NS; Onuchic, Ana C; Nonogaki, Sueli; Fernandes, Patrícia D; Pinheiro, Mônica C; Rohde, Ciro BS; Chammas, Roger; Jancar, Sonia

    2010-01-01

    Phagocytosis of apoptotic cells by macrophages induces a suppressor phenotype. Previous data from our group suggested that this occurs via Platelet-activating factor receptor (PAF-R)-mediated pathways. In the present study, we investigated the impact of apoptotic cell inoculation or induction by a chemotherapeutic agent (dacarbazine, DTIC) on tumour growth, microenvironmental parameters and survival, and the effect of treatment with a PAF-R antagonist (WEB2170). These studies were performed in murine tumours: Ehrlich Ascitis Tumour (EAT) and B16F10 melanoma. Tumour growth was assessed by direct counting of EAT cells in the ascitis or by measuring the volume of the solid tumour. Parameters of the tumour microenvironment, such as the frequency of cells expressing cyclo-oxygenase-2 (COX-2), caspase-3 and galectin-3, and microvascular density, were determined by immunohistochemistry. Levels of vascular endothelium growth factor (VEGF) and prostaglandin E2 (PGE2) were determined by ELISA, and levels of nitric oxide (NO) by Griess reaction. PAF-R expression was analysed by immunohistochemistry and flow cytometry. Inoculation of apoptotic cells before EAT implantation stimulated tumour growth. This effect was reversed by in vivo pre-treatment with WEB2170. This treatment also reduced tumour growth and modified the microenvironment by reducing PGE2, VEGF and NO production. In B16F10 melanoma, WEB2170 alone or in association with DTIC significantly reduced tumour volume. Survival of the tumour-bearing mice was not affected by WEB2170 treatment but was significantly improved by the combination of DTIC with WEB2170. Tumour microenvironment elements were among the targets of the combination therapy since the relative frequency of COX-2 and galectin-3 positive cells and the microvascular density within the tumour mass were significantly reduced by treatment with WEB2170 or DTIC alone or in combination. Antibodies to PAF-R stained the cells from inside the tumour, but not the

  1. Parental control and the dopamine D2 receptor gene (DRD2) interaction on emotional eating in adolescence

    NARCIS (Netherlands)

    Strien, van T.; Snoek, H.M.; Zwaluw, van der C.S.; Engels, R.C.

    2010-01-01

    The present study addresses the emergence of emotional eating in adolescence in relation to maternal or paternal psychological control. A reduction of food intake is considered the biological natural response to distress, therefore we tested whether the a-typical stress response of emotional eating

  2. Genetically designed biomolecular capping system for mesoporous silica nanoparticles enables receptor-mediated cell uptake and controlled drug release

    Czech Academy of Sciences Publication Activity Database

    Datz, S.; Argyo, C.; Gattner, M.; Weiss, V.; Brunner, K.; Bretzler, J.; von Schirnding, C.; Torrano, A. A.; Spada, F.; Vrábel, Milan; Engelke, H.; Bräuchle, C.; Carell, T.; Bein, T.

    2016-01-01

    Roč. 8, č. 15 (2016), s. 8101-8110 ISSN 2040-3364 Institutional support: RVO:61388963 Keywords : responsive controlled release * Diels-Alder reactions * human carbonic anhydrase Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 7.367, year: 2016 http://pubs.rsc.org/en/content/articlehtml/2016/nr/c5nr08163g

  3. Death Receptor 3 Signaling Controls the Balance between Regulatory and Effector Lymphocytes in SAMP1/YitFc Mice with Crohn’s Disease-Like Ileitis

    Directory of Open Access Journals (Sweden)

    Zhaodong Li

    2018-03-01

    Full Text Available Death receptor 3 (DR3, a member of the tumor necrosis factor receptor (TNFR superfamily, has been implicated in regulating T-helper type-1 (TH1, type-2 (TH2, and type-17 (TH17 responses as well as regulatory T cell (Treg and innate lymphoid cell (ILC functions during immune-mediated diseases. However, the role of DR3 in controlling lymphocyte functions in inflammatory bowel disease (IBD is not fully understood. Recent studies have shown that activation of DR3 signaling modulates Treg expansion suggesting that stimulation of DR3 represents a potential therapeutic target in human inflammatory diseases, including Crohn’s disease (CD. In this study, we tested a specific DR3 agonistic antibody (4C12 in SAMP1/YitFc (SAMP mice with CD-like ileitis. Interestingly, treatment with 4C12 prior to disease manifestation markedly worsened the severity of ileitis in SAMP mice despite an increase in FoxP3+ lymphocytes in mesenteric lymph node (MLN and small-intestinal lamina propria (LP cells. Disease exacerbation was dominated by overproduction of both TH1 and TH2 cytokines and associated with expansion of dysfunctional CD25−FoxP3+ and ILC group 1 (ILC1 cells. These effects were accompanied by a reduction in CD25+FoxP3+ and ILC group 3 (ILC3 cells. By comparison, genetic deletion of DR3 effectively reversed the inflammatory phenotype in SAMP mice by promoting the expansion of CD25+FoxP3+ over CD25−FoxP3+ cells and the production of IL-10 protein. Collectively, our data demonstrate that DR3 signaling modulates a multicellular network, encompassing Tregs, T effectors, and ILCs, governing disease development and progression in SAMP mice with CD-like ileitis. Manipulating DR3 signaling toward the restoration of the balance between protective and inflammatory lymphocytes may represent a novel and targeted therapeutic modality for patients with CD.

  4. Identification of Interleukin-27 (IL-27)/IL-27 Receptor Subunit Alpha as a Critical Immune Axis for In Vivo HIV Control.

    Science.gov (United States)

    Ruiz-Riol, M; Berdnik, D; Llano, A; Mothe, B; Gálvez, C; Pérez-Álvarez, S; Oriol-Tordera, B; Olvera, A; Silva-Arrieta, S; Meulbroek, M; Pujol, F; Coll, J; Martinez-Picado, J; Ganoza, C; Sanchez, J; Gómez, G; Wyss-Coray, T; Brander, C

    2017-08-15

    Intact and broad immune cell effector functions and specific individual cytokines have been linked to HIV disease outcome, but their relative contribution to HIV control remains unclear. We asked whether the proteome of secreted cytokines and signaling factors in peripheral blood can be used to discover specific pathways critical for host viral control. A custom glass-based microarray, able to measure >600 plasma proteins involved in cell-to-cell communication, was used to measure plasma protein profiles in 96 HIV-infected, treatment-naive individuals with high (>50,000) or low (HIV RNA copies/ml) viral loads. Univariate and regression model analysis demonstrate that plasma levels of soluble interleukin-27 (IL-27) are significantly elevated in individuals with high plasma viremia ( P HIV-DNA copy numbers in peripheral blood mononuclear cells (PBMC) (Rho = 0.4011; P = 0.0027). Moreover, soluble IL-27 plasma levels are negatively associated with the breadth and magnitude of the total virus-specific T-cell responses and directly with plasma levels of molecules involved in Wnt/β-catenin signaling. In addition to IL-27, gene expression levels of the specific IL-27 receptor ( IL27RA ) in PBMC correlated directly with both plasma viral load (Rho = 0.3531; P = 0.0218) and the proviral copy number in the peripheral blood as an indirect measure of partial viral reservoir (Rho = 0.4580; P = 0.0030). These results were validated in unrelated cohorts of early infected subjects as well as subjects before and after initiation of antiretroviral treatment, and they identify IL-27 and its specific receptor as a critical immune axis for the antiviral immune response and as robust correlates of viral load and proviral reservoir size in PBMC. IMPORTANCE The detailed knowledge of immune mechanisms that contribute to HIV control is a prerequisite for the design of effective treatment strategies to achieve HIV cure. Cells communicate with each other by secreting signaling proteins, and

  5. Transcriptomic analysis identifies gene networks regulated by estrogen receptor α (ERα) and ERβ that control distinct effects of different botanical estrogens

    Science.gov (United States)

    Gong, Ping; Madak-Erdogan, Zeynep; Li, Jilong; Cheng, Jianlin; Greenlief, C. Michael; Helferich, William G.; Katzenellenbogen, John A.

    2014-01-01

    The estrogen receptors (ERs) ERα and ERβ mediate the actions of endogenous estrogens as well as those of botanical estrogens (BEs) present in plants. BEs are ingested in the diet and also widely consumed by postmenopausal women as dietary supplements, often as a substitute for the loss of endogenous estrogens at menopause. However, their activities and efficacies, and similarities and differences in gene expression programs with respect to endogenous estrogens such as estradiol (E2) are not fully understood. Because gene expression patterns underlie and control the broad physiological effects of estrogens, we have investigated and compared the gene networks that are regulated by different BEs and by E2. Our aim was to determine if the soy and licorice BEs control similar or different gene expression programs and to compare their gene regulations with that of E2. Gene expression was examined by RNA-Seq in human breast cancer (MCF7) cells treated with control vehicle, BE or E2. These cells contained three different complements of ERs, ERα only, ERα+ERβ, or ERβ only, reflecting the different ratios of these two receptors in different human breast cancers and in different estrogen target cells. Using principal component, hierarchical clustering, and gene ontology and interactome analyses, we found that BEs regulated many of the same genes as did E2. The genes regulated by each BE, however, were somewhat different from one another, with some genes being regulated uniquely by each compound. The overlap with E2 in regulated genes was greatest for the soy isoflavones genistein and S-equol, while the greatest difference from E2 in gene expression pattern was observed for the licorice root BE liquiritigenin. The gene expression pattern of each ligand depended greatly on the cell background of ERs present. Despite similarities in gene expression pattern with E2, the BEs were generally less stimulatory of genes promoting proliferation and were more pro-apoptotic in their

  6. A Molecular Case-Control Study on the Association of Melatonin Hormone and rs#10830963 Single Nucleotide Polymorphism in its Receptor MTNR1B Gene with Breast Cancer

    Directory of Open Access Journals (Sweden)

    Nadia A Abd El Moneim

    2015-01-01

    Full Text Available Background: The main function of the pineal hormone melatonin which is mediated via its two receptors, MTNR1A and MTNR1B, is to mediate dark signals in addition to anti-oxidation, immune system enhancement, protection from radiation, and anti-cancer functions. A common single nucleotide polymorphism in the MTNR1B gene is rs#10830963, which is well known as a risk factor for type 2 diabetes mellitus. This study intends to figure out the role of melatonin and its receptor MTNR1B gene rs#10830963 polymorphism in breast cancer incidence, diagnosis and prognosis. Methods: This study included 43 females with breast cancer and 45 apparently normal healthy females. Restriction fragment length polymorphism-PCR was used for amplification and genotyping of the MTNR1B gene rs#10830963 polymorphism in whole blood. Serum melatonin levels were measured using a ready-for-use radioimmunoassay kit. Results: For the MTNR1B gene rs#10830963 polymorphism, we observed a significantly higher GG genotype frequency among cases (72.1% than controls (13.3%, with a diagnostic sensitivity of 83.78% and specificity of 76.47%. The cases had a frequency of 11.6% for the CC genotype and 16.3% for the CG genotype which was significantly lower compared to controls that had a 44.4% frequency of the CC genotype and 42.2% frequency of the CG genotype. The GG genotype had a significant association with larger tumor volume (P=0.048. Serum melatonin levels were significantly lower among breast cancer patients than controls. Using the ROC curve analysis, serum melatonin showed a significant AUC (72.6%, P39.5 pg/ml. Conclusion: The risk for breast cancer incidence increased as the serum levels of melatonin decreased and in females homozygous for the G allele (GG genotype of the MTNR1B gene rs#10830963 polymorphism. The GG genotype was found to be associated with increased breast tumor volume as a marker of a poor prognosis breast cancer.

  7. Photo-antagonism of the GABAA receptor.

    Science.gov (United States)

    Mortensen, Martin; Iqbal, Favaad; Pandurangan, Arun P; Hannan, Saad; Huckvale, Rosemary; Topf, Maya; Baker, James R; Smart, Trevor G

    2014-07-29

    Neurotransmitter receptor trafficking is fundamentally important for synaptic transmission and neural network activity. GABAA receptors and inhibitory synapses are vital components of brain function, yet much of our knowledge regarding receptor mobility and function at inhibitory synapses is derived indirectly from using recombinant receptors, antibody-tagged native receptors and pharmacological treatments. Here we describe the use of a set of research tools that can irreversibly bind to and affect the function of recombinant and neuronal GABAA receptors following ultraviolet photoactivation. These compounds are based on the competitive antagonist gabazine and incorporate a variety of photoactive groups. By using site-directed mutagenesis and ligand-docking studies, they reveal new areas of the GABA binding site at the interface between receptor β and α subunits. These compounds enable the selected inactivation of native GABAA receptor populations providing new insight into the function of inhibitory synapses and extrasynaptic receptors in controlling neuronal excitation.

  8. The non-receptor tyrosine kinase Lyn controls neutrophil adhesion by recruiting the CrkL–C3G complex and activating Rap1 at the leading edge

    Science.gov (United States)

    He, Yuan; Kapoor, Ashish; Cook, Sara; Liu, Shubai; Xiang, Yang; Rao, Christopher V.; Kenis, Paul J. A.; Wang, Fei

    2011-01-01

    Establishing new adhesions at the extended leading edges of motile cells is essential for stable polarity and persistent motility. Despite recent identification of signaling pathways that mediate polarity and chemotaxis in neutrophils, little is known about molecular mechanisms governing cell–extracellular-matrix (ECM) adhesion in these highly polarized and rapidly migrating cells. Here, we describe a signaling pathway in neutrophils that is essential for localized integrin activation, leading edge attachment and persistent migration during chemotaxis. This pathway depends upon Gi-protein-mediated activation and leading edge recruitment of Lyn, a non-receptor tyrosine kinase belonging to the Src kinase family. We identified the small GTPase Rap1 as a major downstream effector of Lyn to regulate neutrophil adhesion during chemotaxis. Depletion of Lyn in neutrophil-like HL-60 cells prevented chemoattractant-induced Rap1 activation at the leading edge of the cell, whereas ectopic expression of Rap1 largely rescued the defects induced by Lyn depletion. Furthermore, Lyn controls spatial activation of Rap1 by recruiting the CrkL–C3G protein complex to the leading edge. Together, these results provide novel mechanistic insights into the poorly understood signaling network that controls leading edge adhesion during chemotaxis of neutrophils, and possibly other amoeboid cells. PMID:21628423

  9. IL-4 receptor-alpha-dependent control of Cryptococcus neoformans in the early phase of pulmonary infection.

    Directory of Open Access Journals (Sweden)

    Andreas Grahnert

    Full Text Available Cryptococcus neoformans is an opportunistic fungal pathogen that causes lung inflammation and meningoencephalitis in immunocompromised people. Previously we showed that mice succumb to intranasal infection by induction of pulmonary interleukin (IL-4Rα-dependent type 2 immune responses, whereas IL-12-dependent type 1 responses confer resistance. In the experiments presented here, IL-4Rα⁻/⁻ mice unexpectedly show decreased fungal control early upon infection with C. neoformans, whereas wild-type mice are able to control fungal growth accompanied by enhanced macrophage and dendritic cell recruitment to the site of infection. Lower pulmonary recruitment of macrophages and dendritic cells in IL-4Rα⁻/⁻ mice is associated with reduced pulmonary expression of CCL2 and CCL20 chemokines. Moreover, IFN-γ and nitric oxide production are diminished in IL-4Rα⁻/⁻ mice compared to wild-type mice. To directly study the potential mechanism(s responsible for reduced production of IFN-γ, conventional dendritic cells were stimulated with C. neoformans in the presence of IL-4 which results in increased IL-12 production and reduced IL-10 production. Together, a beneficial role of early IL-4Rα signaling is demonstrated in pulmonary cryptococcosis, which contrasts with the well-known IL-4Rα-mediated detrimental effects in the late phase.

  10. Toll-like receptor 9 gene expression in the post-thrombotic syndrome, residual thrombosis and recurrent deep venous thrombosis: A case-control study.

    Science.gov (United States)

    Cheung, Y Whitney; Bouman, Annemieke C; Castoldi, Elisabetta; Wielders, Simone J; Spronk, Henri M H; Ten Cate, Hugo; Ten Cate-Hoek, Arina J; Ten Wolde, Marije

    2016-04-01

    Animal models suggest that toll-like receptor 9 (TLR9) promotes thrombus resolution after acute deep venous thrombosis (DVT). We hypothesized that TLR9 expression is lower in patients with post-thrombotic syndrome (PTS) and investigated the role of TLR9 in residual thrombosis (RT) and recurrence. Patients with a history of DVT with PTS (cases, n=30) and without PTS after minimal 24 months follow-up (controls, n=30) were selected. Healthy individuals (HI, n=29) without DVT were included as reference. TLR9 mRNA expression in leukocytes was determined by qPCR and normalized to the housekeeping succinate dehydrogenase subunit A gene using the ΔCt method. Sub analyses were performed to explore the TLR9 expression in patients with and without RT and multiple DVT episodes. The median TLR9 expression was 0.45 (interquartile range 0.31 to 0.93), 0.39 (0.25 to 0.69) and 0.62 (0.32 to 0.75) in cases, controls and HI respectively (p=0.61). The median TLR9 expression was 0.39 (0.26 to 0.51) in patients with RT compared to 0.55 (0.30 to 0.86, p=0.13) in those without. The median TLR9 expression was significantly lower in patients who had one DVT compared to patients with recurrent DVT, 0.37 (0.23 to 0.63) versus 0.55 (0.43 to 0.96) respectively (p<0.01). No significant difference in TLR9 expression was found between cases, controls and HI. However TLR9 expression seems lower in individuals with DVT and RT, albeit not significant. Interestingly, TLR9 might play a role in recurrent DVT, as the TLR9 expression was significantly higher in patients with recurrent DVT. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. FokI polymorphism in the vitamin D receptor gene (VDR and its association with lumbar spine pathologies in the Italian population: a case-control study.

    Directory of Open Access Journals (Sweden)

    Alessandra Colombini

    Full Text Available Alterations in vitamin D homeostasis, mainly involving its nuclear receptor (VDR, could have a role in the pathophysiology of the spine. The association between VDR polymorphisms and spine disorders has been analyzed in different ethnic groups, focusing on the functional FokI polymorphism. However, so far, inconsistent findings were reported. The aims of this study were to evaluate, in the Italian white population, the VDR FokI polymorphism frequencies distribution in subjects with clearly defined lumbar spinal pathologies compared to asymptomatic controls and to analyze the interplay of genetic and conventional risk factors. Using a case-control design, 267 patients with spinal disorders and 220 asymptomatic controls were enrolled, evaluating their exposition to putative risk factors. Patients' clinical assessment was performed by Magnetic Resonance Imaging. FokI polymorphism (rs2228570 was detected by PCR-RFLP. Genotypes were designated by a lowercase letter (f allele, T nucleotide for the presence of the restriction site and by a capital letter (F allele, C nucleotide for its absence. Family history, higher age and BMI, exposure to vibration, physical job demand, smoking habit and lower practice of leisure physical activity were associated with spinal disorders. The FF genotype and F allele represented approximately 2-fold risk factors to develop discopathies and/or osteochondrosis concomitant with disc herniation, while f allele was protective. In conclusion, the link we observed between VDR FokI variants and specific lumbar spine pathologies suggests that spinal tissue degeneration is influenced by the genetic background. Future studies should evaluate the signaling pathways involving alterations in VDR and influencing the development and/or progression of spine disorders.

  12. Identification of selected in vitro generated phase-I metabolites of the steroidal selective androgen receptor modulator MK-0773 for doping control purposes.

    Science.gov (United States)

    Lagojda, Andreas; Kuehne, Dirk; Krug, Oliver; Thomas, Andreas; Wigger, Tina; Karst, Uwe; Schänzer, Wilhelm; Thevis, Mario

    2016-01-01

    Research into developing anabolic agents for various therapeutic purposes has been pursued for decades. As the clinical utility of anabolic-androgenic steroids has been found to be limited because of their lack of tissue selectivity and associated off-target effects, alternative drug entities have been designed and are commonly referred to as selective androgen receptor modulators (SARMs). While most of these SARMs are of nonsteroidal structure, the drug candidate MK-0773 comprises a 4-aza-steroidal nucleus. Besides the intended therapeutic use, SARMs have been found to be illicitly distributed and misused as doping agents in sport, necessitating frequently updated doping control analytical assays. As steroidal compounds reportedly undergo considerable metabolic transformations, the phase-I metabolism of MK-0773 was simulated using human liver microsomal (HLM) preparations and electrochemical conversion. Subsequently, major metabolic products were identified and characterized employing liquid chromatography-high-resolution/high- accuracy tandem mass spectrometry with electrospray (ESI) and atmospheric pressure chemical ionization (APCI) as well as nuclear magnetic resonance (NMR) spectroscopy. MK-0773 produced numerous phase-I metabolites under the chosen in vitro incubation reactions, mostly resulting from mono- and bisoxygenation of the steroid. HLM yielded at least 10 monooxygenated species, while electrochemistry-based experiments resulted predominantly in three monohydroxylated metabolites. Elemental composition data and product ion mass spectra were generated for these analytes, ESI/APCI measurements corroborated the formation of at least two N-oxygenated metabolites, and NMR data obtained from electrochemistry-derived products supported structures suggested for three monohydroxylated compounds. Hereby, the hydroxylation of the A-ring located N- bound methyl group was found to be of particular intensity. In the absence of controlled elimination studies, the

  13. The nuclear hormone receptor family member NR5A2 controls aspects of multipotent progenitor cell formation and acinar differentiation during pancreatic organogenesis.

    Science.gov (United States)

    Hale, Michael A; Swift, Galvin H; Hoang, Chinh Q; Deering, Tye G; Masui, Toshi; Lee, Youn-Kyoung; Xue, Jumin; MacDonald, Raymond J

    2014-08-01

    The orphan nuclear receptor NR5A2 is necessary for the stem-like properties of the epiblast of the pre-gastrulation embryo and for cellular and physiological homeostasis of endoderm-derived organs postnatally. Using conditional gene inactivation, we show that Nr5a2 also plays crucial regulatory roles during organogenesis. During the formation of the pancreas, Nr5a2 is necessary for the expansion of the nascent pancreatic epithelium, for the subsequent formation of the multipotent progenitor cell (MPC) population that gives rise to pre-acinar cells and bipotent cells with ductal and islet endocrine potential, and for the formation and differentiation of acinar cells. At birth, the NR5A2-deficient pancreas has defects in all three epithelial tissues: a partial loss of endocrine cells, a disrupted ductal tree and a >90% deficit of acini. The acinar defects are due to a combination of fewer MPCs, deficient allocation of those MPCs to pre-acinar fate, disruption of acinar morphogenesis and incomplete acinar cell differentiation. NR5A2 controls these developmental processes directly as well as through regulatory interactions with other pancreatic transcriptional regulators, including PTF1A, MYC, GATA4, FOXA2, RBPJL and MIST1 (BHLHA15). In particular, Nr5a2 and Ptf1a establish mutually reinforcing regulatory interactions and collaborate to control developmentally regulated pancreatic genes by binding to shared transcriptional regulatory regions. At the final stage of acinar cell development, the absence of NR5A2 affects the expression of Ptf1a and its acinar specific partner Rbpjl, so that the few acinar cells that form do not complete differentiation. Nr5a2 controls several temporally distinct stages of pancreatic development that involve regulatory mechanisms relevant to pancreatic oncogenesis and the maintenance of the exocrine phenotype. © 2014. Published by The Company of Biologists Ltd.

  14. Risk of thromboembolism with thrombopoietin receptor agonists in adult patients with thrombocytopenia: Systematic review and meta-analysis of randomized controlled trials.

    Science.gov (United States)

    Catalá-López, Ferrán; Corrales, Inmaculada; de la Fuente-Honrubia, César; González-Bermejo, Diana; Martín-Serrano, Gloria; Montero, Dolores; Saint-Gerons, Diego Macías

    2015-12-21

    Romiplostim and eltrombopag are thrombopoietin receptor (TPOr) agonists that promote megakaryocyte differentiation, proliferation and platelet production. In 2012, a systematic review and meta-analysis reported a non-statistically significant increased risk of thromboembolic events for these drugs, but analyses were limited by lack of statistical power. Our objective was to update the 2012 meta-analysis examining whether TPOr agonists affect thromboembolism occurrence in adult thrombocytopenic patients. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs). Updated searches were conduced on PubMed, Cochrane Central, and publicly available registries (up to December 2014). RCTs using romiplostim or eltrombopag in at least one group were included. Relative risks (RR), absolute risk ratios (ARR) and number needed to harm (NNH) were estimated. Heterogeneity was analyzed using Cochran's Q test and I(2) statistic. Fifteen studies with 3026 adult thrombocytopenic patients were included. Estimated frequency of thromboembolism was 3.69% (95% CI: 2.95-4.61%) for TPOr agonists and 1.46% (95% CI: 0.89-2.40%) for controls. TPOr agonists were associated with a RR of thromboembolism of 1.81 (95% CI: 1.04-3.14) and an ARR of 2.10% (95% CI: 0.03-3.90%) meaning a NNH of 48. Overall, we did not find evidence of statistical heterogeneity (p=0.43; I(2)=1.60%). Our updated meta-analysis suggested that TPOr agonists are associated with a higher risk of thromboemboembolic events compared with controls, and supports the current recommendations included in the European product information on this respect. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

  15. Genetic Variations in the Human G Protein-coupled Receptor Class C, Group 6, Member A (GPRC6A) Control Cell Surface Expression and Function

    DEFF Research Database (Denmark)

    Jorgensen, Stine; Have, Christian Theil; Underwood, Christina Rye

    2017-01-01

    -expressed murine and goldfish orthologs. The latter orthologs are Gq-coupled and lead to intracellular accumulation of inositol phosphates and calcium release. In the present study we cloned the bonobo chimpanzee GPRC6A receptor, which is 99% identical to the human receptor, and show that it is cell surface...

  16. Nucleus Accumbens Dopamine D1-Receptor-Expressing Neurons Control the Acquisition of Sign-Tracking to Conditioned Cues in Mice

    Directory of Open Access Journals (Sweden)

    Tom Macpherson

    2018-06-01

    Full Text Available Following repeated pairings, the reinforcing and motivational properties (incentive salience of a reward can be transferred onto an environmental stimulus which can then elicit conditioned responses, including Pavlovian approach behavior to the stimulus (a sign-tracking response. In rodents, acquisition of sign-tracking in autoshaping paradigms is sensitive to lesions and dopamine D1 receptor antagonism of the nucleus accumbens (NAc of the ventral striatum. However, currently, the possible roles of dorsal striatal subregions, as well as of the two major striatal neuron types, dopamine D1-/D2-expressing medium spiny neurons (MSNs, in controlling the development of conditioned responses is still unclear and warrants further study. Here, for the first time, we used a transgenic mouse line combined with striatal subregion-specific AAV virus injections to separately express tetanus toxin in D1-/D2- MSNs in the NAc, dorsomedial striatum, and dorsolateral striatum, to permanently block neurotransmission in these neurons during acquisition of an autoshaping task. Neurotransmission blocking of NAc D1-MSNs inhibited the acquisition of sign-tracking responses when the initial conditioned response for each conditioned stimulus presentation was examined, confirming our initial hypothesis. These findings suggest that activity in NAc D1-MSNs contributes to the attribution of incentive salience to conditioned stimuli.

  17. Sex- and age-related differences in ribosomal proteins L17 and L37, as well as androgen receptor protein, in the song control system of zebra finches.

    Science.gov (United States)

    Tang, Y P; Wade, J

    2010-12-29

    The zebra finch song system is sexually dimorphic--only males sing, and the morphology of forebrain regions controlling the learning and production of this song is greatly enhanced in males compared to females. Masculinization appears to involve effects of steroid hormones as well as other factors, perhaps including the expression of sex chromosome genes (males: ZZ, females: ZW). The present study investigated three proteins--two encoded by Z-linked genes, ribosomal proteins L17 and L37 (RPL17 and RPL37), including their co-localization with androgen receptor (AR), from post-hatching day 25 to adulthood. Extensive co-expression of AR with the ribosomal proteins was detected in the three song nuclei investigated (HVC, robust nucleus of the arcopallium (RA), and Area X) across these ages. In general, more cells expressed each of these proteins in males compared to females, and the sex differences increased as animals matured. Specific patterns differed across regions and between RPL17 and RPL37, which suggest potential roles of one or both of these proteins in the incorporation and/or differentiation of song system cells. Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

  18. Enhanced Effector Function of CD8+ T Cells From Healthy Controls and HIV-Infected Patients Occurs Through Thrombin Activation of Protease-Activated Receptor 1

    Science.gov (United States)

    Hurley, Amanda; Smith, Mindy; Karpova, Tatiana; Hasley, Rebecca B.; Belkina, Natalya; Shaw, Stephen; Balenga, Nariman; Druey, Kirk M.; Nickel, Erin; Packard, Beverly; Imamichi, Hiromi; Hu, Zonghui; Follmann, Dean; McNally, James; Higgins, Jeanette; Sneller, Michael; Lane, H. Clifford; Catalfamo, Marta

    2013-01-01

    Disruption of vascular integrity by trauma and other tissue insults leads to inflammation and activation of the coagulation cascade. The serine protease thrombin links these 2 processes. The proinflammatory function of thrombin is mediated by activation of protease-activated receptor 1 (PAR-1). We found that peripheral blood effector memory CD4+ and CD8+ T lymphocytes expressed PAR-1 and that expression was increased in CD8+ T cells from human immunodeficiency virus (HIV)–infected patients. Thrombin enhanced cytokine secretion in CD8+ T cells from healthy controls and HIV-infected patients. In addition, thrombin induced chemokinesis, but not chemotaxis, of CD8+ T cells, which led to structural changes, including cell polarization and formation of a structure rich in F-actin and phosphorylated ezrin-radexin-moesin proteins. These findings suggest that thrombin mediates cross-talk between the coagulation system and the adaptive immune system at sites of vascular injury through increased T-cell motility and production of proinflammatory cytokines. PMID:23204166

  19. Enhanced effector function of CD8(+) T cells from healthy controls and HIV-infected patients occurs through thrombin activation of protease-activated receptor 1.

    Science.gov (United States)

    Hurley, Amanda; Smith, Mindy; Karpova, Tatiana; Hasley, Rebecca B; Belkina, Natalya; Shaw, Stephen; Balenga, Nariman; Druey, Kirk M; Nickel, Erin; Packard, Beverly; Imamichi, Hiromi; Hu, Zonghui; Follmann, Dean; McNally, James; Higgins, Jeanette; Sneller, Michael; Lane, H Clifford; Catalfamo, Marta

    2013-02-15

    Disruption of vascular integrity by trauma and other tissue insults leads to inflammation and activation of the coagulation cascade. The serine protease thrombin links these 2 processes. The proinflammatory function of thrombin is mediated by activation of protease-activated receptor 1 (PAR-1). We found that peripheral blood effector memory CD4(+) and CD8(+) T lymphocytes expressed PAR-1 and that expression was increased in CD8(+) T cells from human immunodeficiency virus (HIV)-infected patients. Thrombin enhanced cytokine secretion in CD8(+) T cells from healthy controls and HIV-infected patients. In addition, thrombin induced chemokinesis, but not chemotaxis, of CD8(+) T cells, which led to structural changes, including cell polarization and formation of a structure rich in F-actin and phosphorylated ezrin-radexin-moesin proteins. These findings suggest that thrombin mediates cross-talk between the coagulation system and the adaptive immune system at sites of vascular injury through increased T-cell motility and production of proinflammatory cytokines.

  20. Synergistic action of octopamine receptor agonists on the activity of selected novel insecticides for control of dengue vector Aedes aegypti (Diptera: Culicidae) mosquito.

    Science.gov (United States)

    Ahmed, Mohamed Ahmed Ibrahim; Vogel, Christoph Franz Adam

    2015-05-01

    Studying insecticide resistance in mosquitoes has attracted the attention of many scientists to elucidate the pathways of resistance development and to design novel strategies in order to prevent or minimize the spread and evolution of resistance. Here, we tested the synergistic action of piperonyl butoxide (PBO) and two octopamine receptor (OR) agonists, amitraz (AMZ) and chlordimeform (CDM) on selected novel insecticides to increase their lethal action on the fourth instar larvae of Aedes aegypti L. However, chlorfenapyr was the most toxic insecticide (LC50 = 193, 102, and 48 ng/ml, after 24, 48, and 72 h exposure, respectively) tested. Further, PBO synergized all insecticides and the most toxic combinatorial insecticide was nitenpyram even after 48 and 72 h exposure. In addition, OR agonists significantly synergized most of the selected insecticides especially after 48 and 72 h exposure. The results imply that the synergistic effects of amitraz are a promising approach in increasing the potency of certain insecticides in controlling the dengue vector Ae. aegypti mosquito. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Metformin and insulin receptors

    International Nuclear Information System (INIS)

    Vigneri, R.; Gullo, D.; Pezzino, V.

    1984-01-01

    The authors evaluated the effect of metformin (N,N-dimethylbiguanide), a biguanide known to be less toxic than phenformin, on insulin binding to its receptors, both in vitro and in vivo. Specific 125 I-insulin binding to cultured IM-9 human lymphocytes and MCF-7 human breast cancer cells was determined after preincubation with metformin. Specific 125 I-insulin binding to circulating monocytes was also evaluated in six controls, eight obese subjects, and six obese type II diabetic patients before and after a short-term treatment with metformin. Plasma insulin levels and blood glucose were also measured on both occasions. Metformin significantly increased insulin binding in vitro to both IM-9 lymphocytes and MCF-7 cells; the maximum increment was 47.1% and 38.0%, respectively. Metformin treatment significantly increased insulin binding in vivo to monocytes of obese subjects and diabetic patients. Scatchard analysis indicated that the increased binding was mainly due to an increase in receptor capacity. Insulin binding to monocytes of normal controls was unchanged after metformin as were insulin levels in all groups; blood glucose was significantly reduced after metformin only in diabetic patients. These data indicate that metformin increases insulin binding to its receptors in vitro and in vivo. The effect in vivo is observed in obese subjects and in obese type II diabetic patients, paralleling the clinical effectiveness of this antidiabetic agent, and is not due to receptor regulation by circulating insulin, since no variation in insulin levels was recorded

  2. Interleukin-4 (IL4 and Interleukin-4 receptor (IL4RA polymorphisms in asthma: a case control study

    Directory of Open Access Journals (Sweden)

    Lorente Félix

    2005-11-01

    Full Text Available Abstract Background IL4/IL4RA pathway plays an important role in atopy and asthma. Different polymorphisms in IL4 and IL4RA genes have been described. Particularly, -33C>TIL4 and 576Q>RIL4RA SNPs have been independently associated to atopy and asthma. The purpose of this study was to analyse these polymorphisms in a population of patients with a well-characterized asthma phenotype. Methods A total of 212 unrelated Caucasian individuals, 133 patients with asthma and 79 healthy subjects without symptoms or history of asthma or atopy and with negative skin prick tests were recruited. Lung function was measured by spirometry and asthma was specialist physician-diagnosed according to the ATS (American Thoracic Society criteria and classified following the GINA (Global Initiative for Asthma guidelines. Skin prick tests were performed according to EAACI recommendations. -33C>TIL4 was studied with TaqMan assay and 576Q>RIL4RA by PCR-RFLP technique. Hardy-Weinberg equilibrium was analysed in all groups. Dichotomous variables were analysed using χ2, Fisher exact test, Monte Carlo simulation test and odds ratio test. To model the effects of multiple covariates logistic regression was used. Results No statistically significant differences between the group of patients with asthma and the controls were found when the allele and genotype distribution of -33C>TIL4 and 576Q>RIL4RA polymorphisms were compared. However, the T allele of the -33C>TIL4 SNP was more frequent in patients with persistent asthma. Multivariate analysis adjusted for age and sex confirmed that carriers of allele T had an increased risk of persistent asthma (OR:2.77, 95%CI:1.18–6.49; p = 0.019. Analysis of combination of polymorphisms showed that patients carrying both the T allele of -33C>TIL4 and the A allele of 576Q>RIL4RA had an increased risk of asthma. This association was particularly observed in persistent asthma [Fisher's p value = 0.0021, Monte Carlo p value (after 104

  3. Common variation in the vitamin D receptor gene and risk of inflammatory bowel disease in an Irish case-control study.

    LENUS (Irish Health Repository)

    Hughes, David J

    2012-02-01

    OBJECTIVE: Vitamin D may protect against the development of inflammatory bowel disease (IBD). Several preliminary studies in separate geographical locations suggest that these effects may be partly mediated by genetic variants of the vitamin D receptor (VDR). The data, however, are yet to be confirmed in large European cohorts. This study aimed to determine if common VDR polymorphisms affected IBD risk in an Irish population. MATERIALS AND METHODS: The study was based on a cohort of 1359 Irish participants. Frequencies of the common VDR gene polymorphisms rs2228570 (FokI), rs1544410 (BsmI), rs7975232 (ApaI), and rs731236 (TaqI) were determined using allele-specific PCR in a case-control analysis of 660 patients with IBD and 699 controls. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between these variants and risk of IBD. RESULTS: There was no statistically significant effect observed on IBD risk for any of the four VDR polymorphisms tested. Furthermore, no significant differences were observed in susceptibility when the population was stratified by sex or IBD subtype (Crohn\\'s disease or ulcerative colitis). Notably, however, there was an increased risk observed for both IBD and ulcerative colitis associated with heterozygote carriage of the FokI allele that approached significance (OR=1.21, 95% CI=0.95-1.53, P=0.12 and OR=1.36, 95% CI=0.98-1.89, P=0.06, respectively), this merits further investigation. CONCLUSION: This study indicates that there is no major effect for common variation in the VDR gene alone on predisposition to IBD in the Irish population.

  4. Preparation, formulation and quality control of one step kit 99m Tc - EDDA/HYNIC-Tyr3-Octreotide as a peptide radiopharmaceutical for imaging somatostatin receptor positive tumors

    International Nuclear Information System (INIS)

    Gandomkar, M.; Najafi, R.; Sadat-Ebrahimi, E.; Babaei, M.H.

    2004-01-01

    The high expression of somatostatin receptors in many tumours, have made receptor scintigraphy with 11I n-DTPA-Octreotide a widely used procedure in nuclear medicine. Despite its clinical success, some limitation and drawbacks of radiolabelling with 11I n remain, especially those concerned with the cost, availability and physical decay properties of this radionuclide. 99m Tc - EDDA/HYNIC-Tyr 3 -Octreotide was studied as a new agent with the potential to replace octreoscan in somatostatin receptor scintigraphy. This hydrazino nicotinic acid derivatized somatostatin complex contains ethylenediamine N, N diacetic acid as a co-ligand resulting in a high in vitro and in vivo stability. High labeling yields (>90%) were achieved at high specific activities. Characterization via HPLC, biodistribution and receptor binding of the resulting complex are described. The formulation developed enables rapid and simple labeling of 99m Tc - EDDA/HYNIC-TOC in a manner suitable for clinical setting

  5. Thyroid Stimulating Hormone Receptor

    Directory of Open Access Journals (Sweden)

    Murat Tuncel

    2017-02-01

    Full Text Available Thyroid stimulating hormone receptor (TSHR plays a pivotal role in thyroid hormone metabolism. It is a major controller of thyroid cell function and growth. Mutations in TSHR may lead to several thyroid diseases, most commonly hyperthyroidism. Although its genetic and epigenetic alterations do not directly lead to carcinogenesis, it has a crucial role in tumor growth, which is initiated by several oncogenes. This article will provide a brief review of TSHR and related diseases.

  6. Peripherally Administered Y2-Receptor Antagonist BIIE0246 Prevents Diet-Induced Obesity in Mice With Excess Neuropeptide Y, but Enhances Obesity in Control Mice.

    Science.gov (United States)

    Ailanen, Liisa; Vähätalo, Laura H; Salomäki-Myftari, Henriikka; Mäkelä, Satu; Orpana, Wendy; Ruohonen, Suvi T; Savontaus, Eriika

    2018-01-01

    Neuropeptide Y (NPY) plays an important role in the regulation of energy homeostasis in the level of central and sympathetic nervous systems (SNSs). Genetic silencing of peripheral Y 2 -receptors have anti-obesity effects, but it is not known whether pharmacological blocking of peripheral Y 2 -receptors would similarly benefit energy homeostasis. The effects of a peripherally administered Y 2 -receptor antagonist were studied in healthy and energy-rich conditions with or without excess NPY. Genetically obese mice overexpressing NPY in brain noradrenergic nerves and SNS (OE-NPY DβH ) represented the situation of elevated NPY levels, while wildtype (WT) mice represented the normal NPY levels. Specific Y 2 -receptor antagonist, BIIE0246, was administered (1.3 mg/kg/day, i.p.) for 2 or 4.5 weeks to OE-NPY DβH and WT mice feeding on chow or Western diet. Treatment with Y 2 -receptor antagonist increased body weight gain in both genotypes on chow diet and caused metabolic disturbances (e.g., hyperinsulinemia and hypercholesterolemia), especially in WT mice. During energy surplus (i.e., on Western diet), blocking of Y 2 -receptors induced obesity in WT mice, whereas OE-NPY DβH mice showed reduced fat mass gain, hepatic glycogen and serum cholesterol levels relative to body adiposity. Thus, it can be concluded that with normal NPY levels, peripheral Y 2 -receptor antagonist has no potential for treating obesity, but oppositely may even induce metabolic disorders. However, when energy-rich diet is combined with elevated NPY levels, e.g., stress combined with an unhealthy diet, Y 2 -receptor antagonism has beneficial effects on metabolic status.

  7. Concentration of Endogenous Secretory Receptor for Advanced Glycation End Products and Matrix Gla Protein in Controlled and Uncontrolled Type 2 Diabetes Mellitus Patients

    Directory of Open Access Journals (Sweden)

    Dwi Yuniati Daulay

    2013-04-01

    Full Text Available BACKGROUND: Advanced glycation end products (AGE and their receptor (RAGE system play an important role in the development of diabetic vascular complications. Recently, an endogenous secretory RAGE (esRAGE has been identified as a novel splice variant, which lacks the transmembrane domain and is secreted in human sera. Interestingly, it was reported that esRAGE binds AGE ligands and neutralizes AGE actions. Many studies have reported that diabetes mellitus correlates with vascular calcification event and increases progressively in uncontrolled diabetes. Matrix Gla Protein (MGP is known to act as an inhibitor in vascular calcification. The aim of this study was to observe progress of vascular calcification in uncontrolled diabetes patient by biochemical markers MGP as inhibitor in vascular calcification, via mechanism of AGEs. METHODS: This study was an observational study with cross sectional design on adult type 2 diabetic male patients who were defined by the 2011 Indonesian diabetes mellitus consensus criteria. RESULTS: The results of this study showed that there was a positive significant correlation between esRAGE and HbA1C (r=0.651, p=0.009, and negative correlation between MGP and HbA1C (r=-0.465, p=0.081 in controlled diabetes group. In uncontrolled diabetes group there was a positive significant correlation between MGP and HbA1C (r=0.350, p=0.023, despite the fact esRAGE showed no significant correlation with HbA1C. There was no significant difference in level of esRAGE and MGP in controlled and uncontrolled diabetes group, but MGP showed lower level in uncontrolled diabetes group, contrary to esRAGE that had higher concentration. CONCLUSIONS: In diabetes condition, complications of vascular calcification are caused by the mechanism of increased AGE formation represented by esRAGE. In diabetes control it is very important to keep the blood vessels from complications caused by vascular calcification. KEYWORDS: type 2 diabetes mellitus

  8. Prognostic Impact of Erythropoietin Expression and Erythropoietin Receptor Expression on Locoregional Control and Survival of Patients Irradiated for Stage II/III Non-Small-Cell Lung Cancer

    International Nuclear Information System (INIS)

    Rades, Dirk; Setter, Cornelia; Dahl, Olav; Schild, Steven E.; Noack, Frank

    2011-01-01

    Purpose: Prognostic factors can guide the physician in selecting the optimal treatment for an individual patient. This study investigates the prognostic value of erythropoietin (EPO) and EPO receptor (EPO-R) expression of tumor cells for locoregional control and survival in non-small-cell lung cancer (NSCLC) patients. Methods and Materials: Fourteen factors were investigated in 62 patients irradiated for stage II/III NSCLC, as follows: age, gender, Karnofsky performance score (KPS), histology, grading, TNM/American Joint Committee on Cancer (AJCC) stage, surgery, chemotherapy, pack years (average number of packages of cigarettes smoked per day multiplied by the number of years smoked), smoking during radiotherapy, hemoglobin levels during radiotherapy, EPO expression, and EPO-R expression. Additionally, patients with tumors expressing both EPO and EPO-R were compared to those expressing either EPO or EPO-R and to those expressing neither EPO nor EPO-R. Results: On univariate analysis, improved locoregional control was associated with AJCC stage II cancer (p 70 (p = 0.08), an N stage of 0 to 1 (p = 0.07), and no EPO-R expression (p = 0.10). On multivariate analysis, AJCC stage II and no EPO expression remained significant. No smoking during radiotherapy was almost significant. On univariate analysis, improved survival was associated with N stage 0 to 1 (p = 0.009), surgery (p = 0.039), hemoglobin levels of ≥12 g/d (p = 0.016), and no EPO expression (p = 0.001). On multivariate analysis, N stage 0 to 1 and no EPO expression maintained significance. Hemoglobin levels of ≥12 g/d were almost significant. On subgroup analyses, patients with tumors expressing both EPO and EPO-R had worse outcomes than those expressing either EPO or EPO-R and those expressing neither EPO nor RPO-R. Conclusions: EPO expression of tumor cells was an independent prognostic factor for locoregional control and survival in patients irradiated for NSCLC. EPO-R expression showed a trend

  9. Treatment with GLP1 receptor agonists reduce serum CRP concentrations in patients with type 2 diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials.

    Science.gov (United States)

    Mazidi, Mohsen; Karimi, Ehsan; Rezaie, Peyman; Ferns, Gordon A

    2017-07-01

    To undertake a systematic review and meta-analysis of randomized controlled trials of the effect of glucagon-like peptide-1 receptor agonist (GLP-1 RAs) therapy on serum C-reactive protein (CRP) concentrations. PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases were searched for the period up until March 16, 2016. Prospective studies evaluating the impact of GLP-1 RAs on serum CRP were identified. A random effects model (using the DerSimonian-Laird method) and generic inverse variance methods were used for quantitative data synthesis. Sensitivity analysis was conducted using the leave-one-out method. Heterogeneity was quantitatively assessed using the I 2 index. Random effects meta-regression was performed using unrestricted maximum likelihood method to evaluate the impact of potential moderator. International Prospective Register for Systematic Reviews (PROSPERO) number CRD42016036868. Meta-analysis of the data from 7 treatment arms revealed a significant reduction in serum CRP concentrations following treatment with GLP-1 RAs (WMD -2.14 (mg/dL), 95% CI -3.51, -0.78, P=0.002; I 2 96.1%). Removal of one study in the meta-analysis did not change the result in the sensitivity analysis (WMD -2.14 (mg/dL), 95% CI -3.51, -0.78, P=0.002; I 2 96.1%), indicating that our results could not be solely attributed to the effect of a single study. Random effects meta-regression was performed to evaluate the impact of potential moderator on the estimated effect size. Changes in serum CRP concentration were associated with the duration of treatment (slope -0.097, 95% CI -0.158, -0.042, Pmeta-analysis suggests that GLP-1 RAs therapy causes a significant reduction in CRP. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Correlation between familial cancer history and epidermal growth factor receptor mutations in Taiwanese never smokers with non-small cell lung cancer: a case-control study.

    Science.gov (United States)

    Cheng, Po-Chung; Cheng, Yun-Chung

    2015-03-01

    Lung cancer is a leading cause of cancer deaths in the world. Cigarette smoking remains a prominent risk factor, but lung cancer incidence has been increasing in never smokers. Genetic abnormalities including epidermal growth factor receptor (EGFR) mutations predominate in never smoking lung cancer patients. Furthermore, familial aggregations of patients with these mutations reflect heritable susceptibility to lung cancer. The correlation between familial cancer history and EGFR mutations in never smokers with lung cancer requires investigation. This was a retrospective case-control study that evaluated the prevalence of EGFR mutations in lung cancer patients with familial cancer history. Never smokers with lung cancer treated at a hospital in Taiwan between April 2012 and May 2014 were evaluated. Inclusion criteria were never smokers with non-small cell lung cancer (NSCLC). Exclusion criteria involved patients without records of familial cancer history or tumor genotype. This study included 246 never smokers with lung cancer. The study population mainly involved never smoking women with a mean age of 60 years, and the predominant tumor histology was adenocarcinoma. Lung cancer patients with familial cancer history had an increased prevalence of EGFR mutations compared to patients without family history [odds ratio (OR): 5.9; 95% confidence interval (CI): 3.3-10.6; Pnon-pulmonary cancers (OR: 5.0; 95% CI: 2.5-10.0; Pnever smoking lung cancer patients with familial cancer history. Moreover, a sizable proportion of never smoking cancer patients harbored these mutations. These observations have implications for the treatment of lung cancer in never smokers.

  11. Examination of Org 26576, an AMPA receptor positive allosteric modulator, in patients diagnosed with major depressive disorder: an exploratory, randomized, double-blind, placebo-controlled trial.

    Science.gov (United States)

    Nations, Kari R; Dogterom, Peter; Bursi, Roberta; Schipper, Jacques; Greenwald, Scott; Zraket, David; Gertsik, Lev; Johnstone, Jack; Lee, Allen; Pande, Yogesh; Ruigt, Ge; Ereshefsky, Larry

    2012-12-01

    Org 26576 acts by modulating ionotropic AMPA-type glutamate receptors to enhance glutamatergic neurotransmission. The aim of this Phase 1b study (N=54) was to explore safety, tolerability, pharmacokinetics, and pharmacodynamics of Org 26576 in depressed patients. Part I (N=24) evaluated the maximum tolerated dose (MTD) and optimal titration schedule in a multiple rising dose paradigm (range 100 mg BID to 600 mg BID); Part II (N=30) utilized a parallel groups design (100 mg BID, 400 mg BID, placebo) to examine all endpoints over a 28-day dosing period. Based on the number of moderate intensity adverse events reported at the 600 mg BID dose level, the MTD established in Part I was 450 mg BID. Symptomatic improvement as measured by the Montgomery-Asberg Depression Rating Scale was numerically greater in the Org 26576 groups than in the placebo group in both study parts. In Part II, the 400 mg BID dose was associated with improvements in executive functioning and speed of processing cognitive tests. Org 26576 was also associated with growth hormone increases and cortisol decreases at the end of treatment but did not influence prolactin or brain-derived neurotrophic factor. The quantitative electroencephalogram index Antidepressant Treatment Response at Week 1 was able to significantly predict symptomatic response at endpoint in the active treatment group, as was early improvement in social acuity. Overall, Org 26576 demonstrated good tolerability and pharmacokinetic properties in depressed patients, and pharmacodynamic endpoints suggested that it may show promise in future well-controlled, adequately powered proof of concept trials.

  12. Chemokine Ligand 5 (CCL5 and chemokine receptor (CCR5 genetic variants and prostate cancer risk among men of African Descent: a case-control study

    Directory of Open Access Journals (Sweden)

    Kidd LaCreis R

    2012-11-01

    Full Text Available Abstract Background Chemokine and chemokine receptors play an essential role in tumorigenesis. Although chemokine-associated single nucleotide polymorphisms (SNPs are associated with various cancers, their impact on prostate cancer (PCA among men of African descent is unknown. Consequently, this study evaluated 43 chemokine-associated SNPs in relation to PCA risk. We hypothesized inheritance of variant chemokine-associated alleles may lead to alterations in PCA susceptibility, presumably due to variations in antitumor immune responses. Methods Sequence variants were evaluated in germ-line DNA samples from 814 African-American and Jamaican men (279 PCA cases and 535 controls using Illumina’s Goldengate genotyping system. Results Inheritance of CCL5 rs2107538 (AA, GA+AA and rs3817655 (AA, AG, AG+AA genotypes were linked with a 34-48% reduction in PCA risk. Additionally, the recessive and dominant models for CCR5 rs1799988 and CCR7 rs3136685 were associated with a 1.52-1.73 fold increase in PCA risk. Upon stratification, only CCL5 rs3817655 and CCR7 rs3136685 remained significant for the Jamaican and U.S. subgroups, respectively. Conclusions In summary, CCL5 (rs2107538, rs3817655 and CCR5 (rs1799988 sequence variants significantly modified PCA susceptibility among men of African descent, even after adjusting for age and multiple comparisons. Our findings are only suggestive and require further evaluation and validation in relation to prostate cancer risk and ultimately disease progression, biochemical/disease recurrence and mortality in larger high-risk subgroups. Such efforts will help to identify genetic markers capable of explaining disproportionately high prostate cancer incidence, mortality, and morbidity rates among men of African descent.

  13. Opiate exposure state controls dopamine D3 receptor and cdk5/calcineurin signaling in the basolateral amygdala during reward and withdrawal aversion memory formation.

    Science.gov (United States)

    Rosen, Laura G; Rushlow, Walter J; Laviolette, Steven R

    2017-10-03

    The dopamine (DA) D3 receptor (D3R) is highly expressed in the basolateral nucleus of the amygdala (BLA), a neural region critical for processing opiate-related reward and withdrawal aversion-related memories. Functionally, D3R transmission is linked to downstream Cdk5 and calcineurin signaling, both of which regulate D3R activity states and play critical roles in memory-related synaptic plasticity. Previous evidence links D3R transmission to opiate-related memory processing, however little is known regarding how chronic opiate exposure may alter D3R-dependent memory mechanisms. Using conditioned place preference (CPP) and withdrawal aversion (conditioned place aversion; CPA) procedures in rats, combined with molecular analyses of BLA protein expression, we examined the effects of chronic opiate exposure on the functional role of intra-BLA D3R transmission during the acquisition of opiate reward or withdrawal aversion memories. Remarkably, we report that the state of opiate exposure during behavioural conditioning (opiate-naïve/non-dependent vs. chronically exposed and in withdrawal) controlled the functional role of intra-BLA D3R transmission during the acquisition of both opiate reward memories and withdrawal-aversion associative memories. Thus, whereas intra-BLA D3R blockade had no effect on opiate reward memory formation in the non-dependent state, blockade of intra-BLA D3R transmission prevented the formation of opiate reward and withdrawal aversion memory in the chronically exposed state. This switch in the functional role of D3R transmission corresponded to significant increases in Cdk5 phosphorylation and total expression levels of calcineurin, and a corresponding decrease in intra-BLA D3R expression. Inhibition of either intra-BLA Cdk5 or calcineurin reversed these effects, switching intra-BLA associative memory formation back to a D3R-independent mechanism. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Preliminary evidence that negative symptom severity relates to multilocus genetic profile for dopamine signaling capacity and D2 receptor binding in healthy controls and in schizophrenia.

    Science.gov (United States)

    Eisenstein, Sarah A; Bogdan, Ryan; Chen, Ling; Moerlein, Stephen M; Black, Kevin J; Perlmutter, Joel S; Hershey, Tamara; Barch, Deanna M

    2017-03-01

    Deficits in central, subcortical dopamine (DA) signaling may underlie negative symptom severity, particularly anhedonia, in healthy individuals and in schizophrenia. To investigate these relationships, we assessed negative symptoms with the Schedule for the Assessment of Negative Symptoms and the Brief Negative Symptom Scale (BNSS) and self-reported anhedonia with the Scales for Physical and Social Anhedonia (SPSA), Temporal Experience of Pleasure Scale, and Snaith-Hamilton Pleasure Scale in 36 healthy controls (HC), 27 siblings (SIB) of individuals with schizophrenia, and 66 individuals with schizophrenia or schizoaffective disorder (SCZ). A subset of participants (N = 124) were genotyped for DA-related polymorphisms in genes for DRD4, DRD2/ANKK1, DAT1, and COMT, which were used to construct biologically-informed multi-locus genetic profile (MGP) scores reflective of subcortical dopaminergic signaling. DA receptor type 2 (D2R) binding was assessed among a second subset of participants (N = 23) using PET scans with the D2R-selective, non-displaceable radioligand (N-[ 11 C]methyl)benperidol. Higher MGP scores, reflecting elevated subcortical dopaminergic signaling capacity, were associated with less negative symptom severity, as measured by the BNSS, across all participants. In addition, higher striatal D2R binding was associated with less physical and social anhedonia, as measured by the SPSA, across HC, SIB, and SCZ. The current preliminary findings support the hypothesis that subcortical DA function may contribute to negative symptom severity and self-reported anhedonia, independent of diagnostic status. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Involvement of the Niacin Receptor GPR109a in the LocalControl of Glucose Uptake in Small Intestine of Type 2Diabetic Mice

    Directory of Open Access Journals (Sweden)

    Tung Po Wong

    2015-09-01

    Full Text Available Niacin is a popular nutritional supplement known to reduce the risk of cardiovascular diseases by enhancing high-density lipoprotein levels. Despite such health benefits, niacin impairs fasting blood glucose. In type 2 diabetes (T2DM, an increase in jejunal glucose transport has been well documented; however, this is intriguingly decreased during niacin deficient state. In this regard, the role of the niacin receptor GPR109a in T2DM jejunal glucose transport remains unknown. Therefore, the effects of diabetes and high-glucose conditions on GPR109a expression were studied using jejunal enterocytes of 10-week-old m+/db and db/db mice, as well as Caco-2 cells cultured in 5.6 or 25.2 mM glucose concentrations. Expression of the target genes and proteins were quantified using real-time polymerase chain reaction (RT-PCR and Western blotting. Glucose uptake in Caco-2 cells and everted mouse jejunum was measured using liquid scintillation counting. 10-week T2DM increased mRNA and protein expression levels of GPR109a in jejunum by 195.0% and 75.9%, respectively, as compared with the respective m+/db control; high-glucose concentrations increased mRNA and protein expression of GPR109a in Caco-2 cells by 130.2% and 69.0%, respectively, which was also confirmed by immunohistochemistry. In conclusion, the enhanced GPR109a expression in jejunal enterocytes of T2DM mice and high-glucose treated Caco-2 cells suggests that GPR109a is involved in elevating intestinal glucose transport observed in diabetes.

  16. 5-HT2C receptor involvement in the control of persistence in the reinforced spatial alternation animal model of obsessive-compulsive disorder.

    Science.gov (United States)

    Papakosta, Vassiliki-Maria; Kalogerakou, Stamatina; Kontis, Dimitris; Anyfandi, Eleni; Theochari, Eirini; Boulougouris, Vasileios; Papadopoulos, Sokrates; Panagis, George; Tsaltas, Eleftheria

    2013-04-15

    The serotonergic system is implicated in the pathophysiology of obsessive-compulsive disorder (OCD). However, the distinct role of serotonin (5-HT) receptor subtypes remains unclear. This study investigates the contribution of 5-HT2A and 5-HT2C receptors in the modulation of persistence in the reinforced spatial alternation model of OCD. Male Wistar rats were assessed for spontaneous and pharmacologically induced (by m-chlorophenylpiperazine: mCPP) directional persistence in the reinforced alternation OCD model. Systemic administration of mCPP (non-specific 5-HT agonist, 2.5mg/kg), M100907 (selective 5-HT2A receptor antagonist, 0.08 mg/kg), SB242084 (selective 5-HT2C receptor antagonist, 0.5 mg/kg) and vehicle was used. Experiment 1 investigated M100907 and SB242084 effects in animals spontaneously exhibiting high and low persistence during the early stages of alternation training. Experiment 2 investigated M100900 and SB242084 effects on mCPP-induced persistence. Under the regime used in Experiment 1, 5-HT2A or 5-HT2C receptor antagonism did not affect spontaneous directional persistence in either high or low persistence groups. In Experiment 2, 5-HT2C but not 5-HT2A receptor antagonism significantly reduced, but did not abolish, mCPP-induced directional persistence. These findings suggest that 5-HT2C but not 5-HT2A receptors contribute to the modulation of mCPP-induced persistent behaviour, raising the possibility that the use of 5-HT2C antagonists may have a therapeutic value in OCD. Copyright © 2013 Elsevier B.V. All rights reserved.

  17. Serum levels of TWEAK and scavenger receptor CD163 in type 1 diabetes mellitus: relationship with cardiovascular risk factors. a case-control study.

    Directory of Open Access Journals (Sweden)

    Gemma Llauradó

    Full Text Available OBJECTIVE: To test the usefulness of serum concentrations of tumor necrosis factor-like weak inducer of apoptosis (sTWEAK and soluble scavenger receptor CD163 (sCD163 as markers of subtle inflammation in patients with type 1 diabetes mellitus (T1DM without clinical cardiovascular (CV disease and to evaluate their relationship with arterial stiffness (AS. METHODS: Sixty-eight patients with T1DM and 68 age and sex-matched, healthy subjects were evaluated. Anthropometrical variables and CV risk factors were recorded. Serum concentrations of sTWEAK and sCD163 were measured. AS was assessed by aortic pulse wave velocity (aPWV. All statistical analyses were stratified by gender. RESULTS: T1DM patients showed lower serum concentrations of sTWEAK (Men: 1636.5 (1146.3-3754.8 pg/mL vs. 765.9 (650.4-1097.1 pg/mL; p<0.001. Women: 1401.0 (788.0-2422.2 pg/mL vs. 830.1 (562.6-1175.9 pg/mL; p = 0.011 compared with their respective controls. Additionally, T1DM men had higher serum concentrations of sCD163 (285.0 (247.7-357.1 ng/mL vs. 224.8 (193.3-296.5 ng/mL; p = 0.012 compared with their respective controls. sTWEAK correlated negatively with aPWV in men (r = -0.443; p<0.001. However, this association disappeared after adjusting for potential confounders. In men, the best multiple linear regression model showed that the independent predictors of sTWEAK were T1DM and WHR (R(2 = 0.640; p<0.001. In women, T1DM and SBP were the independent predictors for sTWEAK (R(2 = 0.231; p = 0.001. CONCLUSION: sTWEAK is decreased in T1DM patients compared with age and sex-matched healthy subjects after adjusting for classic CV risk factors, although sTWEAK levels may be partially influenced by some of them. Additionally, T1DM men have higher serum concentrations of sCD163. These results point out an association between the inflammatory system and CV risk in T1DM.

  18. Effect of histamine-2-receptor antagonists versus sucralfate on stress ulcer prophylaxis in mechanically ventilated patients: a meta-analysis of 10 randomized controlled trials.

    Science.gov (United States)

    Huang, Jiahao; Cao, Yunfei; Liao, Cun; Wu, Liucheng; Gao, Feng

    2010-01-01

    We conducted a meta-analysis in order to investigate the effect of histamine-2-receptor antagonists (H2RA) versus sucralfate on stress ulcer prophylaxis in mechanically ventilated patients in the intensive care unit (ICU). A systematic literature search of Medline, EMBASE, Cochrane Central Register of Controlled Trials (1966 to January 2010) was conducted using specific search terms. A review of Web of Science and a manual review of references were also performed. Eligible studies were randomized control trials (RCTs) that compared H2RA and sucralfate for the prevention of stress ulcer in mechanically ventilated patients. Main outcome measures were rates of overt bleeding, clinically important gastrointestinal (GI) bleeding, ventilator-associated pneumonia, gastric colonization and ICU mortality. Ten RCTs with 2,092 participants on mechanical ventilation were identified. Meta-analysis showed there was a trend toward decreased overt bleeding when H2RA was compared with sucralfate (OR = 0.87, 95% CI: 0.49 to 1.53). A total of 12 clinically important GI bleeding events occurred among 667 patients (1.8%) in the H2RA group compared with 26 events among 673 patients (3.9%) in the sucralfate groups. Prophylaxis with sucralfate decreased the incidence of gastric colonization (OR = 2.03, 95% CI: 1.29 to 3.19) and ventilator-associated pneumonia (OR = 1.32, 95% CI: 1.07 to 1.64). Subgroup analysis showed H2RA was not superior to sucralfate in reducing early-onset pneumonia (OR = 0.62, 95%CI: 0.36 to 1.07) but had a higher late-onset pneumonia rate (OR = 4.36, 95%CI: 2.09 to 9.09) relative to sucralfate. No statistically significant reduction was observed in mortality of ICU between groups (OR = 1.08, 95% CI: 0.86 to 1.34). In patients with mechanical ventilation, H2RA resulted in no differential effectiveness in treating overt bleeding, but had higher rates of gastric colonization and ventilator-associated pneumonia. Additional RCTs of stress ulcer prophylaxis with H2RA and

  19. Regulation of rat hepatocyte function by P2Y receptors: focus on control of glycogen phosphorylase and cyclic AMP by 2-methylthioadenosine 5'-diphosphate.

    Science.gov (United States)

    Dixon, C Jane; Hall, John F; Webb, Tania E; Boarder, Michael R

    2004-10-01

    Hepatocyte function is regulated by several P2Y receptor subtypes. Here we report that 2-methylthioadenosine 5'-diphosphate (2-MeSADP), an agonist at P2Y(1), P2Y(12), and P2Y(13) receptors, potently (threshold 30 nM) stimulates glycogen phosphorylase in freshly isolated rat hepatocytes. Antagonism by N(6)-methyl 2'-deoxyadenosine 3',5'-bisphosphate (MRS 2179) confirms that this response is mediated by P2Y(1) receptors. In addition, in these cells, both 2-MeSADP and UTP inhibited glucagon-stimulated cyclic AMP accumulation. This inhibitory effect of 2-MeSADP was not reversed by the P2Y(1) antagonists, adenosine-3'-phosphate-5'-phosphate (A3P5P) or MRS 2179, both in the range 1 to 300 microM, indicating that it was not mediated by P2Y(1) receptors. This contrasts with the increase in cytosolic free Ca(2+) concentration ([Ca(2+)](c)) induced by 2-MeSADP, which has shown to be inhibited by A3P5P. Pertussis toxin abolished the inhibitory effect of both UTP and 2-MeSADP. After culture of cells for 48 h, the ability of 2-MeSADP to inhibit cyclic AMP accumulation was greatly diminished. Reverse transcriptase-polymerase chain reaction analysis revealed that during this culture period, there was a decline in the ability to detect transcripts for P2Y(12) and P2Y(13) receptors, both of which are activated by 2-MeSADP and negatively coupled to adenylyl cyclase. However, in freshly isolated cells, the P2Y(12) and P2Y(13) receptor antagonist, 2-propylthio-beta,gamma-dichloromethylene-d-ATP (AR-C67085) (10 nM to 300 microM) did not alter the ability of 2-MeSADP to inhibit glucagon-stimulated cyclic AMP accumulation. We conclude that 2-MeSADP regulates rat hepatocyte glycogen phosphorylase by acting on P2Y(1) receptors coupled to raised [Ca(2+)](c), and by inhibiting cyclic AMP levels by an unknown G(i)-coupled receptor subtype, distinct from P2Y(1), P2Y(12), or P2Y(13) receptors.

  20. Dynamics of receptor-operated Ca(2+) currents through TRPC channels controlled via the PI(4,5)P2-PLC signaling pathway.

    Science.gov (United States)

    Mori, Masayuki X; Itsuki, Kyohei; Hase, Hideharu; Sawamura, Seishiro; Kurokawa, Tatsuki; Mori, Yasuo; Inoue, Ryuji

    2015-01-01

    Transient receptor potential canonical (TRPC) channels are Ca(2+)-permeable, nonselective cation channels that carry receptor-operated Ca(2+) currents (ROCs) triggered by receptor-induced, phospholipase C (PLC)-catalyzed hydrolysis of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. Within the vasculature, TRPC channel ROCs contribute to smooth muscle cell depolarization, vasoconstriction, and vascular remodeling. However, TRPC channel ROCs exhibit a variable response to receptor-stimulation, and the regulatory mechanisms governing TRPC channel activity remain obscure. The variability of ROCs may be explained by their complex regulation by PI(4,5)P2 and its metabolites, which differentially affect TRPC channel activity. To resolve the complex regulation of ROCs, the use of voltage-sensing phosphoinositide phosphatases and model simulation have helped to reveal the time-dependent contribution of PI(4,5)P2 and the possible role of PI(4,5)P2 in the regulation of ROCs. These approaches may provide unprecedented insight into the dynamics of PI(4,5)P2 regulation of TRPC channels and the fundamental mechanisms underlying transmembrane ion flow. Within that context, we summarize the regulation of TRPC channels and their coupling to receptor-mediated signaling, as well as the application of voltage-sensing phosphoinositide phosphatases to this research. We also discuss the controversial bidirectional effects of PI(4,5)P2 using a model simulation that could explain the complicated effects of PI(4,5)P2 on different ROCs.

  1. Impact of adjuvant inhibition of vascular endothelial growth factor receptor tyrosine kinases on tumor growth delay and local tumor control after fractionated irradiation in human squamous cell carcinomas in nude mice

    International Nuclear Information System (INIS)

    Zips, Daniel; Hessel, Franziska; Krause, Mechthild; Schiefer, Yvonne; Hoinkis, Cordelia; Thames, Howard D.; Haberey, Martin; Baumann, Michael

    2005-01-01

    Purpose: Previous experiments have shown that adjuvant inhibition of the vascular endothelial growth factor receptor after fractionated irradiation prolonged tumor growth delay and may also improve local tumor control. To test the latter hypothesis, local tumor control experiments were performed. Methods and materials: Human FaDu and UT-SCC-14 squamous cell carcinomas were studied in nude mice. The vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584 (50 mg/kg body weight b.i.d.) was administered for 75 days after irradiation with 30 fractions within 6 weeks. Tumor growth time and tumor control dose 50% (TCD 50 ) were determined and compared to controls (carrier without PTK787/ZK222584). Results: Adjuvant administration of PTK787/ZK222584 significantly prolonged tumor growth time to reach 5 times the volume at start of drug treatment by an average of 11 days (95% confidence interval 0.06;22) in FaDu tumors and 29 days (0.6;58) in UT-SCC-14 tumors. In both tumor models, TCD 50 values were not statistically significantly different between the groups treated with PTK787/ZK222584 compared to controls. Conclusions: Long-term inhibition of angiogenesis after radiotherapy significantly reduced the growth rate of local recurrences but did not improve local tumor control. This indicates that recurrences after irradiation depend on vascular endothelial growth factor-driven angiogenesis, but surviving tumor cells retain their clonogenic potential during adjuvant antiangiogenic treatment with PTK787/ZK222584

  2. Circadian control of p75 neurotrophin receptor leads to alternate activation of Nrf2 and c-Rel to reset energy metabolism in astrocytes via brain-derived neurotrophic factor.

    Science.gov (United States)

    Ishii, Tetsuro; Warabi, Eiji; Mann, Giovanni E

    2018-05-01

    Circadian clock genes regulate energy metabolism partly through neurotrophins in the body. The low affinity neurotrophin receptor p75 NTR is a clock component directly regulated by the transcriptional factor Clock:Bmal1 complex. Brain-derived neurotrophic factor (BDNF) is expressed in the brain and plays a key role in coordinating metabolic interactions between neurons and astrocytes. BDNF transduces signals through TrkB and p75 NTR receptors. This review highlights a novel molecular mechanism by which BDNF via circadian control of p75 NTR leads to daily resetting of glucose and glycogen metabolism in brain astrocytes to accommodate their functional interaction with neurons. Astrocytes store glycogen as an energy reservoir to provide active neurons with the glycolytic metabolite lactate. Astrocytes predominantly express the truncated receptor TrkB.T1 which lacks an intracellular receptor tyrosine kinase domain. TrkB.T1 retains the capacity to regulate cell morphology through regulation of Rho GTPases. In contrast, p75 NTR mediates generation of the bioactive lipid ceramide upon stimulation with BDNF and inhibits PKA activation. As ceramide directly activates PKCζ, we discuss the importance of the TrkB.T1-p75 NTR -ceramide-PKCζ signaling axis in the stimulation of glycogen and lipid synthesis and activation of RhoA. Ceramide-PKCζ-casein kinase 2 signaling activates Nrf2 to support oxidative phosphorylation via upregulation of antioxidant enzymes. In the absence of p75 NTR , TrkB.T1 functionally interacts with adenosine A 2A R and dopamine D1R receptors to enhance cAMP-PKA signaling and activate Rac1 and NF-κB c-Rel, favoring glycogen hydrolysis, gluconeogenesis and aerobic glycolysis. Thus, diurnal changes in p75 NTR levels in astrocytes resets energy metabolism via BDNF to accommodate their metabolic interaction with neurons. Copyright © 2018 Elsevier Inc. All rights reserved.

  3. Imidazoline2 (I2) receptor- and alpha2-adrenoceptor-mediated modulation of hypothalamic-pituitary-adrenal axis activity in control and acute restraint stressed rats.

    Science.gov (United States)

    Finn, David P; Hudson, Alan L; Kinoshita, Hiroshi; Coventry, Toni L; Jessop, David S; Nutt, David J; Harbuz, Michael S

    2004-03-01

    Central noradrenaline regulates the activity of the hypothalamic-pituitary-adrenal (HPA) axis and the neuroendocrine response to stress. alpha2-adrenoceptors and imidazoline2 (I2) receptors modulate the activity of the central noradrenergic system. The present set of experiments investigated the role of alpha2-adrenoceptors and I2 receptors in the regulation of HPA axis activity under basal conditions and during exposure to the acute psychological stress of restraint. Three separate experiments were carried out in which rats were given an i.p. injection of either saline vehicle, the combined alpha2-adrenoceptor antagonist and I2 receptor ligand idazoxan (10 mg/kg), the selective I2 receptor ligand BU224 (2.5 or 10 mg/kg) or the selective alpha2-adrenoceptor antagonist RX821002 (2.5 mg/kg) with or without restraint stress. Drugs were administered immediately prior to restraint of 60 min duration. Blood was sampled pre-injection, 30, 60 and 240 min post-injection and plasma corticosterone was measured by radioimmunoassay. In experiment 1, idazoxan increased plasma corticosterone levels in naive animals and potentiated the corticosterone response to acute restraint stress. In experiment 2, BU224 administration increased plasma corticosterone levels in a dose-related manner in naive rats. The results of experiment 3 indicated that RX821002 also elevated plasma corticosterone levels in naive rats, however, only BU224 potentiated the corticosterone response to restraint stress. These studies suggest that both alpha2-adrenoceptors and I2 receptors play a role in modulating basal HPA axis activity and that I2 receptors may play a more important role than alpha2-adrenoceptors in modulating the HPA axis response to the acute psychological stress of restraint.

  4. Dianicline, a novel α4β2 nicotinic acetylcholine receptor partial agonist, for smoking cessation: a randomized placebo-controlled clinical trial

    DEFF Research Database (Denmark)

    Tonstad, Serena; Holme, Ingar; Tønnesen, Philip

    2011-01-01

    Dianicline is a α4β2 nicotinic acetylcholine receptor partial agonist, a class of drugs that includes varenicline and cytisine. Varenicline is efficacious for smoking cessation, while cytisine has not been studied systematically. The efficacy of dianicline has not been previously tested in an ade......Dianicline is a α4β2 nicotinic acetylcholine receptor partial agonist, a class of drugs that includes varenicline and cytisine. Varenicline is efficacious for smoking cessation, while cytisine has not been studied systematically. The efficacy of dianicline has not been previously tested...

  5. Regulation of Toll-like receptor 2 interaction with Ecgp96 controls Escherichia coli K1 invasion of brain endothelial cells

    OpenAIRE

    Krishnan, Subramanian; Chen, Shuang; Turcatel, Gianluca; Arditi, Moshe; Prasadarao, Nemani V.

    2012-01-01

    The interaction of outer membrane protein A (OmpA) with its receptor, Ecgp96 (a homologue of Hsp90β) is critical for the pathogenesis of E. coli K1 meningitis. Since Hsp90 chaperones Toll-like receptors (TLRs), we examined the role of TLRs in E. coli K1 infection. Herein, we show that newborn TLR2−/− mice are resistant to E. coli K1 meningitis, while TLR4−/− mice succumb to infection sooner. In vitro, OmpA+ E. coli infection selectively upregulates Ecgp96 and TLR2 in human brain microvascular...

  6. The effects of d-amphetamine on extrastriatal dopamine D{sub 2}/D{sub 3} receptors: a randomized, double-blind, placebo-controlled PET study with [{sup 11}C]FLB 457 in healthy subjects

    Energy Technology Data Exchange (ETDEWEB)

    Aalto, Sargo [University of Turku, Turku PET Centre, Turku (Finland); Aabo Akademi University, Department of Psychology, Turku (Finland); Hirvonen, Jussi; Kajander, Jaana; Naagren, Kjell; Rinne, Juha O. [University of Turku, Turku PET Centre, Turku (Finland); Kaasinen, Valtteri [University of Turku, Department of Neurology, P.O. Box 52, Turku (Finland); Hagelberg, Nora [University of Turku, Turku PET Centre, Turku (Finland); Turku University Central Hospital, Department of Anaesthesiology, Intensive Care, Emergency Care and Pain Medicine, Turku (Finland); Seppaelae, Timo [Drug Research Unit, National Public Health Institute, Helsinki (Finland); Scheinin, Harry [University of Turku, Turku PET Centre, Turku (Finland); University of Turku, Department of Pharmacology, Drug Development and Therapeutics, Turku (Finland); Hietala, Jarmo [University of Turku, Turku PET Centre, Turku (Finland); University of Turku, Department of Psychiatry, Turku (Finland)

    2009-03-15

    The dopamine D{sub 2}/D{sub 3} receptor ligand [{sup 11}C]FLB 457 and PET enable quantification of low-density extrastriatal D{sub 2}/D{sub 3} receptors, but it is uncertain whether [{sup 11}C]FLB 457 can be used for measuring extrastriatal dopamine release. We studied the effects of d-amphetamine (0.3 mg/kg i.v.) on extrastriatal [{sup 11}C]FLB 457 binding potential (BP{sub ND}) in a randomized, double-blind, placebo-controlled study including 24 healthy volunteers. The effects of d-amphetamine on [{sup 11}C]FLB 457 BP{sub ND} and distribution volume (V{sub T}) in the frontal cortex were not different from those of placebo. Small decreases in [{sup 11}C]FLB 457 BP{sub ND} were observed only in the posterior cingulate and hippocampus. The regional changes in [{sup 11}C]FLB 457 BP{sub ND} did not correlate with d-amphetamine-induced changes in subjective ratings of euphoria. This placebo-controlled study showed that d-amphetamine does not induce marked changes in measures of extrastriatal dopamine D{sub 2}/D{sub 3} receptor binding. Our results indicate that [{sup 11}C]FLB 457 PET is not a useful method for measuring extrastriatal dopamine release in humans. (orig.)

  7. Quantitative receptor radioautography in the study of receptor-receptor interactions in the nucleus tractus solitarii

    Directory of Open Access Journals (Sweden)

    Fior-Chadi D.R.

    1998-01-01

    Full Text Available The nucleus tractus solitarii (NTS in the dorsomedial medulla comprises a wide range of neuropeptides and biogenic amines. Several of them are related to mechanisms of central blood pressure control. Angiotensin II (Ang II, neuropeptide Y (NPY and noradrenaline (NA are found in the NTS cells, as well as their receptors. Based on this observation we have evaluated the modulatory effect of these peptide receptors on a2-adrenoceptors in the NTS. Using quantitative receptor radioautography, we observed that NPY and Ang II receptors decreased the affinity of a2-adrenoceptors for their agonists in the NTS of the rat. Cardiovascular experiments agreed with the in vitro data. Coinjection of a threshold dose of Ang II or of the NPY agonists together with an ED50 dose of adrenergic agonists such as NA, adrenaline and clonidine counteracted the depressor effect produced by the a2-agonist in the NTS. The results provide evidence for the existence of an antagonistic interaction between Ang II at1 receptors and NPY receptor subtypes with the a2-adrenoceptors in the NTS. This receptor interaction may reduce the transduction over the a2-adrenoceptors which can be important in central cardiovascular regulation and in the development of hypertension

  8. The NOD-like receptor signalling pathway in Helicobacter pylori infection and related gastric cancer: a case-control study and gene expression analyses.

    Directory of Open Access Journals (Sweden)

    Natalia Castaño-Rodríguez

    Full Text Available BACKGROUND: Currently, it is well established that cancer arises in chronically inflamed tissue. A number of NOD-like receptors (NLRs form inflammasomes, intracellular multiprotein complexes critical for generating mature pro-inflammatory cytokines (IL-1β and IL-18. As chronic inflammation of the gastric mucosa is a consequence of Helicobacter pylori infection, we investigated the role of genetic polymorphisms and expression of genes involved in the NLR signalling pathway in H. pylori infection and related gastric cancer (GC. MATERIALS AND METHODS: Fifty-one genetic polymorphisms were genotyped in 310 ethnic Chinese (87 non-cardia GC cases and 223 controls with functional dyspepsia. In addition, gene expression of 84 molecules involved in the NLR signalling pathway was assessed in THP-1 cells challenged with two H. pylori strains, GC026 (GC and 26695 (gastritis. RESULTS: CARD8-rs11672725, NLRP3-rs10754558, NLRP3-rs4612666, NLRP12-rs199475867 and NLRX1-rs10790286 showed significant associations with GC. On multivariate analysis, CARD8-rs11672725 remained a risk factor (OR: 4.80, 95% CI: 1.39-16.58. Further, NLRP12-rs2866112 increased the risk of H. pylori infection (OR: 2.13, 95% CI: 1.22-3.71. Statistical analyses assessing the joint effect of H. pylori infection and the selected polymorphisms revealed strong associations with GC (CARD8, NLRP3, CASP1 and NLRP12 polymorphisms. In gene expression analyses, five genes encoding NLRs were significantly regulated in H. pylori-challenged cells (NLRC4, NLRC5, NLRP9, NLRP12 and NLRX1. Interestingly, persistent up-regulation of NFKB1 with simultaneous down-regulation of NLRP12 and NLRX1 was observed in H. pylori GC026-challenged cells. Further, NF-κB target genes encoding pro-inflammatory cytokines, chemokines and molecules involved in carcinogenesis were markedly up-regulated in H. pylori GC026-challenged cells. CONCLUSIONS: Novel associations between polymorphisms in the NLR signalling pathway (CARD8

  9. The BRAIN TRIAL: a randomised, placebo controlled trial of a Bradykinin B2 receptor antagonist (Anatibant in patients with traumatic brain injury

    Directory of Open Access Journals (Sweden)

    Rätsep Indrek

    2009-12-01

    Full Text Available Abstract Background Cerebral oedema is associated with significant neurological damage in patients with traumatic brain injury. Bradykinin is an inflammatory mediator that may contribute to cerebral oedema by increasing the permeability of the blood-brain barrier. We evaluated the safety and effectiveness of the non-peptide bradykinin B2 receptor antagonist Anatibant in the treatment of patients with traumatic brain injury. During the course of the trial, funding was withdrawn by the sponsor. Methods Adults with traumatic brain injury and a Glasgow Coma Scale score of 12 or less, who had a CT scan showing an intracranial abnormality consistent with trauma, and were within eight hours of their injury were randomly allocated to low, medium or high dose Anatibant or to placebo. Outcomes were Serious Adverse Events (SAE, mortality 15 days following injury and in-hospital morbidity assessed by the Glasgow Coma Scale (GCS, the Disability Rating Scale (DRS and a modified version of the Oxford Handicap Scale (HIREOS. Results 228 patients out of a planned sample size of 400 patients were randomised. The risk of experiencing one or more SAEs was 26.4% (43/163 in the combined Anatibant treated group, compared to 19.3% (11/57 in the placebo group (relative risk = 1.37; 95% CI 0·76 to 2·46. All cause mortality in the Anatibant treated group was 19% and in the placebo group 15.8% (relative risk 1.20, 95% CI 0.61 to 2.36. The mean GCS at discharge was 12.48 in the Anatibant treated group and 13.0 in the placebo group. Mean DRS was 11.18 Anatibant versus 9.73 placebo, and mean HIREOS was 3.94 Anatibant versus 3.54 placebo. The differences between the mean levels for GCS, DRS and HIREOS in the Anatibant and placebo groups, when adjusted for baseline GCS, showed a non-significant trend for worse outcomes in all three measures. Conclusion This trial did not reach the planned sample size of 400 patients and consequently, the study power to detect an increase in

  10. The BRAIN TRIAL: a randomised, placebo controlled trial of a Bradykinin B2 receptor antagonist (Anatibant) in patients with traumatic brain injury.

    Science.gov (United States)

    Shakur, Haleema; Andrews, Peter; Asser, Toomas; Balica, Laura; Boeriu, Cristian; Quintero, Juan Diego Ciro; Dewan, Yashbir; Druwé, Patrick; Fletcher, Olivia; Frost, Chris; Hartzenberg, Bennie; Mantilla, Jorge Mejia; Murillo-Cabezas, Francisco; Pachl, Jan; Ravi, Ramalingam R; Rätsep, Indrek; Sampaio, Cristina; Singh, Manmohan; Svoboda, Petr; Roberts, Ian

    2009-12-03

    Cerebral oedema is associated with significant neurological damage in patients with traumatic brain injury. Bradykinin is an inflammatory mediator that may contribute to cerebral oedema by increasing the permeability of the blood-brain barrier. We evaluated the safety and effectiveness of the non-peptide bradykinin B2 receptor antagonist Anatibant in the treatment of patients with traumatic brain injury. During the course of the trial, funding was withdrawn by the sponsor. Adults with traumatic brain injury and a Glasgow Coma Scale score of 12 or less, who had a CT scan showing an intracranial abnormality consistent with trauma, and were within eight hours of their injury were randomly allocated to low, medium or high dose Anatibant or to placebo. Outcomes were Serious Adverse Events (SAE), mortality 15 days following injury and in-hospital morbidity assessed by the Glasgow Coma Scale (GCS), the Disability Rating Scale (DRS) and a modified version of the Oxford Handicap Scale (HIREOS). 228 patients out of a planned sample size of 400 patients were randomised. The risk of experiencing one or more SAEs was 26.4% (43/163) in the combined Anatibant treated group, compared to 19.3% (11/57) in the placebo group (relative risk = 1.37; 95% CI 0.76 to 2.46). All cause mortality in the Anatibant treated group was 19% and in the placebo group 15.8% (relative risk 1.20, 95% CI 0.61 to 2.36). The mean GCS at discharge was 12.48 in the Anatibant treated group and 13.0 in the placebo group. Mean DRS was 11.18 Anatibant versus 9.73 placebo, and mean HIREOS was 3.94 Anatibant versus 3.54 placebo. The differences between the mean levels for GCS, DRS and HIREOS in the Anatibant and placebo groups, when adjusted for baseline GCS, showed a non-significant trend for worse outcomes in all three measures. This trial did not reach the planned sample size of 400 patients and consequently, the study power to detect an increase in the risk of serious adverse events was reduced. This trial

  11. Efficacy and Acceptability of Glycemic Control of Glucagon-Like Peptide-1 Receptor Agonists among Type 2 Diabetes: A Systematic Review and Network Meta-Analysis.

    Directory of Open Access Journals (Sweden)

    Zhixia Li

    Full Text Available To synthesize current evidence of the impact of Glucagon-like peptide-1 receptor agonists (GLP-1 RAs on hypoglycemia, treatment discontinuation and glycemic level in patients with type 2 diabetes.Systematic review and network meta-analysis.Literature search (Medline, Embase, the Cochrane library, website of clinical trial, bibliographies of published systematic reviews.Randomized controlled trials with available data comparing GLP-1 RAs with placebo or traditional anti-diabetic drugs in patients with type 2 diabetes.Traditional pairwise meta-analyses within DerSimonian-Laird random effects model and network meta-analysis within a Bayesian framework were performed to calculate odds ratios for the incidence of hypoglycemia, treatment discontinuation, HbA1c<7.0% and HbA1c<6.5%. Ranking probabilities for all treatments were estimated to obtain a treatment hierarchy using the surface under the cumulative ranking curve (SUCRA and mean ranks.78 trials with 13 treatments were included. Overall, all GLP-1 RAs except for albiglutide increased the risk of hypoglycemia when compared to placebo. Reduction in the incidence of hypoglycemia was found for all GLP-1 RAs versus insulin (except for dulaglutide and sulphonylureas. For the incidence of treatment discontinuation, increase was found for exenatide, liraglutide, lixisenatide and taspoglutide versus placebo, insulin and sitagliptin. For glycemic level, decrease was found for all GLP-1 RAs versus placebo. Dulaglutide, exenatide long-acting release (exe_lar, liraglutide and taspoglutide had significant lowering effect when compared with sitagliptin (HbA1c<7.0% and insulin (HbA1c<6.5%. Finally, according to SUCRAs, placebo, thiazolidinediones and albiglutide had the best decrease effect on hypoglycemia; sulphanylureas, sitagliptin and insulin decrease the incidence of treatment discontinuation most; exe_lar and dulaglutide had the highest impact on glycemic level among 13 treatments.Among 13 treatments, GLP

  12. Peroxisome proliferator-activated receptor γ controls ingestive behavior, agouti-related protein, and neuropeptide Y mRNA in the arcuate hypothalamus.

    Science.gov (United States)

    Garretson, John T; Teubner, Brett J W; Grove, Kevin L; Vazdarjanova, Almira; Ryu, Vitaly; Bartness, Timothy J

    2015-03-18

    Peroxisome proliferator-activated receptor γ (PPARγ) is clinically targeted for type II diabetes treatment; however, rosiglitazone (ROSI), a PPARγ agonist, increases food intake and body/fat mass as side-effects. Mechanisms for these effects and the role of PPARγ in feeding are not understood. Therefore, we tested this role in Siberian hamsters, a model of human energy balance, and C57BL/6 mice. We tested the following: (1) how ROSI and/or GW9662 (2-chloro-5-nitro-N-phenylbenzamide; PPARγ antagonist) injected intraperitoneally or into the third ventricle (3V) affected Siberian hamster feeding behaviors; (2) whether food deprivation (FD) co-increases agouti-related protein (AgRP) and PPARγ mRNA expression in Siberian hamsters and mice; (3) whether intraperitoneally administered ROSI increases AgRP and NPY in ad libitum-fed animals; (4) whether intraperitoneally administered PPARγ antagonism blocks FD-induced increases in AgRP and NPY; and finally, (5) whether intraperitoneally administered PPARγ modulation affects plasma ghrelin. Third ventricular and intraperitoneally administered ROSI increased food hoarding and intake for 7 d, an effect attenuated by 3V GW9662, and also prevented (intraperitoneal) FD-induced feeding. FD hamsters and mice increased AgRP within the arcuate hypothalamic nucleus with concomitant increases in PPARγ exclusively within AgRP/NPY neurons. ROSI increased AgRP and NPY similarly to FD, and GW9662 prevented FD-induced increases in AgRP and NPY in both species. Neither ROSI nor GW9662 affected plasma ghrelin. Thus, we demonstrated that PPARγ activation is sufficient to trigger food hoarding/intake, increase AgRP/NPY, and possibly is necessary for FD-induced increases in feeding and AgRP/NPY. These findings provide initial evidence that FD-induced increases in AgRP/NPY may be a direct PPARγ-dependent process that controls ingestive behaviors. Copyright © 2015 the authors 0270-6474/15/354571-11$15.00/0.

  13. The zinc sensing receptor, ZnR/GPR39, controls proliferation and differentiation of colonocytes and thereby tight junction formation in the colon.

    Science.gov (United States)

    Cohen, L; Sekler, I; Hershfinkel, M

    2014-06-26

    The intestinal epithelium is a renewable tissue that requires precise balance between proliferation and differentiation, an essential process for the formation of a tightly sealed barrier. Zinc deficiency impairs the integrity of the intestinal epithelial barrier and is associated with ulcerative and diarrheal pathologies, but the mechanisms underlying the role of Zn(2+) are not well understood. Here, we determined a role of the colonocytic Zn(2+) sensing receptor, ZnR/GPR39, in mediating Zn(2+)-dependent signaling and regulating the proliferation and differentiation of colonocytes. Silencing of ZnR/GPR39 expression attenuated Zn(2+)-dependent activation of ERK1/2 and AKT as well as downstream activation of mTOR/p70S6K, pathways that are linked with proliferation. Consistently, ZnR/GPR39 silencing inhibited HT29 and Caco-2 colonocyte proliferation, while not inducing caspase-3 cleavage. Remarkably, in differentiating HT29 colonocytes, silencing of ZnR/GPR39 expression inhibited alkaline phosphatase activity, a marker of differentiation. Furthermore, Caco-2 colonocytes showed elevated expression of ZnR/GPR39 during differentiation, whereas silencing of ZnR/GPR39 decreased monolayer transepithelial electrical resistance, suggesting compromised barrier formation. Indeed, silencing of ZnR/GPR39 or chelation of Zn(2+) by the cell impermeable chelator CaEDTA was followed by impaired expression of the junctional proteins, that is, occludin, zonula-1 (ZO-1) and E-cadherin. Importantly, colon tissues of GPR39 knockout mice also showed a decrease in expression levels of ZO-1 and occludin compared with wildtype mice. Altogether, our results indicate that ZnR/GPR39 has a dual role in promoting proliferation of colonocytes and in controlling their differentiation. The latter is followed by ZnR/GPR39-dependent expression of tight junctional proteins, thereby leading to formation of a sealed intestinal epithelial barrier. Thus, ZnR/GPR39 may be a therapeutic target for promoting

  14. Seventh Symposium on Subtypes of Musccarinic Receptors.

    Science.gov (United States)

    1997-01-01

    nociceptive pain, are less than ideal. For mild to moderate pain, the first line of therapy includes aspirin, acetaminophen/ paracetamol , and nonsteroidal...due to receptor degradation triggered by prolonged carbachol occupancy. This down-regulation was accompanied by uncoupling of the M2-receptors after 24...be under control by the m3 mAChR, suggesting a complex receptor regulation of phosphoinositide metabolism, including degradation and synthesis. Future

  15. Genomewide Analysis of Aryl Hydrocarbon Receptor Binding Targets Reveals an Extensive Array of Gene Clusters that Control Morphogenetic and Developmental Programs

    Science.gov (United States)

    Sartor, Maureen A.; Schnekenburger, Michael; Marlowe, Jennifer L.; Reichard, John F.; Wang, Ying; Fan, Yunxia; Ma, Ci; Karyala, Saikumar; Halbleib, Danielle; Liu, Xiangdong; Medvedovic, Mario; Puga, Alvaro

    2009-01-01

    Background The vertebrate aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates cellular responses to environmental polycyclic and halogenated compounds. The naive receptor is believed to reside in an inactive cytosolic complex that translocates to the nucleus and induces transcription of xenobiotic detoxification genes after activation by ligand. Objectives We conducted an integrative genomewide analysis of AHR gene targets in mouse hepatoma cells and determined whether AHR regulatory functions may take place in the absence of an exogenous ligand. Methods The network of AHR-binding targets in the mouse genome was mapped through a multipronged approach involving chromatin immunoprecipitation/chip and global gene expression signatures. The findings were integrated into a prior functional knowledge base from Gene Ontology, interaction networks, Kyoto Encyclopedia of Genes and Genomes pathways, sequence motif analysis, and literature molecular concepts. Results We found the naive receptor in unstimulated cells bound to an extensive array of gene clusters with functions in regulation of gene expression, differentiation, and pattern specification, connecting multiple morphogenetic and developmental programs. Activation by the ligand displaced the receptor from some of these targets toward sites in the promoters of xenobiotic metabolism genes. Conclusions The vertebrate AHR appears to possess unsuspected regulatory functions that may be potential targets of environmental injury. PMID:19654925

  16. A randomized controlled non-inferiority study comparing the antiemetic effect between intravenous granisetron and oral azasetron based on estimated 5-HT3 receptor occupancy.

    Science.gov (United States)

    Endo, Junki; Iihara, Hirotoshi; Yamada, Maya; Yanase, Koumei; Kamiya, Fumihiko; Ito, Fumitaka; Funaguchi, Norihiko; Ohno, Yasushi; Minatoguchi, Shinya; Itoh, Yoshinori

    2012-09-01

    The acute antiemetic effect was compared between oral azasetron and intravenous granisetron based on the 5-hydroxytryptamine(3) (5-HT(3)) receptor occupancy theory. Receptor occupancy was estimated from reported data on plasma concentrations and affinity constants to 5-HT(3) receptor. A randomized non-inferiority study comparing acute antiemetic effects between oral azasetron and intravenous granisetron was performed in 105 patients receiving the first course of carboplatin-based chemotherapy for lung cancer. Azasetron exhibited the highest 5-HT(3) receptor occupancy among various first-generation 5-HT(3) antagonists. The complete response to oral azasetron was shown to be non-inferior to that of intravenous granisetron, in which the risk difference was 0.0004 (95% confidence interval: -0.0519-0.0527). The lower limit of the confidence intervals did not exceed the negative non-inferiority margin (-0.1). The complete response during the overall period was not different (68% versus 67%). Oral azasetron was found to be non-inferior to intravenous granisetron in the acute antiemetic effect against moderately emetogenic chemotherapy.

  17. Structural Determinants at the Interface of the ARC2 and LRR Domains Control the Activation of the NB-LRR Plant Immune Receptors Rx1 and Gpa2

    NARCIS (Netherlands)

    Slootweg, E.J.; Spiridon, L.N.; Roosien, J.; Butterbach, P.B.E.; Pomp, H.; Westerhof, L.B.; Wilbers, R.H.P.; Bakker, E.H.; Bakker, J.; Petrescu, A.J.; Smant, G.; Goverse, A.

    2013-01-01

    Many plant and animal immune receptors have a modular NB-LRR architecture in which a nucleotide-binding switch domain (NB-ARC) is tethered to a leucine-rich repeat sensor domain (LRR). The cooperation between the switch and sensor domains, which regulates the activation of these proteins, is poorly

  18. Nucleus Accumbens Dopamine D2-Receptor Expressing Neurons Control Behavioral Flexibility in a Place Discrimination Task in the IntelliCage

    Science.gov (United States)

    Macpherson, Tom; Morita, Makiko; Wang, Yanyan; Sasaoka, Toshikuni; Sawa, Akira; Hikida, Takatoshi

    2016-01-01

    Considerable evidence has demonstrated a critical role for the nucleus accumbens (NAc) in the acquisition and flexibility of behavioral strategies. These processes are guided by the activity of two discrete neuron types, dopamine D1- or D2-receptor expressing medium spiny neurons (D1-/D2-MSNs). Here we used the IntelliCage, an automated…

  19. Toll-like receptor 9 gene expression in the post-thrombotic syndrome, residual thrombosis and recurrent deep venous thrombosis: A case-control study

    NARCIS (Netherlands)

    Cheung, Y. Whitney; Bouman, Annemieke C.; Castoldi, Elisabetta; Wielders, Simone J.; Spronk, Henri M. H.; ten Cate, Hugo; ten Cate-Hoek, Arina J.; ten Wolde, Marije

    2016-01-01

    Animal models suggest that toll-like receptor 9 (TLR9) promotes thrombus resolution after acute deep venous thrombosis (DVT). We hypothesized that TLR9 expression is lower in patients with post-thrombotic syndrome (PTS) and investigated the role of TLR9 in residual thrombosis (RT) and recurrence.

  20. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial

    DEFF Research Database (Denmark)

    NN, NN; Yusuf, S; Teo, K

    2008-01-01

    BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors reduce major cardiovascular events, but are not tolerated by about 20% of patients. We therefore assessed whether the angiotensin-receptor blocker telmisartan would be effective in patients intolerant to ACE inhibitors with cardiovascular...

  1. The angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomised, placebo-controlled, double-blind trial

    DEFF Research Database (Denmark)

    Sandset, Else Charlotte; Bath, Philip M W; Boysen, Gudrun

    2011-01-01

    BACKGROUND: Raised blood pressure is common in acute stroke, and is associated with an increased risk of poor outcomes. We aimed to examine whether careful blood-pressure lowering treatment with the angiotensin-receptor blocker candesartan is beneficial in patients with acute stroke and raised bl...

  2. The LDL receptor.

    Science.gov (United States)

    Goldstein, Joseph L; Brown, Michael S

    2009-04-01

    In this article, the history of the LDL receptor is recounted by its codiscoverers. Their early work on the LDL receptor explained a genetic cause of heart attacks and led to new ways of thinking about cholesterol metabolism. The LDL receptor discovery also introduced three general concepts to cell biology: receptor-mediated endocytosis, receptor recycling, and feedback regulation of receptors. The latter concept provides the mechanism by which statins selectively lower plasma LDL, reducing heart attacks and prolonging life.

  3. Dynamics of receptor-operated Ca2+ Currents Through TRPC Channels Controlled via the PI(4,5P2-PLC Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Masayuki X Mori

    2015-02-01

    Full Text Available Transient receptor potential canonical (TRPC channels are Ca2+-permeable, nonselective cation channels that carry receptor-operated Ca2+ currents (ROCs triggered by receptor-induced, phospholipase C (PLC-catalyzed hydrolysis of phosphatidylinositol 4,5-bisphosphate (PI(4,5P2. Within the vasculature, TRPC channel ROCs contribute to smooth muscle cell depolarization, vasoconstriction and vascular remodeling. However, TRPC channel ROCs exhibit a variable response to receptor-stimulation, and the regulatory mechanisms governing TRPC channel activity remain obscure. The variability of ROCs may be explained by their complex regulation by PI(4,5P2 and its metabolites, which differentially affect TRPC channel activity. To resolve the complex regulation of ROCs, the use of voltage-sensing phosphoinositide phosphatases and model simulation have helped to reveal the time-dependent contribution of PI(4,5P2 and the possible role of PI(4,5P2 in the regulation of ROCs. These approaches may provide unprecedented insight into the dynamics of PI(4,5P2 regulation of TRPC channels and the fundamental mechanisms underlying transmembrane ion flow. Within that context, we summarize the regulation of TRPC channels and their coupling to receptor-mediated signaling, as well as the application of voltage-sensing phosphoinositide phosphatases to this research. We also discuss the controversial bidirectional effects of PI(4,5P2 using a model simulation that could explain the complicated effects of PI(4,5P2 on different ROCs.

  4. Dynamic mobility of functional GABAA receptors at inhibitory synapses.

    Science.gov (United States)

    Thomas, Philip; Mortensen, Martin; Hosie, Alastair M; Smart, Trevor G

    2005-07-01

    Importing functional GABAA receptors into synapses is fundamental for establishing and maintaining inhibitory transmission and for controlling neuronal excitability. By introducing a binding site for an irreversible inhibitor into the GABAA receptor alpha1 subunit channel lining region that can be accessed only when the receptor is activated, we have determined the dynamics of receptor mobility between synaptic and extrasynaptic locations in hippocampal pyramidal neurons. We demonstrate that the cell surface GABAA receptor population shows no fast recovery after irreversible inhibition. In contrast, after selective inhibition, the synaptic receptor population rapidly recovers by the import of new functional entities within minutes. The trafficking pathways that promote rapid importation of synaptic receptors do not involve insertion from intracellular pools, but reflect receptor diffusion within the plane of the membrane. This process offers the synapse a rapid mechanism to replenish functional GABAA receptors at inhibitory synapses and a means to control synaptic efficacy.

  5. Atypical chemokine receptors in cancer: friends or foes?

    Science.gov (United States)

    Massara, Matteo; Bonavita, Ornella; Mantovani, Alberto; Locati, Massimo; Bonecchi, Raffaella

    2016-06-01

    The chemokine system is a fundamental component of cancer-related inflammation involved in all stages of cancer development. It controls not only leukocyte infiltration in primary tumors but also angiogenesis, cancer cell proliferation, and migration to metastatic sites. Atypical chemokine receptors are a new, emerging class of regulators of the chemokine system. They control chemokine bioavailability by scavenging, transporting, or storing chemokines. They can also regulate the activity of canonical chemokine receptors with which they share the ligands by forming heterodimers or by modulating their expression levels or signaling activity. Here, we summarize recent results about the role of these receptors (atypical chemokine receptor 1/Duffy antigen receptor for chemokine, atypical chemokine receptor 2/D6, atypical chemokine receptor 3/CXC-chemokine receptor 7, and atypical chemokine receptor 4/CC-chemokine receptor-like 1) on the tumorigenesis process, indicating that their effects are strictly dependent on the cell type on which they are expressed and on their coexpression with other chemokine receptors. Indeed, atypical chemokine receptors inhibit tumor growth and progression through their activity as negative regulators of chemokine bioavailability, whereas, on the contrary, they can promote tumorigenesis when they regulate the signaling of other chemokine receptors, such as CXC-chemokine receptor 4. Thus, atypical chemokine receptors are key components of the regulatory network of inflammation and immunity in cancer and may have a major effect on anti-inflammatory and immunotherapeutic strategies. © Society for Leukocyte Biology.

  6. Clinical Efficacy of Jinshuibao Capsules Combined with Angiotensin Receptor Blockers in Patients with Early Diabetic Nephropathy: A Meta-Analysis of Randomized Controlled Trials

    Directory of Open Access Journals (Sweden)

    Qiang Lu

    2018-01-01

    Full Text Available Background. Jinshuibao capsules (JSB have been widely used to treat early diabetic nephropathy (DN, but the specific effects are still inconsistent. A meta-analysis of randomized controlled trials (RCTs was conducted to evaluate the clinical efficacy of JSB for early DN. Methods. Four international databases and four Chinese databases were searched from publication dates to March 1, 2018. The RCTs reporting the results of JSB’s specific effects were included, and comparisons were between JSB combined with Angiotensin Receptor Blockers (ARBs as experimental intervention and ARBs as the control. Included studies’ quality was evaluated and the extracted data were analyzed with RevMan 5.3 software. Results. Twenty-six RCTs including 2198 early DN participants were adopted in the meta-analysis. The results showed that, compared with the ARBs alone, JSB could remarkably improve the ORR (OR = 3.84; 95% CI: 2.37~6.24; P<0.00001 and decrease 24 h UTP (MD = −93.32; 95% CI: −128.60 ~-58.04; P<0.00001, UAER (MD = −24.02; 95% CI: −30.93 ~-17.11; P<0.00001, BUN (MD = −0.26; 95%: −0.44 ~-0.08; P=0.005, Scr (MD = −9.07; 95% CI: −14.26 ~-3.88; P=0.0006, ACR (MD = −17.55; 95% CI: −22.81 ~-12.29; P<0.00001, Cys-C (MD = −0.60; 95% CI: −0.88 ~-0.32; P<0.00001, SBP (MD = −3.08; 95% CI: −4.65 ~-1.52; P=0.0001, DBP (MD = −2.09; 95% CI: −4.00 ~-0.19; P=0.03, and TG (MD = −0.36; 95% CI: −0.50 ~-0.21; P<0.00001. However, it showed no significant differences in TC (MD = −0.32; 95% CI: −0.69~0.04; P=0.08, FBG (MD = 0.04; 95% CI: −0.39~0.47; P=0.87, HbA1c (MD = −0.26; 95% CI: −0.59~0.06; P=0.11, and β2-MG (MD = −15.61; 95% CI: −32.95~1.73; P=0.08. Conclusions. This study indicates that JSB is an effective accessory therapeutic medicine for patients with early DN. It contributes to decreasing blood pressure and the content of triglyceride and improving the renal function of early DN patients. However, there is still a

  7. Dynamics of the actin cytoskeleton mediates receptor cross talk: An emerging concept in tuning receptor signaling

    Science.gov (United States)

    Mattila, Pieta K.; Batista, Facundo D.

    2016-01-01

    Recent evidence implicates the actin cytoskeleton in the control of receptor signaling. This may be of particular importance in the context of immune receptors, such as the B cell receptor, where dysregulated signaling can result in autoimmunity and malignancy. Here, we discuss the role of the actin cytoskeleton in controlling receptor compartmentalization, dynamics, and clustering as a means to regulate receptor signaling through controlling the interactions with protein partners. We propose that the actin cytoskeleton is a point of integration for receptor cross talk through modulation of protein dynamics and clustering. We discuss the implication of this cross talk via the cytoskeleton for both ligand-induced and low-level constitutive (tonic) signaling necessary for immune cell survival. PMID:26833785

  8. Essential Control of the Function of the Striatopallidal Neuron by Pre-coupled Complexes of Adenosine A2A-Dopamine D2 Receptor Heterotetramers and Adenylyl Cyclase

    Directory of Open Access Journals (Sweden)

    Sergi Ferré

    2018-04-01

    Full Text Available The central adenosine system and adenosine receptors play a fundamental role in the modulation of dopaminergic neurotransmission. This is mostly achieved by the strategic co-localization of different adenosine and dopamine receptor subtypes in the two populations of striatal efferent neurons, striatonigral and striatopallidal, that give rise to the direct and indirect striatal efferent pathways, respectively. With optogenetic techniques it has been possible to dissect a differential role of the direct and indirect pathways in mediating “Go” responses upon exposure to reward-related stimuli and “NoGo” responses upon exposure to non-rewarded or aversive-related stimuli, respectively, which depends on their different connecting output structures and their differential expression of dopamine and adenosine receptor subtypes. The striatopallidal neuron selectively expresses dopamine D2 receptors (D2R and adenosine A2A receptors (A2AR, and numerous experiments using multiple genetic and pharmacological in vitro, in situ and in vivo approaches, demonstrate they can form A2AR-D2R heteromers. It was initially assumed that different pharmacological interactions between dopamine and adenosine receptor ligands indicated the existence of different subpopulations of A2AR and D2R in the striatopallidal neuron. However, as elaborated in the present essay, most evidence now indicates that all interactions can be explained with a predominant population of striatal A2AR-D2R heteromers forming complexes with adenylyl cyclase subtype 5 (AC5. The A2AR-D2R heteromer has a tetrameric structure, with two homodimers, which allows not only multiple allosteric interactions between different orthosteric ligands, agonists, and antagonists, but also the canonical Gs-Gi antagonistic interaction at the level of AC5. We present a model of the function of the A2AR-D2R heterotetramer-AC5 complex, which acts as an integrative device of adenosine and dopamine signals that

  9. Structural Studies of Nicotinic Acetylcholine Receptors

    DEFF Research Database (Denmark)

    Shahsavar, Azadeh; Gajhede, Michael; Kastrup, Jette

    2016-01-01

    Nicotinic acetylcholine receptors (nAChRs) are members of the pentameric ligand-gated ion channel superfamily that play important roles in control of neurotransmitter release in the central and peripheral nervous system. These receptors are important therapeutic targets for development of drugs...

  10. The nuclear receptor gene nhr-25 plays multiple roles in the Caenorhabditis elegans heterochronic gene network to control the larva-to-adult transition

    Czech Academy of Sciences Publication Activity Database

    Hada, K.; Asahina, Masako; Hasegawa, H.; Kanaho, Y.; Slack, F. J.; Niwa, R.

    2010-01-01

    Roč. 344, č. 2 (2010), s. 1100-1109 ISSN 0012-1606 R&D Projects: GA ČR(CZ) GA204/07/0948; GA ČR(CZ) GD204/09/H058 Institutional research plan: CEZ:AV0Z60220518 Keywords : apl-1 * Caenorhabditis elegans * heterochronic gene * heterochronic gene * let-7 * nuclear receptor * nhr-25 Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.094, year: 2010

  11. Thyrotropin Receptor Antibody (TRAb)-IgM Levels Are Markedly Higher Than TRAb-IgG Levels in Graves' Disease Patients and Controls, and TRAb-IgM Production Is Related to Epstein-Barr Virus Reactivation.

    Science.gov (United States)

    Kumata, Keisuke; Nagata, Keiko; Matsushita, Michiko; Kuwamoto, Satoshi; Kato, Masako; Murakami, Ichiro; Fukata, Shuji; Hayashi, Kazuhiko

    2016-10-01

    Graves' disease is an autoimmune thyroid disorder that mainly presents as hyperthyroidism and is caused by thyrotropin receptor antibodies (TRAbs) that stimulate thyroid-stimulating hormone receptors. We previously reported that Graves' disease patients and healthy controls both had Epstein-Barr virus (EBV)-infected TRAb-positive B cells and the EBV-reactivated induction of these B cells in cultures may induce the production of TRAbs. In the present study, we quantified serum TRAb-IgG and TRAb-IgM levels in 34 Graves' disease patients and 15 controls using ELISA to elucidate the mechanisms underlying EBV-related antibody production. As expected, TRAb-IgG and TRAb-IgM levels were higher in Graves' disease patients than in controls; however, TRAb-IgM levels were significantly higher than those of TRAb-IgG levels, whereas total IgM levels were lower than total IgG levels. On the other hand, the enhanced production of TRAb-IgM was frequently observed in patients with EBV reactivation. These results are consistent with the fact that the percentage of autoreactive IgM B cells are higher than that of autoreactive IgG B cells, and support the EBV-related polyclonal B cell activation. It is necessary to clarify the biological characteristics of TRAb-IgM and the relationship between TRAb isotypes and the biology of Graves' disease.

  12. Tyrosine-induced release of dopamine is under inhibitory control of presynaptic dopamine D2 and, probably, D3 receptors in the dorsal striatum, but not in the nucleus accumbens.

    NARCIS (Netherlands)

    Fusa, K.; Saigusa, T.; Koshikawa, N.; Cools, A.R.

    2002-01-01

    Stimulation of dopamine D2-like receptors decreases extracellular dopamine in the dorsal striatum and the nucleus accumbens. It is unknown whether the role of these receptors differs from that of dopamine D3 receptors. It is also unknown to what extent the role of these two types of receptors varies

  13. Tyrosine-induced release of dopamine is under inhibitory control of presynaptic dopamine D2 and, probably, D3 receptors in the dorsal striatum, but not in the nucleus accumbens

    NARCIS (Netherlands)

    Fusa, K.; Saigusa, T.; Koshikawa, N.; Cools, A.R.

    2002-01-01

    Stimulation of dopamine D2-like receptors decreases extracellular dopamine in the dorsal striatum and the nucleus accumbens. It is unknown whether the role of these receptors differs from that of dopamine D3 receptors. It is also unknown to what extent the role of these two types of receptors varies

  14. Effect of GLP-1 receptor agonist treatment on body weight in obese antipsychotic-treated patients with schizophrenia: a randomized, placebo-controlled trial.

    Science.gov (United States)

    Ishøy, Pelle L; Knop, Filip K; Broberg, Brian V; Bak, Nikolaj; Andersen, Ulrik B; Jørgensen, Niklas R; Holst, Jens J; Glenthøj, Birte Y; Ebdrup, Bjørn H

    2017-02-01

    Schizophrenia is associated with cardiovascular co-morbidity and a reduced life-expectancy of up to 20 years. Antipsychotics are dopamine D 2 receptor antagonists and are the standard of medical care in schizophrenia, but the drugs are associated with severe metabolic side effects such as obesity and diabetes. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are registered for treatment of both obesity and type 2 diabetes. We investigated metabolic effects of the GLP-1RA, exenatide once-weekly, in non-diabetic, antipsychotic-treated, obese patients with schizophrenia. Antipsychotic-treated, obese, non-diabetic, schizophrenia spectrum patients were randomized to double-blinded adjunctive treatment with once-weekly subcutaneous exenatide (n = 23) or placebo (n = 22) injections for 3 months. The primary outcome was loss of body weight after treatment and repeated measures analysis of variance was used as statistical analysis. Between March 2013 and June 2015, 40 patients completed the trial. At baseline, mean body weight was 118.3 ± 16.0 kg in the exenatide group and 111.7 ± 18.0 kg in the placebo group, with no group differences ( P = .23). The exenatide and placebo groups experienced significant ( P = .004), however similar ( P = .98), weight losses of 2.24 ± 3.3 and 2.23 ± 4.4 kg, respectively, after 3 months of treatment. Treatment with exenatide once-weekly did not promote weight loss in obese, antipsychotic-treated patients with schizophrenia compared to placebo. Our results could suggest that the body weight-lowering effect of GLP-1RAs involves dopaminergic signaling, but blockade of other receptor systems may also play a role. Nevertheless, anti-obesity regimens effective in the general population may not be readily implemented in antipsychotic-treated patients with schizophrenia. © 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

  15. Vasopressin V1a receptors are present in the carotid body and contribute to the control of breathing in male Sprague-Dawley rats.

    Science.gov (United States)

    Żera, Tymoteusz; Przybylski, Jacek; Grygorowicz, Tomasz; Kasarełło, Kaja; Podobińska, Martyna; Mirowska-Guzel, Dagmara; Cudnoch-Jędrzejewska, Agnieszka

    2018-04-01

    Vasopressin (AVP) maintains body homeostasis by regulating water balance, cardiovascular system and stress response. AVP inhibits breathing through central vasopressin 1a receptors (V1aRs). Chemoreceptors within carotid bodies (CBs) detect chemical and hormonal signals in the bloodstream and provide sensory input to respiratory and cardiovascular centers of the brainstem. In the study we investigated if CBs contain V1aRs and how the receptors are involved in the regulation of ventilation by AVP. We first immunostained CBs for V1aRs and tyrosine hydroxylase, a marker of chemoreceptor type I (glomus) cells. In urethane-anesthetized adult Sprague-Dawley male rats, we then measured hemodynamic and respiratory responses to systemic (intravenous) or local (carotid artery) administration of AVP prior and after systemic blockade of V1aRs. Immunostaining of CBs showed colocalization of V1aRs and tyrosine hydroxylase within glomus cells. Systemic administration of AVP increased mean arterial blood pressure (MABP) and decreased respiratory rate (RR) and minute ventilation (MV). Local administration of AVP increased MV and RR without significant changes in MABP or heart rate. Pretreatment with V1aR antagonist abolished responses to local and intravenous AVP administration. Our findings show that chemosensory cells within CBs express V1aRs and that local stimulation of the CB with AVP increases ventilation, which is contrary to systemic effects of AVP manifested by decreased ventilation. The responses are mediated by V1aRs, as blockade of the receptors prevents changes in ventilation. We hypothesize that excitatory effects of AVP within the CB provide a counterbalancing mechanism for the inhibitory effects of systemically acting AVP on the respiration. Copyright © 2018 Elsevier Inc. All rights reserved.

  16. Control of βAR- and N-methyl-D-aspartate (NMDA Receptor-Dependent cAMP Dynamics in Hippocampal Neurons.

    Directory of Open Access Journals (Sweden)

    Andrew Chay

    2016-02-01

    Full Text Available Norepinephrine, a neuromodulator that activates β-adrenergic receptors (βARs, facilitates learning and memory as well as the induction of synaptic plasticity in the hippocampus. Several forms of long-term potentiation (LTP at the Schaffer collateral CA1 synapse require stimulation of both βARs and N-methyl-D-aspartate receptors (NMDARs. To understand the mechanisms mediating the interactions between βAR and NMDAR signaling pathways, we combined FRET imaging of cAMP in hippocampal neuron cultures with spatial mechanistic modeling of signaling pathways in the CA1 pyramidal neuron. Previous work implied that cAMP is synergistically produced in the presence of the βAR agonist isoproterenol and intracellular calcium. In contrast, we show that when application of isoproterenol precedes application of NMDA by several minutes, as is typical of βAR-facilitated LTP experiments, the average amplitude of the cAMP response to NMDA is attenuated compared with the response to NMDA alone. Models simulations suggest that, although the negative feedback loop formed by cAMP, cAMP-dependent protein kinase (PKA, and type 4 phosphodiesterase may be involved in attenuating the cAMP response to NMDA, it is insufficient to explain the range of experimental observations. Instead, attenuation of the cAMP response requires mechanisms upstream of adenylyl cyclase. Our model demonstrates that Gs-to-Gi switching due to PKA phosphorylation of βARs as well as Gi inhibition of type 1 adenylyl cyclase may underlie the experimental observations. This suggests that signaling by β-adrenergic receptors depends on temporal pattern of stimulation, and that switching may represent a novel mechanism for recruiting kinases involved in synaptic plasticity and memory.

  17. The nuclear receptor NHR-25 cooperates with the Wnt/ .beta.-catenin asymmetry pathway to control differentiation of the T seam cell in C. elegans

    Czech Academy of Sciences Publication Activity Database

    Hajdušková, Martina; Jindra, Marek; Herman, M. A.; Asahina, Masako

    2009-01-01

    Roč. 122, č. 17 (2009), s. 3051-3060 ISSN 0021-9533 R&D Projects: GA ČR(CZ) GA204/07/0948; GA ČR(CZ) GD204/09/H058; GA MŠk 2B06129 Institutional research plan: CEZ:AV0Z60220518; CEZ:AV0Z50070508 Keywords : nuclear receptor * Wnt /.beta.-catenin signaling * Caenorhabditis elegans Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 6.144, year: 2009

  18. Brain nuclear receptors and body weight regulation

    Science.gov (United States)

    Neural pathways, especially those in the hypothalamus, integrate multiple nutritional, hormonal, and neural signals, resulting in the coordinated control of body weight balance and glucose homeostasis. Nuclear receptors (NRs) sense changing levels of nutrients and hormones, and therefore play essent...

  19. Transcription factor FOXO1 promotes cell migration toward exogenous ATP via controlling P2Y1 receptor expression in lymphatic endothelial cells.

    Science.gov (United States)

    Niimi, Kenta; Ueda, Mizuha; Fukumoto, Moe; Kohara, Misaki; Sawano, Toshinori; Tsuchihashi, Ryo; Shibata, Satoshi; Inagaki, Shinobu; Furuyama, Tatsuo

    2017-08-05

    Sprouting migration of lymphatic endothelial cell (LEC) is a pivotal step in lymphangiogenic process. However, its molecular mechanism remains unclear including effective migratory attractants. Meanwhile, forkhead transcription factor FOXO1 highly expresses in LEC nuclei, but its significance in LEC migratory activity has not been researched. In this study, we investigated function of FOXO1 transcription factor associated with LEC migration toward exogenous ATP which has recently gathered attentions as a cell migratory attractant. The transwell membrane assay indicated that LECs migrated toward exogenous ATP, which was impaired by FOXO1 knockdown. RT-PCR analysis showed that P2Y1, a purinergic receptor, expression was markedly reduced by FOXO1 knockdown in LECs. Moreover, P2Y1 blockage impaired LEC migration toward exogenous ATP. Western blot analysis revealed that Akt phosphorylation contributed to FOXO1-dependent LEC migration toward exogenous ATP and its blockage affected LEC migratory activity. Furthermore, luciferase reporter assay and ChIP assay suggested that FOXO1 directly bound to a conserved binding site in P2RY1 promoter and regulated its activity. These results indicated that FOXO1 serves a pivotal role in LEC migration toward exogenous ATP via direct transcriptional regulation of P2Y1 receptor. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Rho-kinase signaling controls nucleocytoplasmic shuttling of class IIa Histone Deacetylase (HDAC7) and transcriptional activation of orphan nuclear receptor NR4A1

    Energy Technology Data Exchange (ETDEWEB)

    Compagnucci, Claudia; Barresi, Sabina [Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Gesù Children’s Hospital, IRCCS, Rome (Italy); Petrini, Stefania [Research Laboratories, Confocal Microscopy Core Facility, Bambino Gesù Children’s Hospital, IRCCS, Rome (Italy); Bertini, Enrico [Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Gesù Children’s Hospital, IRCCS, Rome (Italy); Zanni, Ginevra, E-mail: ginevra.zanni@opbg.net [Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Gesù Children’s Hospital, IRCCS, Rome (Italy)

    2015-04-03

    Rho-kinase (ROCK) has been well documented to play a key role in RhoA-induced actin remodeling. ROCK activation results in myosin light chain (MLC) phosphorylation either by direct action on MLC kinase (MLCK) or by inhibition of MLC phosphatase (MLCP), modulating actin–myosin contraction. We found that inhibition of the ROCK pathway in induced pluripotent stem cells, leads to nuclear export of HDAC7 and transcriptional activation of the orphan nuclear receptor NR4A1 while in cells with constitutive ROCK hyperactivity due to loss of function of the RhoGTPase activating protein Oligophrenin-1 (OPHN1), the orphan nuclear receptor NR4A1 is downregulated. Our study identify a new target of ROCK signaling via myosin phosphatase subunit (MYPT1) and Histone Deacetylase (HDAC7) at the nuclear level and provide new insights in the cellular functions of ROCK. - Highlights: • ROCK regulates nucleocytoplasmic shuttling of HDAC7 via phosphorylation of MYPT1. • Nuclear export of HDAC7 and upregulation of NR4A1 occurs with low ROCK activity. • High levels of ROCK activity due to OPHN1 loss of function downregulate NR4A1.

  1. Transcriptional Control of Vascular Smooth Muscle Cell Proliferation by Peroxisome Proliferator-Activated Receptor-γ: Therapeutic Implications for Cardiovascular Diseases

    Directory of Open Access Journals (Sweden)

    Florence Gizard

    2008-01-01

    Full Text Available Proliferation of vascular smooth muscle cells (SMCs is a critical process for the development of atherosclerosis and complications of procedures used to treat atherosclerotic diseases, including postangioplasty restenosis, vein graft failure, and transplant vasculopathy. Peroxisome proliferator-activated receptor (PPAR γ is a member of the nuclear hormone receptor superfamily and the molecular target for the thiazolidinediones (TZD, used clinically to treat insulin resistance in patients with type 2 diabetes. In addition to their efficacy to improve insulin sensitivity, TZD exert a broad spectrum of pleiotropic beneficial effects on vascular gene expression programs. In SMCs, PPARγ is prominently upregulated during neointima formation and suppresses the proliferative response to injury of the arterial wall. Among the molecular target genes regulated by PPARγ in SMCs are genes encoding proteins involved in the regulation of cell-cycle progression, cellular senescence, and apoptosis. This inhibition of SMC proliferation is likely to contribute to the prevention of atherosclerosis and postangioplasty restenosis observed in animal models and proof-of-concept clinical studies. This review will summarize the transcriptional target genes regulated by PPARγ in SMCs and outline the therapeutic implications of PPARγ activation for the treatment and prevention of atherosclerosis and its complications.

  2. Lactate Transport and Receptor Actions in Retina

    DEFF Research Database (Denmark)

    Kolko, Miriam; Vosborg, Fia; Henriksen, Jens Ulrik Lütken

    2016-01-01

    known as HCAR1, may contribute importantly to the control of retinal cell functions in health and disease. GPR81, a G-protein coupled receptor, is known to downregulate cAMP both in adipose and nervous tissue. The receptor also acts through other down-stream mechanisms to control functions......In retina, like in brain, lactate equilibrates across cell membranes via monocarboxylate transporters and in the extracellular space by diffusion, forming a basis for the action of lactate as a transmitter of metabolic signals. In the present paper, we argue that the lactate receptor GPR81, also...

  3. Receptor-receptor interactions within receptor mosaics. Impact on neuropsychopharmacology.

    Science.gov (United States)

    Fuxe, K; Marcellino, D; Rivera, A; Diaz-Cabiale, Z; Filip, M; Gago, B; Roberts, D C S; Langel, U; Genedani, S; Ferraro, L; de la Calle, A; Narvaez, J; Tanganelli, S; Woods, A; Agnati, L F

    2008-08-01

    Future therapies for diseases associated with altered dopaminergic signaling, including Parkinson's disease, schizophrenia and drug addiction or drug dependence may substantially build on the existence of intramembrane receptor-receptor interactions within dopamine receptor containing receptor mosaics (RM; dimeric or high-order receptor oligomers) where it is believed that the dopamine D(2) receptor may operate as the 'hub receptor' within these complexes. The constitutive adenosine A(2A)/dopamine D(2) RM, located in the dorsal striato-pallidal GABA neurons, are of particular interest in view of the demonstrated antagonistic A(2A)/D(2) interaction within these heteromers; an interaction that led to the suggestion and later demonstration that A(2A) antagonists could be used as novel anti-Parkinsonian drugs. Based on the likely existence of A(2A)/D(2)/mGluR5 RM located both extrasynaptically on striato-pallidal GABA neurons and on cortico-striatal glutamate terminals, multiple receptor-receptor interactions within this RM involving synergism between A(2A)/mGluR5 to counteract D(2) signaling, has led to the proposal of using combined mGluR5 and A(2A) antagonists as a future anti-Parkinsonian treatment. Based on the same RM in the ventral striato-pallidal GABA pathways, novel strategies for the treatment of schizophrenia, building on the idea that A(2A) agonists and/or mGluR5 agonists will help reduce the increased dopaminergic signaling associated with this disease, have been suggested. Such treatment may ensure the proper glutamatergic drive from the mediodorsal thalamic nucleus to the prefrontal cortex, one which is believed to be reduced in schizophrenia due to a dominance of D(2)-like signaling in the ventral striatum. Recently, A(2A) receptors also have been shown to counteract the locomotor and sensitizing actions of cocaine and increases in A(2A) receptors have also been observed in the nucleus accumbens after extended cocaine self-administration, probably

  4. Cocaine Inhibits Dopamine D2 Receptor Signaling via Sigma-1-D2 Receptor Heteromers

    Science.gov (United States)

    Navarro, Gemma; Moreno, Estefania; Bonaventura, Jordi; Brugarolas, Marc; Farré, Daniel; Aguinaga, David; Mallol, Josefa; Cortés, Antoni; Casadó, Vicent; Lluís, Carmen; Ferre, Sergi

    2013-01-01

    Under normal conditions the brain maintains a delicate balance between inputs of reward seeking controlled by neurons containing the D1-like family of dopamine receptors and inputs of aversion coming from neurons containing the D2-like family of dopamine receptors. Cocaine is able to subvert these balanced inputs by altering the cell signaling of these two pathways such that D1 reward seeking pathway dominates. Here, we provide an explanation at the cellular and biochemical level how cocaine may achieve this. Exploring the effect of cocaine on dopamine D2 receptors function, we present evidence of σ1 receptor molecular and functional interaction with dopamine D2 receptors. Using biophysical, biochemical, and cell biology approaches, we discovered that D2 receptors (the long isoform of the D2 receptor) can complex with σ1 receptors, a result that is specific to D2 receptors, as D3 and D4 receptors did not form heteromers. We demonstrate that the σ1-D2 receptor heteromers consist of higher order oligomers, are found in mouse striatum and that cocaine, by binding to σ1 -D2 receptor heteromers, inhibits downstream signaling in both cultured cells and in mouse striatum. In contrast, in striatum from σ1 knockout animals these complexes are not found and this inhibition is not seen. Taken together, these data illuminate the mechanism by which the initial exposure to cocaine can inhibit signaling via D2 receptor containing neurons, destabilizing the delicate signaling balance influencing drug seeking that emanates from the D1 and D2 receptor containing neurons in the brain. PMID:23637801

  5. Multiple kisspeptin receptors in early Osteichthyans provide new insights into the evolution of this receptor family

    DEFF Research Database (Denmark)

    Pasquier, J.; Lafont, A._G.; Jeng, S.-R.

    2012-01-01

    Deorphanization of GPR54 receptor a decade ago led to the characterization of the kisspeptin receptor (Kissr) in mammals and the discovery of its major role in the brain control of reproduction. While a single gene encodes for Kissr in eutherian mammals including human, other vertebrates present ...

  6. Structural determinants at the interface of the ARC2 and leucine-rich repeat domains control the activation of the plant immune receptors Rx1 and Gpa2.

    Science.gov (United States)

    Slootweg, Erik J; Spiridon, Laurentiu N; Roosien, Jan; Butterbach, Patrick; Pomp, Rikus; Westerhof, Lotte; Wilbers, Ruud; Bakker, Erin; Bakker, Jaap; Petrescu, Andrei-José; Smant, Geert; Goverse, Aska

    2013-07-01

    Many plant and animal immune receptors have a modular nucleotide-binding-leucine-rich repeat (NB-LRR) architecture in which a nucleotide-binding switch domain, NB-ARC, is tethered to a LRR sensor domain. The cooperation between the switch and sensor domains, which regulates the activation of these proteins, is poorly understood. Here, we report structural determinants governing the interaction between the NB-ARC and LRR in the highly homologous plant immune receptors Gpa2 and Rx1, which recognize the potato cyst nematode Globodera pallida and Potato virus X, respectively. Systematic shuffling of polymorphic sites between Gpa2 and Rx1 showed that a minimal region in the ARC2 and N-terminal repeats of the LRR domain coordinate the activation state of the protein. We identified two closely spaced amino acid residues in this region of the ARC2 (positions 401 and 403) that distinguish between autoactivation and effector-triggered activation. Furthermore, a highly acidic loop region in the ARC2 domain and basic patches in the N-terminal end of the LRR domain were demonstrated to be required for the physical interaction between the ARC2 and LRR. The NB-ARC and LRR domains dissociate upon effector-dependent activation, and the complementary-charged regions are predicted to mediate a fast reassociation, enabling multiple rounds of activation. Finally, we present a mechanistic model showing how the ARC2, NB, and N-terminal half of the LRR form a clamp, which regulates the dissociation and reassociation of the switch and sensor domains in NB-LRR proteins.

  7. The putative glutamate receptor 1.1 (AtGLR1.1) in Arabidopsis thaliana regulates abscisic acid biosynthesis and signaling to control development and water loss.

    Science.gov (United States)

    Kang, Jiman; Mehta, Sohum; Turano, Frank J

    2004-10-01

    The involvement of the putative glutamate receptor 1.1 (AtGLR1.1) gene in the regulation of abscisic acid (ABA) biosynthesis and signaling was investigated in Arabidopsis. Seeds from AtGLR1.1-deficient (antiAtGLR1.1) lines had increased sensitivity to exogenous ABA with regard to the effect of the hormone on the inhibition of seed germination and root growth. Seed germination, which was inhibited by an animal ionotropic glutamate receptor antagonist, 6,7-dinitroquinoxaline-2,3-[1H,4H]-dione, was restored by co-incubation with an inhibitor of ABA biosynthesis, fluridone. These results confirm that germination in antiAtGLR1.1 lines was inhibited by increased ABA. When antiAtGLR1.1 and WT seeds were co-incubated in fluridone and exogenous ABA, the antiAtGLR1.1 seeds were more sensitive to ABA. In addition, the antiAtGLR1.1 lines exhibited altered expression of ABA biosynthetic (ABA) and signaling (ABI) genes, when compared with WT. Combining the physiological and molecular results suggest that ABA biosynthesis and signaling in antiAtGLR1.1 lines are altered. ABA levels in leaves of antiAtGLR1.1 lines are higher than those in WT. In addition, the antiAtGLR1.1 lines had reduced stomatal apertures, and exhibited enhanced drought tolerance due to deceased water loss compared with WT lines. The results from these experiments imply that ABA biosynthesis and signaling can be regulated through AtGLR1.1 to trigger pre- and post-germination arrest and changes in whole plant responses to water stress. Combined with our earlier results, these findings suggest that AtGLR1.1 integrates and regulates the different aspects of C, N and water balance that are required for normal plant growth and development.

  8. Cell adhesion controlled by adhesion G protein-coupled receptor GPR124/ADGRA2 is mediated by a protein complex comprising intersectins and Elmo-Dock.

    Science.gov (United States)

    Hernández-Vásquez, Magda Nohemí; Adame-García, Sendi Rafael; Hamoud, Noumeira; Chidiac, Rony; Reyes-Cruz, Guadalupe; Gratton, Jean Philippe; Côté, Jean-François; Vázquez-Prado, José

    2017-07-21

    Developmental angiogenesis and the maintenance of the blood-brain barrier involve endothelial cell adhesion, which is linked to cytoskeletal dynamics. GPR124 (also known as TEM5/ADGRA2) is an adhesion G protein-coupled receptor family member that plays a pivotal role in brain angiogenesis and in ensuring a tight blood-brain barrier. However, the signaling properties of GPR124 remain poorly defined. Here, we show that ectopic expression of GPR124 promotes cell adhesion, additive to extracellular matrix-dependent effect, coupled with filopodia and lamellipodia formation and an enrichment of a pool of the G protein-coupled receptor at actin-rich cellular protrusions containing VASP, a filopodial marker. Accordingly, GPR124-expressing cells also displayed increased activation of both Rac and Cdc42 GTPases. Mechanistically, we uncover novel direct interactions between endogenous GPR124 and the Rho guanine nucleotide exchange factors Elmo/Dock and intersectin (ITSN). Small fragments of either Elmo or ITSN1 that bind GPR124 blocked GPR124-induced cell adhesion. In addition, Gβγ interacts with the C-terminal tail of GPR124 and promotes the formation of a GPR124-Elmo complex. Furthermore, GPR124 also promotes the activation of the Elmo-Dock complex, as measured by Elmo phosphorylation on a conserved C-terminal tyrosine residue. Interestingly, Elmo and ITSN1 also interact with each other independently of their GPR124-recognition regions. Moreover, endogenous phospho-Elmo and ITSN1 co-localize with GPR124 at lamellipodia of adhering endothelial cells, where GPR124 expression contributes to polarity acquisition during wound healing. Collectively, our results indicate that GPR124 promotes cell adhesion via Elmo-Dock and ITSN. This constitutes a previously unrecognized complex formed of atypical and conventional Rho guanine nucleotide exchange factors for Rac and Cdc42 that is putatively involved in GPR124-dependent angiogenic responses. © 2017 by The American Society for

  9. β cell membrane remodelling and procoagulant events occur in inflammation-driven insulin impairment: a GLP-1 receptor dependent and independent control.

    Science.gov (United States)

    Gleizes, Céline; Kreutter, Guillaume; Abbas, Malak; Kassem, Mohamad; Constantinescu, Andrei Alexandru; Boisramé-Helms, Julie; Yver, Blandine; Toti, Florence; Kessler, Laurence

    2016-02-01

    Inflammation and hyperglycaemia are associated with a prothrombotic state. Cell-derived microparticles (MPs) are the conveyors of active procoagulant tissue factor (TF) and circulate at high concentration in diabetic patients. Liraglutide, a glucagon-like peptide (GLP)-1 analogue, is known to promote insulin secretion and β-cell preservation. In this in vitro study, we examined the link between insulin impairment, procoagulant activity and plasma membrane remodelling, under inflammatory conditions. Rin-m5f β-cell function, TF activity mediated by MPs and their modulation by 1 μM liraglutide were examined in a cell cross-talk model. Methyl-β-cyclodextrine (MCD), a cholesterol depletor, was used to evaluate the involvement of raft on TF activity, MP shedding and insulin secretion as well as Soluble N-éthylmaleimide-sensitive-factor Attachment protein Receptor (SNARE)-dependent exocytosis. Cytokines induced a two-fold increase in TF activity at MP surface that was counteracted by liraglutide. Microparticles prompted TF activity on the target cells and a two-fold decrease in insulin secretion via protein kinase A (PKA) and p38 signalling, that was also abolished by liraglutide. Large lipid raft clusters were formed in response to cytokines and liraglutide or MCD-treated cells showed similar patterns. Cells pre-treated by saturating concentration of the GLP-1r antagonist exendin (9-39), showed a partial abolishment of the liraglutide-driven insulin secretion and liraglutide-decreased TF activity. Measurement of caspase 3 cleavage and MP shedding confirmed the contribution of GLP-1r-dependent and -independent pathways. Our results confirm an integrative β-cell response to GLP-1 that targets receptor-mediated signalling and membrane remodelling pointing at the coupling of insulin secretion and inflammation-driven procoagulant events. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and

  10. The 5-HT2C receptor agonist lorcaserin reduces nicotine self-administration, discrimination, and reinstatement: relationship to feeding behavior and impulse control.

    Science.gov (United States)

    Higgins, Guy A; Silenieks, Leo B; Rossmann, Anne; Rizos, Zoe; Noble, Kevin; Soko, Ashlie D; Fletcher, Paul J

    2012-04-01

    Lorcaserin ((1R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCl) is a selective 5-HT(2C) receptor agonist with clinical efficacy in phase-III obesity trials. Based on evidence that this drug class also affects behaviors motivated by drug reinforcement, we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement, as well as the stimulant and discriminative stimulus properties of nicotine in the rat. Acutely administered lorcaserin (0.3-3 mg/kg, subcutaneous (SC)) dose dependently reduced feeding induced by 22-h food deprivation or palatability. Effects up to 1 mg/kg were consistent with a specific effect on feeding motivation. Lorcaserin (0.6-1 mg/kg, SC) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement. In this dose range lorcaserin also reversed the motor stimulant effect of nicotine, reduced intravenous self-administration of nicotine, and attenuated the nicotine cue in rats trained to discriminate nicotine from saline. Lorcaserin also reduced the reinstatement of nicotine-seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement. Lorcaserin did not reinstate nicotine-seeking behavior or substitute for a nicotine cue. Finally, lorcaserin (0.3-1 mg/kg) reduced nicotine-induced increases in anticipatory responding, a measure of impulsive action, in rats performing the five-choice serial reaction time task. Importantly, these results indicate that lorcaserin, and likely other selective 5-HT(2C) receptor agonists, similarly affect both food- and nicotine-motivated behaviors, and nicotine-induced impulsivity. Collectively, these findings highlight a therapeutic potential for 5-HT(2C) agonists such as lorcaserin beyond obesity into addictive behaviors, such as nicotine dependence.

  11. Acetylcholine receptor antibody

    Science.gov (United States)

    ... medlineplus.gov/ency/article/003576.htm Acetylcholine receptor antibody To use the sharing features on this page, please enable JavaScript. Acetylcholine receptor antibody is a protein found in the blood of ...

  12. Cooperative ethylene receptor signaling

    OpenAIRE

    Liu, Qian; Wen, Chi-Kuang

    2012-01-01

    The gaseous plant hormone ethylene is perceived by a family of five ethylene receptor members in the dicotyledonous model plant Arabidopsis. Genetic and biochemical studies suggest that the ethylene response is suppressed by ethylene receptor complexes, but the biochemical nature of the receptor signal is unknown. Without appropriate biochemical measures to trace the ethylene receptor signal and quantify the signal strength, the biological significance of the modulation of ethylene responses ...

  13. Androgen insensitivity syndrome: gonadal androgen receptor activity

    International Nuclear Information System (INIS)

    Coulam, C.B.; Graham, M.L.; Spelsberg, T.C.

    1984-01-01

    To determine whether abnormalities of the androgen receptor previously observed in skin fibroblasts from patients with androgen insensitivity syndrome also occur in the gonads of affected individuals, androgen receptor activity in the gonads of a patient with testicular feminization syndrome was investigated. Using conditions for optimal recovery of androgen receptor from human testes established by previous studies, we detected the presence of a high-affinity (dissociation constant . 3.2 X 10(-10) mol/L), low-capacity (4.2 X 10(-12) mol/mg DNA), androgen-binding protein when tritium-labeled R1881 was incubated at 4 degrees C with nuclear extracts from the gonads of control patients or from a patient with testicular feminization syndrome but not when incubated at 37 degrees C. Thus this patient has an androgen receptor with a temperature lability similar to that of receptors from normal persons

  14. Efficacy and safety of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Asian patients with hypertension: a randomized, double-blind, placebo-controlled study.

    Science.gov (United States)

    Kario, Kazuomi; Sun, Ningling; Chiang, Fu-Tien; Supasyndh, Ouppatham; Baek, Sang Hong; Inubushi-Molessa, Akiko; Zhang, Ying; Gotou, Hiromi; Lefkowitz, Martin; Zhang, Jack

    2014-04-01

    LCZ696 (Japanese adopted name: sucabitril valsartan sodium hydrate), a first-in-class angiotensin receptor neprilysin inhibitor, concomitantly inhibits neprilysin and blocks angiotensin type 1 receptor. This randomized, double-blind, placebo-controlled study, the first in Asia for this drug, evaluated the dose-related efficacy and safety of LCZ696 in patients with hypertension using 24-hour ambulatory blood pressure (BP) monitoring. Asian patients aged ≥18 years (n=389) with hypertension were randomized to receive LCZ696 100 mg (n=100), 200 mg (n=101), 400 mg (n=96), or placebo (n=92) for 8 weeks. The primary end point was mean difference across the 3 single-dose pairwise comparisons of LCZ696 versus placebo in clinic diastolic BP after 8-week treatment. Key secondary efficacy variables included changes in clinic systolic BP and pulse pressure and changes in 24-hour, daytime, and nighttime ambulatory BPs and pulse pressure. Safety assessments included recording all adverse events and serious adverse events. A total of 362 patients completed the study. Reductions in clinic systolic BP, diastolic BP (Phypertension in Asian population and, in general, is safe and well tolerated. Clinical Trial Information- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01193101.

  15. Membrane Trafficking of Death Receptors: Implications on Signalling

    Directory of Open Access Journals (Sweden)

    Wulf Schneider-Brachert

    2013-07-01

    Full Text Available Death receptors were initially recognised as potent inducers of apoptotic cell death and soon ambitious attempts were made to exploit selective ignition of controlled cellular suicide as therapeutic strategy in malignant diseases. However, the complexity of death receptor signalling has increased substantially during recent years. Beyond activation of the apoptotic cascade, involvement in a variety of cellular processes including inflammation, proliferation and immune response was recognised. Mechanistically, these findings raised the question how multipurpose receptors can ensure selective activation of a particular pathway. A growing body of evidence points to an elegant spatiotemporal regulation of composition and assembly of the receptor-associated signalling complex. Upon ligand binding, receptor recruitment in specialized membrane compartments, formation of receptor-ligand clusters and internalisation processes constitute key regulatory elements. In this review, we will summarise the current concepts of death receptor trafficking and its implications on receptor-associated signalling events.

  16. T cell factor-1 controls the lifetime of CD4+ CD8+ thymocytes in vivo and distal T cell receptor α-chain rearrangement required for NKT cell development.

    Directory of Open Access Journals (Sweden)

    Archna Sharma

    Full Text Available Natural killer T (NKT cells are a component of innate and adaptive immune systems implicated in immune, autoimmune responses and in the control of obesity and cancer. NKT cells develop from common CD4+ CD8+ double positive (DP thymocyte precursors after the rearrangement and expression of T cell receptor (TCR Vα14-Jα18 gene. Temporal regulation and late appearance of Vα14-Jα18 rearrangement in immature DP thymocytes has been demonstrated. However, the precise control of lifetime of DP thymocytes in vivo that enables distal rearrangements remains incompletely defined. Here we demonstrate that T cell factor (TCF-1, encoded by the Tcf7 gene, is critical for the extended lifetime of DP thymocytes. TCF-1-deficient DP thymocytes fail to undergo TCR Vα14-Jα18 rearrangement and produce significantly fewer NKT cells. Ectopic expression of Bcl-xL permits Vα14-Jα18 rearrangement and rescues NKT cell development. We report that TCF-1 regulates expression of RORγt, which regulates DP thymocyte survival by controlling expression of Bcl-xL. We posit that TCF-1 along with its cofactors controls the lifetime of DP thymocytes in vivo.

  17. The angiotensin II receptor antagonist telmisartan reduces urinary albumin excretion in patients with isolated systolic hypertension: results of a randomized, double-blind, placebo-controlled trial

    NARCIS (Netherlands)

    Vogt, Liffert; Navis, Gerjan; Koester, Juergen; Manolis, Athanasios J.; Reid, John L.; de Zeeuw, Dick

    2005-01-01

    Objective To examine the effect of telmisartan or hydrochlorothiazide on the control of urinary albumin excretion (UAE) in patients with isolated systolic hypertension (ISH) unselected for albuminuria in a pre-planned substudy of a large, multicentre, double-blind, placebo-controlled, randomized

  18. The angiotensin II receptor antagonist telmisartan reduces urinary albumin excretion in patients with isolated systolic hypertension: results of a randomized, double-blind, placebo-controlled trial

    NARCIS (Netherlands)

    Vogt, Liffert; Navis, Gerjan; Köster, Jürgen; Manolis, Athanasios J.; Reid, John L.; de Zeeuw, Dick

    2005-01-01

    To examine the effect of telmisartan or hydrochlorothiazide on the control of urinary albumin excretion (UAE) in patients with isolated systolic hypertension (ISH) unselected for albuminuria in a pre-planned substudy of a large, multicentre, double-blind, placebo-controlled, randomized study. The

  19. Role of adenosine receptors in caffeine tolerance

    Energy Technology Data Exchange (ETDEWEB)

    Holtzman, S.G.; Mante, S.; Minneman, K.P. (Emory Univ. School of Medicine, Atlanta, GA (USA))

    1991-01-01

    Caffeine is a competitive antagonist at adenosine receptors. Receptor up-regulation during chronic drug treatment has been proposed to be the mechanism of tolerance to the behavioral stimulant effects of caffeine. This study reassessed the role of adenosine receptors in caffeine tolerance. Separate groups of rats were given scheduled access to drinking bottles containing plain tap water or a 0.1% solution of caffeine. Daily drug intake averaged 60-75 mg/kg and resulted in complete tolerance to caffeine-induced stimulation of locomotor activity, which could not be surmounted by increasing the dose of caffeine. 5'-N-ethylcarboxamidoadenosine (0.001-1.0 mg/kg) dose dependently decreased the locomotor activity of caffeine-tolerant rats and their water-treated controls but was 8-fold more potent in the latter group. Caffeine (1.0-10 mg/kg) injected concurrently with 5-N-ethylcarboxamidoadenosine antagonized the decreases in locomotor activity comparably in both groups. Apparent pA2 values for tolerant and control rats also were comparable: 5.05 and 5.11. Thus, the adenosine-antagonist activity of caffeine was undiminished in tolerant rats. The effects of chronic caffeine administration on parameters of adenosine receptor binding and function were measured in cerebral cortex. There were no differences between brain tissue from control and caffeine-treated rats in number and affinity of adenosine binding sites or in receptor-mediated increases (A2 adenosine receptor) and decreases (A1 adenosine receptor) in cAMP accumulation. These results are consistent with theoretical arguments that changes in receptor density should not affect the potency of a competitive antagonist. Experimental evidence and theoretical considerations indicate that up-regulation of adenosine receptors is not the mechanism of tolerance to caffeine-induced stimulation of locomotor activity.

  20. Role of adenosine receptors in caffeine tolerance

    International Nuclear Information System (INIS)

    Holtzman, S.G.; Mante, S.; Minneman, K.P.

    1991-01-01

    Caffeine is a competitive antagonist at adenosine receptors. Receptor up-regulation during chronic drug treatment has been proposed to be the mechanism of tolerance to the behavioral stimulant effects of caffeine. This study reassessed the role of adenosine receptors in caffeine tolerance. Separate groups of rats were given scheduled access to drinking bottles containing plain tap water or a 0.1% solution of caffeine. Daily drug intake averaged 60-75 mg/kg and resulted in complete tolerance to caffeine-induced stimulation of locomotor activity, which could not be surmounted by increasing the dose of caffeine. 5'-N-ethylcarboxamidoadenosine (0.001-1.0 mg/kg) dose dependently decreased the locomotor activity of caffeine-tolerant rats and their water-treated controls but was 8-fold more potent in the latter group. Caffeine (1.0-10 mg/kg) injected concurrently with 5-N-ethylcarboxamidoadenosine antagonized the decreases in locomotor activity comparably in both groups. Apparent pA2 values for tolerant and control rats also were comparable: 5.05 and 5.11. Thus, the adenosine-antagonist activity of caffeine was undiminished in tolerant rats. The effects of chronic caffeine administration on parameters of adenosine receptor binding and function were measured in cerebral cortex. There were no differences between brain tissue from control and caffeine-treated rats in number and affinity of adenosine binding sites or in receptor-mediated increases (A2 adenosine receptor) and decreases (A1 adenosine receptor) in cAMP accumulation. These results are consistent with theoretical arguments that changes in receptor density should not affect the potency of a competitive antagonist. Experimental evidence and theoretical considerations indicate that up-regulation of adenosine receptors is not the mechanism of tolerance to caffeine-induced stimulation of locomotor activity

  1. The frequencies of Killer immunoglobulin-like receptors and their HLA ligands in chronic inflammatory demyelinating polyradiculoneuropathy are similar to those in Guillian Barre syndrome but differ from those of controls, suggesting a role for NK cells in pathogenesis.

    Science.gov (United States)

    Blum, Stefan; Csurhes, Peter; McCombe, Pamela

    2015-08-15

    Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired inflammatory neuropathy, which has similar clinical and pathological features to Guillain-Barré Syndrome (GBS), but differs in time course. We investigated the frequency of genes encoding Killer immunoglobulin-like receptors and their HLA ligands in subjects with CIDP, in subjects with GBS and in healthy controls. There were no differences in KIR gene frequency among the 3 groups. The gene frequencies for HLA-B Bw4-I were significantly greater in CIDP than HC, but did not differ from GBS. The frequency of the combination of 3DL1/HLA-B Bw4I was greater in CIDP than HC, but did not differ from that of GBS. These data raise the possibility of NK cell function being an important factor in the pathogenesis of CIDP. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. The autism-associated MET receptor tyrosine kinase engages early neuronal growth mechanism and controls glutamatergic circuits development in the forebrain.

    Science.gov (United States)

    Peng, Y; Lu, Z; Li, G; Piechowicz, M; Anderson, M; Uddin, Y; Wu, J; Qiu, S

    2016-07-01

    The human MET gene imparts a replicated risk for autism spectrum disorder (ASD), and is implicated in the structural and functional integrity of brain. MET encodes a receptor tyrosine kinase, MET, which has a pleiotropic role in embryogenesis and modifies a large number of neurodevelopmental events. Very little is known, however, on how MET signaling engages distinct cellular events to collectively affect brain development in ASD-relevant disease domains. Here, we show that MET protein expression is dynamically regulated and compartmentalized in developing neurons. MET is heavily expressed in neuronal growth cones at early developmental stages and its activation engages small GTPase Cdc42 to promote neuronal growth, dendritic arborization and spine formation. Genetic ablation of MET signaling in mouse dorsal pallium leads to altered neuronal morphology indicative of early functional maturation. In contrast, prolonged activation of MET represses the formation and functional maturation of glutamatergic synapses. Moreover, manipulating MET signaling levels in vivo in the developing prefrontal projection neurons disrupts the local circuit connectivity made onto these neurons. Therefore, normal time-delimited MET signaling is critical in regulating the timing of neuronal growth, glutamatergic synapse maturation and cortical circuit function. Dysregulated MET signaling may lead to pathological changes in forebrain maturation and connectivity, and thus contribute to the emergence of neurological symptoms associated with ASD.

  3. Lack of effect of the glucagon-like peptide-1 receptor agonist liraglutide on psoriasis in glucose-tolerant patients – a randomized placebo-controlled trial

    DEFF Research Database (Denmark)

    Faurschou, A; Gyldenløve, M; Rohde, U

    2015-01-01

    BACKGROUND: It has been proposed that glucagon-like peptide-1 receptor (GLP-1R) agonists used for the treatment of patients with type 2 diabetes might also improve their psoriasis. OBJECTIVE: To assess the efficacy and safety of the GLP-1R agonist liraglutide in glucose-tolerant patients with pla...... end points were improvement in PASI and dermatology life quality index (DLQI). Secondary end points included changes in weight and high sensitive C-reactive protein (hsCRP) levels, as well as adverse events. RESULTS: After 8 weeks of treatment, no significant change in PASI was found.......2 (liraglutide); P = 0.992). Liraglutide treatment resulted in a bodyweight loss of 4.7 ± 2.5 kg compared with 1.6 ± 2.7 kg in the placebo group (P = 0.014) accompanied by decreased cholesterol levels. No serious adverse events occurred during the 8-week observation period. The most common complaint...... was transient nausea, which occurred in 45% of the liraglutide-treated patients but in none from the placebo group. CONCLUSION: Liraglutide treatment for 8 weeks did not significantly change PASI, DLQI, or hsCRP in a small group of glucose-tolerant obese patients with plaque psoriasis compared with placebo...

  4. 17 beta-estradiol and tamoxifen upregulate estrogen receptor beta expression and control podocyte signaling pathways in a model of type 2 diabetes.

    Science.gov (United States)

    Catanuto, Paola; Doublier, Sophie; Lupia, Enrico; Fornoni, Alessia; Berho, Mariana; Karl, Michael; Striker, Gary E; Xia, Xiaomei; Elliot, Sharon

    2009-06-01

    Diabetic nephropathy remains one of the most important causes of end-stage renal disease. This is particularly true for women from racial/ethnic minorities. Although administration of 17beta-estradiol to diabetic animals has been shown to reduce extracellular matrix deposition in glomeruli and mesangial cells, effects on podocytes are lacking. Given that podocyte injury has been implicated as a factor leading to the progression of proteinuria and diabetic nephropathy, we treated db/db mice, a model of type 2 diabetic glomerulosclerosis, with 17beta-estradiol or tamoxifen to determine whether these treatments reduce podocyte injury and decrease glomerulosclerosis. We found that albumin excretion, glomerular volume, and extracellular matrix accumulation were decreased in these mice compared to placebo treatment. Podocytes isolated from all treatment groups were immortalized and these cell lines were found to express the podocyte markers WT-1, nephrin, and the TRPC6 cation channel. Tamoxifen and 17beta-estradiol treatment decreased podocyte transforming growth factor-beta mRNA expression but increased that of the estrogen receptor subtype beta protein. 17beta-estradiol, but not tamoxifen, treatment decreased extracellular-regulated kinase phosphorylation. These data, combined with improved albumin excretion, reduced glomerular size, and decreased matrix accumulation, suggest that both 17beta-estradiol and tamoxifen may protect podocytes against injury and therefore ameliorate diabetic nephropathy.

  5. Transmembrane Tumor Necrosis Factor Controls Myeloid-Derived Suppressor Cell Activity via TNF Receptor 2 and Protects from Excessive Inflammation during BCG-Induced Pleurisy

    Directory of Open Access Journals (Sweden)

    Leslie Chavez-Galan

    2017-08-01

    Full Text Available Pleural tuberculosis (TB is a form of extra-pulmonary TB observed in patients infected with Mycobacterium tuberculosis. Accumulation of myeloid-derived suppressor cells (MDSC has been observed in animal models of TB and in human patients but their role remains to be fully elucidated. In this study, we analyzed the role of transmembrane TNF (tmTNF in the accumulation and function of MDSC in the pleural cavity during an acute mycobacterial infection. Mycobacterium bovis BCG-induced pleurisy was resolved in mice expressing tmTNF, but lethal in the absence of tumor necrosis factor. Pleural infection induced MDSC accumulation in the pleural cavity and functional MDSC required tmTNF to suppress T cells as did pleural wild-type MDSC. Interaction of MDSC expressing tmTNF with CD4 T cells bearing TNF receptor 2 (TNFR2, but not TNFR1, was required for MDSC suppressive activity on CD4 T cells. Expression of tmTNF attenuated Th1 cell-mediated inflammatory responses generated by the acute pleural mycobacterial infection in association with effective MDSC expressing tmTNF and interacting with CD4 T cells expressing TNFR2. In conclusion, this study provides new insights into the crucial role played by the tmTNF/TNFR2 pathway in MDSC suppressive activity required during acute pleural infection to attenuate excessive inflammation generated by the infection.

  6. Thyroid Hormone Receptor α Controls Developmental Timing and Regulates the Rate and Coordination of Tissue-Specific Metamorphosis in Xenopus tropicalis.

    Science.gov (United States)

    Wen, Luan; Shibata, Yuki; Su, Dan; Fu, Liezhen; Luu, Nga; Shi, Yun-Bo

    2017-06-01

    Thyroid hormone (T3) receptors (TRs) mediate the effects of T3 on organ metabolism and animal development. There are two TR genes, TRα and TRβ, in all vertebrates. During animal development, TRα expression is activated earlier than zygotic T3 synthesis and secretion into the plasma, implicating a developmental role of TRα both in the presence and absence of T3. Using T3-dependent amphibian metamorphosis as a model, we previously proposed a dual-function model for TRs, in particular TRα, during development. That is, unliganded TR represses the expression of T3-inducible genes during premetamorphosis to ensure proper animal growth and prevent premature metamorphosis, whereas during metamorphosis, liganded TR activates target gene transcription to promote the transformation of the tadpole into a frog. To determine if TRα has such a dual function, we generated homozygous TRα-knockout animal lines. We show that, indeed, TRα knockout affects both premetamorphic animal development and metamorphosis. Surprisingly, we observed that TRα is not essential for amphibian metamorphosis, given that homozygous knockout animals complete metamorphosis within a similar time period after fertilization as their wild-type siblings. On the other hand, the timing of metamorphosis for different organs is altered by the knockout; limb metamorphosis occurs earlier, whereas intestinal metamorphosis is completed later than in wild-type siblings. Thus, our studies have demonstrated a critical role of endogenous TRα, not only in regulating both the timing and rate of metamorphosis, but also in coordinating temporal metamorphosis of different organs.

  7. Update in Cardiovascular Safety of Glucagon Like Peptide-1 Receptor Agonists In Patients With Type 2 Diabetes. A Mixed Treatment Comparison Meta-Analysis of Randomised Controlled Trials.

    Science.gov (United States)

    Al Yami, Majed S; Alfayez, Osamah M; Alsheikh, Razan

    2018-03-29

    The aim of this mixed treatment comparison (MTC) meta-analysis was to determine glucagon like peptide-1 (GLP-1) receptor agonists' effects on cardiovascular (CV) outcomes in patients with type 2 diabetes (T2DM). A comprehensive, systematic review was conducted using EMBASE and Medline databases. All included trials were large CV outcome trials of GLP-1 agonists versus placebo in T2DM. The primary outcomes of this MTC meta-analysis were death from CV causes, non-fatal MI, and non-fatal stroke. Hospitalisation for heart failure (HF) was evaluated as a secondary endpoint. A total of four trials, including 33,457 patients, met eligibility criteria and were retained for the meta-analysis. Our pairwise meta-analysis results showed a 13% reduction in death from cardiovascular causes in patients who received GLP-1 agonists versus placebo (RR 0.87, 95% CI: 0.78-0.96). However, no statistically significant reduction was observed with GLP-1 agonists in terms of reducing non-fatal MI (RR 0.95, 95% CI: 0.86-1.04), non-fatal stroke events (RR 0.89, 95% CI: 0.76-1.03), and rates of HF hospitalisation (RR 0.94, 95% CI: 0.84-1.04). The network meta-analysis (NMA) showed no significant differences among all the interventions. Glucagon like peptide-1 therapy was associated with a significant reduction in cardiovascular (CV) death. However, GLP-1 agonists seem to have a safety profile comparable to placebo in terms of reducing non-fatal myocardial infarction (MI), non-fatal stroke events, and rates of HF hospitalisation. Copyright © 2018 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.

  8. BRCA1 is expressed in uterine serous carcinoma (USC) and controls insulin-like growth factor I receptor (IGF-IR) gene expression in USC cell lines.

    Science.gov (United States)

    Amichay, Keren; Kidron, Debora; Attias-Geva, Zohar; Schayek, Hagit; Sarfstein, Rive; Fishman, Ami; Werner, Haim; Bruchim, Ilan

    2012-06-01

    The insulin-like growth factor I receptor (IGF-IR) and BRCA1 affect cell growth and apoptosis. Little information is available about BRCA1 activity on the IGF signaling pathway. This study evaluated the effect of BRCA1 on IGF-IR expression. BRCA1 and IGF-IR immunohistochemistry on archival tissues (35 uterine serous carcinomas [USCs] and 17 metastases) were performed. USPC1 and USPC2 cell lines were transiently cotransfected with an IGF-IR promoter construct driving a luciferase reporter gene and a BRCA1 expression plasmid. Endogenous IGF-IR levels were evaluated by Western immunoblotting. We found high BRCA1 and IGF-IR protein expression in primary and metastatic USC tumors. All samples were immunostained for BRCA1-71% strongly stained; and 33/35 (94%) were stained positive for IGF-IR-2 (6%) strongly stained. No difference in BRCA1 and IGF-IR staining intensity was noted between BRCA1/2 mutation carriers and noncarriers. Metastatic tumors stained more intensely for BRCA1 than did the primary tumor site (P = 0.041) and with borderline significance for IGF-IR (P = 0.069). BRCA1 and IGF-IR staining did not correlate to survival. BRCA1 expression led to 35% and 54% reduction in IGF-IR promoter activity in the USPC1 and USCP2 cell lines, respectively. Western immunoblotting showed a decline in phosphorylated IGF-IR and phosphorylated AKT in both transiently and stably transfected cells. BRCA1 and IGF-IR are highly expressed in USC tumors. BRCA1 suppresses IGF-IR gene expression and activity. These findings suggest a possible biological link between the BRCA1 and the IGF-I signaling pathways in USC. The clinical implications of this association need to be explored.

  9. Angiotensin type 1a receptors in the paraventricular nucleus of the hypothalamus control cardiovascular reactivity and anxiety-like behavior in male mice.

    Science.gov (United States)

    Wang, Lei; Hiller, Helmut; Smith, Justin A; de Kloet, Annette D; Krause, Eric G

    2016-09-01

    This study tested the hypothesis that deletion of angiotensin type 1a receptors (AT1a) from the paraventricular nucleus of hypothalamus (PVN) attenuates anxiety-like behavior, hypothalamic-pituitary-adrenal (HPA) axis activity, and cardiovascular reactivity. We used the Cre/LoxP system to generate male mice with AT1a specifically deleted from the PVN. Deletion of the AT1a from the PVN reduced anxiety-like behavior as indicated by increased time spent in the open arms of the elevated plus maze. In contrast, PVN AT1a deletion had no effect on HPA axis activation subsequent to an acute restraint challenge but did reduce hypothalamic mRNA expression for corticotropin-releasing hormone (CRH). To determine whether PVN AT1a deletion inhibits cardiovascular reactivity, we measured systolic blood pressure, heart rate, and heart rate variability (HRV) using telemetry and found that PVN AT1a deletion attenuated restraint-induced elevations in systolic blood pressure and elicited changes in HRV indicative of reduced sympathetic nervous activity. Consistent with the decreased HRV, PVN AT1a deletion also decreased adrenal weight, suggestive of decreased adrenal sympathetic outflow. Interestingly, the altered stress responsivity of mice with AT1a deleted from the PVN was associated with decreased hypothalamic microglia and proinflammatory cytokine expression. Collectively, these results suggest that deletion of AT1a from the PVN attenuates anxiety, CRH gene transcription, and cardiovascular reactivity and reduced brain inflammation may contribute to these effects. Copyright © 2016 the American Physiological Society.

  10. A search for presynaptic inhibitory histamine receptors in guinea-pig tissues: Further H3 receptors but no evidence for H4 receptors.

    Science.gov (United States)

    Petri, Doris; Schlicker, Eberhard

    2016-07-01

    The histamine H4 receptor is coupled to Gi/o proteins and expressed on inflammatory cells and lymphoid tissues; it was suggested that this receptor also occurs in the brain or on peripheral neurones. Since many Gi/o protein-coupled receptors, including the H3 receptor, serve as presynaptic inhibitory receptors, we studied whether the sympathetic neurones supplying four peripheral tissues and the cholinergic neurones in the hippocampus from the guinea-pig are equipped with release-modulating H4 and H3 receptors. For this purpose, we preincubated tissue pieces from the aorta, atrium, renal cortex and vas deferens with (3)H-noradrenaline and hippocampal slices with (3)H-choline and determined the electrically evoked tritium overflow. The stimulation-evoked overflow in the five superfused tissues was inhibited by the muscarinic receptor agonist oxotremorine, which served as a positive control, but not affected by the H4 receptor agonist 4-methylhistamine. The H3 receptor agonist R-α-methylhistamine inhibited noradrenaline release in the peripheral tissues without affecting acetylcholine release in the hippocampal slices. Thioperamide shifted the concentration-response curve of histamine in the aorta and the renal cortex to the right, yielding apparent pA2 values of 8.0 and 8.1, respectively, which are close to its affinity at other H3 receptors but higher by one log unit than its pKi at the H4 receptor of the guinea-pig. In conclusion, histamine H4 receptors could not be identified in five experimental models of the guinea-pig that are suited for the detection of presynaptic inhibitory receptors whereas H3 receptors could be shown in the peripheral tissues but not in the hippocampus. This article is part of the Special Issue entitled 'Histamine Receptors'. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. GABA receptor imaging

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jong Doo [Yonsei University College of Medicine, Seoul (Korea, Republic of)

    2007-04-15

    GABA is primary an inhibitory neurotransmitter that is localized in inhibitory interneurons. GABA is released from presynaptic terminals and functions by binding to GABA receptors. There are two types of GABA receptors, GABA{sub A}-receptor that allows chloride to pass through a ligand gated ion channel and GABA{sub B}-receptor that uses G-proteins for signaling. The GABA{sub A}-receptor has a GABA binding site as well as a benzodiazepine binding sites, which modulate GABA{sub A}-receptor function. Benzodiazepine GABAA receptor imaging can be accomplished by radiolabeling derivates that activates benzodiazepine binding sites. There has been much research on flumazenil (FMZ) labeled with {sup 11}C-FMZ, a benzodiazepine derivate that is a selective, reversible antagonist to GABAA receptors. Recently, {sup 18}F-fluoroflumazenil (FFMZ) has been developed to overcome {sup 11}C's short half-life. {sup 18}F-FFMZ shows high selective affinity and good pharmacodynamics, and is a promising PET agent with better central benzodiazepine receptor imaging capabilities. In an epileptic focus, because the GABA/benzodiazepine receptor amount is decreased, using '1{sup 1}C-FMZ PET instead of {sup 18}F-FDG, PET, restrict the foci better and may also help find lesions better than high resolution MR. GABA{sub A} receptors are widely distributed in the cerebral cortex, and can be used as an viable neuronal marker. Therefore it can be used as a neuronal cell viability marker in cerebral ischemia. Also, GABA-receptors decrease in areas where neuronal plasticity develops, therefore, GABA imaging can be used to evaluate plasticity. Besides these usages, GABA receptors are related with psychological diseases, especially depression and schizophrenia as well as cerebral palsy, a motor-related disorder, so further in-depth studies are needed for these areas.

  12. GABA receptor imaging

    International Nuclear Information System (INIS)

    Lee, Jong Doo

    2007-01-01

    GABA is primary an inhibitory neurotransmitter that is localized in inhibitory interneurons. GABA is released from presynaptic terminals and functions by binding to GABA receptors. There are two types of GABA receptors, GABA A -receptor that allows chloride to pass through a ligand gated ion channel and GABA B -receptor that uses G-proteins for signaling. The GABA A -receptor has a GABA binding site as well as a benzodiazepine binding sites, which modulate GABA A -receptor function. Benzodiazepine GABAA receptor imaging can be accomplished by radiolabeling derivates that activates benzodiazepine binding sites. There has been much research on flumazenil (FMZ) labeled with 11 C-FMZ, a benzodiazepine derivate that is a selective, reversible antagonist to GABAA receptors. Recently, 18 F-fluoroflumazenil (FFMZ) has been developed to overcome 11 C's short half-life. 18 F-FFMZ shows high selective affinity and good pharmacodynamics, and is a promising PET agent with better central benzodiazepine receptor imaging capabilities. In an epileptic focus, because the GABA/benzodiazepine receptor amount is decreased, using '1 1 C-FMZ PET instead of 18 F-FDG, PET, restrict the foci better and may also help find lesions better than high resolution MR. GABA A receptors are widely distributed in the cerebral cortex, and can be used as an viable neuronal marker. Therefore it can be used as a neuronal cell viability marker in cerebral ischemia. Also, GABA-receptors decrease in areas where neuronal plasticity develops, therefore, GABA imaging can be used to evaluate plasticity. Besides these usages, GABA receptors are related with psychological diseases, especially depression and schizophrenia as well as cerebral palsy, a motor-related disorder, so further in-depth studies are needed for these areas

  13. Constitutive dimerization of the G-protein coupled receptor, neurotensin receptor 1, reconstituted into phospholipid bilayers.

    Science.gov (United States)

    Harding, Peter J; Attrill, Helen; Boehringer, Jonas; Ross, Simon; Wadhams, George H; Smith, Eleanor; Armitage, Judith P; Watts, Anthony

    2009-02-01

    Neurotensin receptor 1 (NTS1), a Family A G-protein coupled receptor (GPCR), was expressed in Escherichia coli as a fusion with the fluorescent proteins eCFP or eYFP. A fluorophore-tagged receptor was used to study the multimerization of NTS1 in detergent solution and in brain polar lipid bilayers, using fluorescence resonance energy transfer (FRET). A detergent-solubilized receptor was unable to form FRET-competent complexes at concentrations of up to 200 nM, suggesting that the receptor is monomeric in this environment. When reconstituted into a model membrane system at low receptor density, the observed FRET was independent of agonist binding, suggesting constitutive multimer formation. In competition studies, decreased FRET in the presence of untagged NTS1 excludes the possibility of fluorescent protein-induced interactions. A simulation of the experimental data indicates that NTS1 exists predominantly as a homodimer, rather than as higher-order multimers. These observations suggest that, in common with several other Family A GPCRs, NTS1 forms a constitutive dimer in lipid bilayers, stabilized through receptor-receptor interactions in the absence of other cellular signaling components. Therefore, this work demonstrates that well-characterized model membrane systems are useful tools for the study of GPCR multimerization, allowing fine control over system composition and complexity, provided that rigorous control experiments are performed.

  14. Common structural basis for constitutive activity of the ghrelin receptor family

    DEFF Research Database (Denmark)

    Holst, Birgitte; Holliday, Nicholas D; Bach, Anders

    2004-01-01

    Three members of the ghrelin receptor family were characterized in parallel: the ghrelin receptor, the neurotensin receptor 2 and the orphan receptor GPR39. In transiently transfected COS-7 and human embryonic kidney 293 cells, all three receptors displayed a high degree of ligand......-independent signaling activity. The structurally homologous motilin receptor served as a constitutively silent control; upon agonist stimulation, however, it signaled with a similar efficacy to the three related receptors. The constitutive activity of the ghrelin receptor and of neurotensin receptor 2 through the G...... demonstrated that the epitope-tagged ghrelin receptor was constitutively internalized but could be trapped at the cell surface by an inverse agonist, whereas GPR39 remained at the cell surface. Mutational analysis showed that the constitutive activity of both the ghrelin receptor and GPR39 could systematically...

  15. 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.

  16. Experimental Evidence for Differential Susceptibility: Dopamine D4 Receptor Polymorphism (DRD4 VNTR) Moderates Intervention Effects on Toddlers' Externalizing Behavior in a Randomized Controlled Trial

    Science.gov (United States)

    Bakermans-Kranenburg, Marian J.; Van Ijzendoorn, Marinus H.; Pijlman, Femke T. A.; Mesman, Judi; Juffer, Femmie

    2008-01-01

    In a randomized controlled trial we tested the role of genetic differences in explaining variability in intervention effects on child externalizing behavior. One hundred fifty-seven families with 1- to 3-year-old children screened for their relatively high levels of externalizing behavior participated in a study implementing Video-feedback…

  17. Mechanism of A2 adenosine receptor activation. I. Blockade of A2 adenosine receptors by photoaffinity labeling

    International Nuclear Information System (INIS)

    Lohse, M.J.; Klotz, K.N.; Schwabe, U.

    1991-01-01

    It has previously been shown that covalent incorporation of the photoreactive adenosine derivative (R)-2-azido-N6-p-hydroxy-phenylisopropyladenosine [(R)-AHPIA] into the A1 adenosine receptor of intact fat cells leads to a persistent activation of this receptor, resulting in a reduction of cellular cAMP levels. In contrast, covalent incorporation of (R)-AHPIA into human platelet membranes, which contain only stimulatory A2 adenosine receptors, reduces adenylate cyclase stimulation via these receptors. This effect of (R)-AHPIA is specific for the A2 receptor and can be prevented by the adenosine receptor antagonist theophylline. Binding studies indicate that up to 90% of A2 receptors can be blocked by photoincorporation of (R)-AHPIA. However, the remaining 10-20% of A2 receptors are sufficient to mediate an adenylate cyclase stimulation of up to 50% of the control value. Similarly, the activation via these 10-20% of receptors occurs with a half-life that is only 2 times longer than that in control membranes. This indicates the presence of a receptor reserve, with respect to both the extent and the rate of adenylate cyclase stimulation. These observations require a modification of the models of receptor-adenylate cyclase coupling

  18. Dengue virus receptor

    OpenAIRE

    Hidari, Kazuya I.P.J.; Suzuki, Takashi

    2011-01-01

    Dengue virus is an arthropod-borne virus transmitted by Aedes mosquitoes. Dengue virus causes fever and hemorrhagic disorders in humans and non-human primates. Direct interaction of the virus introduced by a mosquito bite with host receptor molecule(s) is crucial for virus propagation and the pathological progression of dengue diseases. Therefore, elucidation of the molecular mechanisms underlying the interaction between dengue virus and its receptor(s) in both humans and mosquitoes is essent...

  19. NMDA receptors and memory encoding.

    Science.gov (United States)

    Morris, Richard G M

    2013-11-01

    It is humbling to think that 30 years have passed since the paper by Collingridge, Kehl and McLennan showing that one of Jeff Watkins most interesting compounds, R-2-amino-5-phosphonopentanoate (d-AP5), blocked the induction of long-term potentiation in vitro at synapses from area CA3 of the hippocampus to CA1 without apparent effect on baseline synaptic transmission (Collingridge et al., 1983). This dissociation was one of the key triggers for an explosion of interest in glutamate receptors, and much has been discovered since that collectively contributes to our contemporary understanding of glutamatergic synapses - their biophysics and subunit composition, of the agonists and antagonists acting on them, and their diverse functions in different networks of the brain and spinal cord. It can be fairly said that Collingridge et al.'s (1983) observation was the stimulus that has led, on the one hand, to structural biological work at the atomic scale describing the key features of NMDA receptors that enables their coincidence function to happen; and, on the other, to work with whole animals investigating the contributions that calcium signalling via this receptor can have on rhythmical activities controlled by spinal circuits, memory encoding in the hippocampus (the topic of this article), visual cortical plasticity, sensitization in pain, and other functions. In this article, I lay out how my then interest in long-term potentiation (LTP) as a model of memory enabled me to recognise the importance of Collingridge et al.'s discovery - and how I and my colleagues endeavoured to take things forward in the area of learning and memory. This is in some respects a personal story, and I tell it as such. The idea that NMDA receptor activation is essential for memory encoding, though not for storage, took time to develop and to be accepted. Along the way, there have been confusions, challenges, and surprises surrounding the idea that activation of NMDA receptors can

  20. Sweet Taste Receptor Signaling Network: Possible Implication for Cognitive Functioning

    Directory of Open Access Journals (Sweden)

    Menizibeya O. Welcome

    2015-01-01

    Full Text Available Sweet taste receptors are transmembrane protein network specialized in the transmission of information from special “sweet” molecules into the intracellular domain. These receptors can sense the taste of a range of molecules and transmit the information downstream to several acceptors, modulate cell specific functions and metabolism, and mediate cell-to-cell coupling through paracrine mechanism. Recent reports indicate that sweet taste receptors are widely distributed in the body and serves specific function relative to their localization. Due to their pleiotropic signaling properties and multisubstrate ligand affinity, sweet taste receptors are able to cooperatively bind multiple substances and mediate signaling by other receptors. Based on increasing evidence about the role of these receptors in the initiation and control of absorption and metabolism, and the pivotal role of metabolic (glucose regulation in the central nervous system functioning, we propose a possible implication of sweet taste receptor signaling in modulating cognitive functioning.

  1. Polymorphisms of genes coding for ghrelin and its receptor in relation to anthropometry, circulating levels of IGF-I and IGFBP-3, and breast cancer risk : a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC)

    NARCIS (Netherlands)

    Dossus, Laure; Mckay, James D.; Canzian, Federico; Wilkening, Stefan; Rinaldi, Sabina; Biessy, Carine; Olsen, Anja; Tjonneland, Anne; Jakobsen, Marianne U.; Overvad, Kim; Clavel-Chapelon, Francoise; Boutron-Ruault, Marie-Christine; Fournier, Agnes; Linseisen, Jakob; Lukanova, Annekatrin; Boeing, Heiner; Fisher, Eva; Trichopoulou, Antonia; Georgila, Christina; Trichopoulos, Dimitrios; Palli, Domenico; Krogh, Vittorio; Tumino, Rosario; Vineis, Paolo; Quiros, Jose Ramon; Sala, Nuria; Martinez-Garcia, Carmen; Dorronsoro, Miren; Chirlaque, Maria-Dolores; Barricarte, Aurelio; van Duijnhoven, Franzel J. B.; Bueno-de-Mesquita, H. B.; van Gils, Carla H.; Peeters, Petra H. M.; Hallmans, Goran; Lenner, Per; Bingham, Sheila; Khaw, Kay Tee; Key, Tim J.; Travis, Ruth C.; Ferrari, Pietro; Jenab, Mazda; Riboli, Elio; Kaaks, Rudolf

    Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, has two major functions: the stimulation of the growth hormone production and the stimulation of food intake. Accumulating evidence also suggests a role of ghrelin in cancer development. We conducted a case-control study on

  2. The Int7G24A variant of transforming growth factor-beta receptor type I is a risk factor for colorectal cancer in the male Spanish population: a case-control study

    International Nuclear Information System (INIS)

    Castillejo, Adela; Guillén-Ponce, Carmen; Carrato, Alfredo; Soto, José-Luís; Mata-Balaguer, Trinidad; Guarinos, Carla; Castillejo, María-Isabel; Martínez-Cantó, Ana; Barberá, Víctor-Manuel; Montenegro, Paola; Ochoa, Enrique; Lázaro, Rafael

    2009-01-01

    The Int7G24A variant of transforming growth factor-beta receptor type I (TGFBR1) has been shown to increase the risk for kidney, ovarian, bladder, lung and breast cancers. Its role in colorectal cancer (CRC) has not been established. The aims of this study were to assess the association of TGFBR1*Int7G24A variant with CRC occurrence, patient age, gender, tumour location and stage. We performed a case-control study with 504 cases of sporadic CRC; and 504 non-cancerous age, gender and ethnically matched controls. Genotyping analysis was performed using allelic discrimination assay by real time PCR. The Int7G24A variant was associated with increased CRC incidence in an additive model of inheritance (P for trend = 0.005). No significant differences were found between Int7G24A genotypes and tumour location or stage. Interestingly, the association of the Int7G24A variant with CRC risk was significant in men (odds ratio 4.10 with 95% confidence intervals 1.41-11.85 for homozygous individuals; P for trend = 0.00023), but not in women. We also observed an increase in susceptibility to CRC for individuals aged less than 70 years. Our data suggest that the Int7G24A variant represents a risk factor for CRC in the male Spanish population

  3. The Int7G24A variant of transforming growth factor-beta receptor type I is a risk factor for colorectal cancer in the male Spanish population: a case-control study

    Directory of Open Access Journals (Sweden)

    Lázaro Rafael

    2009-11-01

    Full Text Available Abstract Background The Int7G24A variant of transforming growth factor-beta receptor type I (TGFBR1 has been shown to increase the risk for kidney, ovarian, bladder, lung and breast cancers. Its role in colorectal cancer (CRC has not been established. The aims of this study were to assess the association of TGFBR1*Int7G24A variant with CRC occurrence, patient age, gender, tumour location and stage. Methods We performed a case-control study with 504 cases of sporadic CRC; and 504 non-cancerous age, gender and ethnically matched controls. Genotyping analysis was performed using allelic discrimination assay by real time PCR. Results The Int7G24A variant was associated with increased CRC incidence in an additive model of inheritance (P for trend = 0.005. No significant differences were found between Int7G24A genotypes and tumour location or stage. Interestingly, the association of the Int7G24A variant with CRC risk was significant in men (odds ratio 4.10 with 95% confidence intervals 1.41-11.85 for homozygous individuals; P for trend = 0.00023, but not in women. We also observed an increase in susceptibility to CRC for individuals aged less than 70 years. Conclusion Our data suggest that the Int7G24A variant represents a risk factor for CRC in the male Spanish population.

  4. Cross-talk between an activator of nuclear receptors-mediated transcription and the D1 dopamine receptor signaling pathway.

    Science.gov (United States)

    Schmidt, Azriel; Vogel, Robert; Rutledge, Su Jane; Opas, Evan E; Rodan, Gideon A; Friedman, Eitan

    2005-03-01

    Nuclear receptors are transcription factors that usually interact, in a ligand-dependent manner, with specific DNA sequences located within promoters of target genes. The nuclear receptors can also be controlled in a ligand-independent manner via the action of membrane receptors and cellular signaling pathways. 5-Tetradecyloxy-2-furancarboxylic acid (TOFA) was shown to stimulate transcription from the MMTV promoter via chimeric receptors that consist of the DNA binding domain of GR and the ligand binding regions of the PPARbeta or LXRbeta nuclear receptors (GR/PPARbeta and GR/LXRbeta). TOFA and hydroxycholesterols also modulate transcription from NF-kappaB- and AP-1-controlled reporter genes and induce neurite differentiation in PC12 cells. In CV-1 cells that express D(1) dopamine receptors, D(1) dopamine receptor stimulation was found to inhibit TOFA-stimulated transcription from the MMTV promoter that is under the control of chimeric GR/PPARbeta and GR/LXRbeta receptors. Treatment with the D(1) dopamine receptor antagonist, SCH23390, prevented dopamine-mediated suppression of transcription, and by itself increased transcription controlled by GR/LXRbeta. Furthermore, combined treatment of CV-1 cells with TOFA and SCH23390 increased transcription controlled by the GR/LXRbeta chimeric receptor synergistically. The significance of this in vitro synergy was demonstrated in vivo, by the observation that SCH23390 (but not haloperidol)-mediated catalepsy in rats was potentiated by TOFA, thus showing that an agent that mimics the in vitro activities of compounds that activate members of the LXR and PPAR receptor families can influence D1 dopamine receptor elicited responses.

  5. Angiotensin receptor blockade in acute stroke. The Scandinavian Candesartan Acute Stroke Trial: rationale, methods and design of a multicentre, randomised- and placebo-controlled clinical trial (NCT00120003)

    DEFF Research Database (Denmark)

    Sandset, Else Charlotte; Murray, Gordon; Boysen, Gudrun Margrethe

    2010-01-01

    AND DESIGN: The Scandinavian Candesartan Acute Stroke Trial is an international randomised, placebo-controlled, double-blind trial of candesartan in acute stroke. We plan to recruit 2500 patients presenting within 30 h of stroke (ischaemic or haemorrhagic) and with systolic blood pressure =140 mm......Hg. The recruited patients are randomly assigned to candesartan or placebo for 7-days (doses increasing from 4 to 16 mg once daily). Randomisation is performed centrally via a secure web interface. The follow-up period is 6-months. Patients are included from the following nine North-European countries: Norway...

  6. Computer-assisted assessment of the Human Epidermal Growth Factor Receptor 2 immunohistochemical assay in imaged histologic sections using a membrane isolation algorithm and quantitative analysis of positive controls

    International Nuclear Information System (INIS)

    Hall, Bonnie H; Ianosi-Irimie, Monica; Javidian, Parisa; Chen, Wenjin; Ganesan, Shridar; Foran, David J

    2008-01-01

    Breast cancers that overexpress the human epidermal growth factor receptor 2 (HER2) are eligible for effective biologically targeted therapies, such as trastuzumab. However, accurately determining HER2 overexpression, especially in immunohistochemically equivocal cases, remains a challenge. Manual analysis of HER2 expression is dependent on the assessment of membrane staining as well as comparisons with positive controls. In spite of the strides that have been made to standardize the assessment process, intra- and inter-observer discrepancies in scoring is not uncommon. In this manuscript we describe a pathologist assisted, computer-based continuous scoring approach for increasing the precision and reproducibility of assessing imaged breast tissue specimens. Computer-assisted analysis on HER2 IHC is compared with manual scoring and fluorescence in situ hybridization results on a test set of 99 digitally imaged breast cancer cases enriched with equivocally scored (2+) cases. Image features are generated based on the staining profile of the positive control tissue and pixels delineated by a newly developed Membrane Isolation Algorithm. Evaluation of results was performed using Receiver Operator Characteristic (ROC) analysis. A computer-aided diagnostic approach has been developed using a membrane isolation algorithm and quantitative use of positive immunostaining controls. By incorporating internal positive controls into feature analysis a greater Area Under the Curve (AUC) in ROC analysis was achieved than feature analysis without positive controls. Evaluation of HER2 immunostaining that utilized membrane pixels, controls, and percent area stained showed significantly greater AUC than manual scoring, and significantly less false positive rate when used to evaluate immunohistochemically equivocal cases. It has been shown that by incorporating both a membrane isolation algorithm and analysis of known positive controls a computer-assisted diagnostic algorithm was

  7. Computer-assisted assessment of the Human Epidermal Growth Factor Receptor 2 immunohistochemical assay in imaged histologic sections using a membrane isolation algorithm and quantitative analysis of positive controls

    Directory of Open Access Journals (Sweden)

    Ianosi-Irimie Monica

    2008-06-01

    Full Text Available Abstract Background Breast cancers that overexpress the human epidermal growth factor receptor 2 (HER2 are eligible for effective biologically targeted therapies, such as trastuzumab. However, accurately determining HER2 overexpression, especially in immunohistochemically equivocal cases, remains a challenge. Manual analysis of HER2 expression is dependent on the assessment of membrane staining as well as comparisons with positive controls. In spite of the strides that have been made to standardize the assessment process, intra- and inter-observer discrepancies in scoring is not uncommon. In this manuscript we describe a pathologist assisted, computer-based continuous scoring approach for increasing the precision and reproducibility of assessing imaged breast tissue specimens. Methods Computer-assisted analysis on HER2 IHC is compared with manual scoring and fluorescence in situ hybridization results on a test set of 99 digitally imaged breast cancer cases enriched with equivocally scored (2+ cases. Image features are generated based on the staining profile of the positive control tissue and pixels delineated by a newly developed Membrane Isolation Algorithm. Evaluation of results was performed using Receiver Operator Characteristic (ROC analysis. Results A computer-aided diagnostic approach has been developed using a membrane isolation algorithm and quantitative use of positive immunostaining controls. By incorporating internal positive controls into feature analysis a greater Area Under the Curve (AUC in ROC analysis was achieved than feature analysis without positive controls. Evaluation of HER2 immunostaining that utilized membrane pixels, controls, and percent area stained showed significantly greater AUC than manual scoring, and significantly less false positive rate when used to evaluate immunohistochemically equivocal cases. Conclusion It has been shown that by incorporating both a membrane isolation algorithm and analysis of known

  8. Platelet dysfunction associated with the novel Trp29Cys thromboxane A₂ receptor variant.

    Science.gov (United States)

    Mumford, A D; Nisar, S; Darnige, L; Jones, M L; Bachelot-Loza, C; Gandrille, S; Zinzindohoue, F; Fischer, A-M; Mundell, S J; Gaussem, P

    2013-03-01

    Genetic variations that affect the structure of the thromboxane A2 receptor (TP receptor) provide insights into the function of this key platelet and vascular receptor, but are very rare in unselected populations. To determine the functional consequences of the TP receptor Trp29Cys (W29C) substitution. We performed a detailed phenotypic analysis of an index case (P1) with reduced platelet aggregation and secretion responses to TP receptor pathway activators, and a heterozygous TP receptor W29C substitution. An analysis of the variant W29C TP receptor expressed in heterologous cells was performed. Total TP receptor expression in platelets from P1 was similar to that of controls, but there was reduced maximum binding and reduced affinity of binding to the TP receptor antagonist [(3) H]SQ29548. HEK293 cells transfected with W29C TP receptor cDNA showed similar total TP receptor expression to wild-type (WT) controls. However, the TP receptor agonist U46619 was less potent at inducing rises in cytosolic free Ca(2+) in HEK293 cells expressing the W29C TP receptor than in WT controls, indicating reduced receptor function. Immunofluorescence microscopy and cell surface ELISA showed intracellular retention and reduced cell surface expression of the W29C TP receptor in HEK293 cells. Consistent with the platelet phenotype, both maximum binding and the affinity of binding of [(3) H]SQ29548 to the W29C TP receptor were reduced compared to WT controls. These findings extend the phenotypic description of the very rare disorder TP receptor deficiency, and show that the W29C substitution reduces TP receptor function by reducing surface receptor expression and by disrupting ligand binding. © 2012 International Society on Thrombosis and Haemostasis.

  9. Soman- or kainic acid-induced convulsions decrease muscarinic receptors but not benzodiazepine receptors

    International Nuclear Information System (INIS)

    Churchill, L.; Pazdernik, T.L.; Cross, R.S.; Nelson, S.R.; Samson, F.E.

    1990-01-01

    [3H]Quinuclidinyl benzilate (QNB) binding to muscarinic receptors decreased in the rat forebrain after convulsions induced by a single dose of either soman, a potent inhibitor of acetylcholinesterase, or kainic acid, an excitotoxin. A Rosenthal plot revealed that the receptors decreased in number rather than affinity. When the soman-induced convulsions were blocked, the decrease in muscarinic receptors at 3 days was less extensive than when convulsions occurred and at 10 days they approached control levels in most of the brain areas. The most prominent decrements in QNB binding were in the piriform cortex where the decline in QNB binding is probably related to the extensive convulsion-associated neuropathology. The decrements in QNB binding after convulsions suggest that the convulsive state leads to a down-regulation of muscarinic receptors in some brain areas. In contrast to the decrease in QNB binding after convulsions, [3H]flunitrazepam binding to benzodiazepine receptors did not change even in the piriform cortex where the loss in muscarinic receptors was most prominent. Thus, it appears that those neuronal processes that bear muscarinic receptors are more vulnerable to convulsion-induced change than those with benzodiazepine receptors

  10. Angiotensin type 2 receptors

    DEFF Research Database (Denmark)

    Sumners, Colin; de Kloet, Annette D; Krause, Eric G

    2015-01-01

    In most situations, the angiotensin AT2-receptor (AT2R) mediates physiological actions opposing those mediated by the AT1-receptor (AT1R), including a vasorelaxant effect. Nevertheless, experimental evidence vastly supports that systemic application of AT2R-agonists is blood pressure neutral...

  11. Adenosine Receptor Heteromers and their Integrative Role in Striatal Function

    Directory of Open Access Journals (Sweden)

    Sergi Ferré

    2007-01-01

    Full Text Available By analyzing the functional role of adenosine receptor heteromers, we review a series of new concepts that should modify our classical views of neurotransmission in the central nervous system (CNS. Neurotransmitter receptors cannot be considered as single functional units anymore. Heteromerization of neurotransmitter receptors confers functional entities that possess different biochemical characteristics with respect to the individual components of the heteromer. Some of these characteristics can be used as a “biochemical fingerprint” to identify neurotransmitter receptor heteromers in the CNS. This is exemplified by changes in binding characteristics that are dependent on coactivation of the receptor units of different adenosine receptor heteromers. Neurotransmitter receptor heteromers can act as “processors” of computations that modulate cell signaling, sometimes critically involved in the control of pre- and postsynaptic neurotransmission. For instance, the adenosine A1-A2A receptor heteromer acts as a concentration-dependent switch that controls striatal glutamatergic neurotransmission. Neurotransmitter receptor heteromers play a particularly important integrative role in the “local module” (the minimal portion of one or more neurons and/or one or more glial cells that operates as an independent integrative unit, where they act as processors mediating computations that convey information from diverse volume-transmitted signals. For instance, the adenosine A2A-dopamine D2 receptor heteromers work as integrators of two different neurotransmitters in the striatal spine module.

  12. Pharmacodynamics and safety of the novel selective progesterone receptor modulator vilaprisan: a double-blind, randomized, placebo-controlled phase 1 trial in healthy women.

    Science.gov (United States)

    Schütt, Barbara; Kaiser, Andreas; Schultze-Mosgau, Marcus-Hillert; Seitz, Christian; Bell, David; Koch, Manuela; Rohde, Beate

    2016-08-01

    Does administration of vilaprisan (VPR) to healthy women for 12 weeks reduce menstrual bleeding? In this 12-week proof-of-concept phase 1 trial, most women (30/33, 90%) who received VPR at daily doses of 1-5 mg reported the absence of menstrual bleeding. Vilaprisan (BAY 1002670) is a novel, highly potent selective progesterone receptor modulator that markedly reduces the growth of human leiomyoma tissue in a preclinical model of uterine fibroids (UFs). In this double-blind, parallel-group study, of the 163 healthy women enrolled 73 were randomized to daily VPR 0.1 mg (n = 12), 0.5 mg (n = 12), 1 mg (n = 13), 2 mg (n = 12), 5 mg (n = 12) or placebo tablets (n = 12) for 12 weeks. Participants were followed up until the start of the second menstrual bleeding after the end of treatment. Trial simulations were used to determine the minimum sample size required to estimate the non-bleeding rate (i.e. self-assessed bleeding intensity of 'none' or 'spotting') using Bayesian dose-response estimation with incorporated prior information. It was estimated that 48 participants in the per-protocol analysis population would be sufficient. Women aged 18-45 years who had been sterilized by tubal ligation were enrolled between November 2011 and May 2012. Participants kept a daily diary of bleeding intensity. Blood and urine samples were taken, and transvaginal ultrasound was performed before treatment, during treatment and follow-up. Endometrial biopsies were obtained during the pretreatment cycle, at the end of the treatment period and during the follow-up phase. The primary outcome was the estimated dose-response curve of the observed non-bleeding rate during Days 10-84 of treatment, excluding the endometrial biopsy day and 2 days after biopsy. Secondary outcomes included return of bleeding during follow-up, size of follicle-like structures and serum hormone levels. Safety assessments included adverse events (AEs), endometrial thickness and histology, laboratory parameters, vital

  13. Role of 4-1BB receptor in the control played by CD8(+ T cells on IFN-gamma production by Mycobacterium tuberculosis antigen-specific CD4(+ T Cells.

    Directory of Open Access Journals (Sweden)

    Carla Palma

    Full Text Available BACKGROUND: Antigen-specific IFN-gamma producing CD4(+ T cells are the main mediators of protection against Mycobacterium tuberculosis infection both under natural conditions and following vaccination. However these cells are responsible for lung damage and poor vaccine efficacy when not tightly controlled. Discovering new tools to control nonprotective antigen-specific IFN-gamma production without affecting protective IFN-gamma is a challenge in tuberculosis research. METHODS AND FINDINGS: Immunization with DNA encoding Ag85B, a candidate vaccine antigen of Mycobacterium tuberculosis, elicited in mice a low but protective CD4(+ T cell-mediated IFN-gamma response, while in mice primed with DNA and boosted with Ag85B protein a massive increase in IFN-gamma response was associated with loss of protection. Both protective and non-protective Ag85B-immunization generated antigen-specific CD8(+ T cells which suppressed IFN-gamma-secreting CD4(+ T cells. However, ex vivo ligation of 4-1BB, a member of TNF-receptor super-family, reduced the massive, non-protective IFN-gamma responses by CD4(+ T cells in protein-boosted mice without affecting the low protective IFN-gamma-secretion in mice immunized with DNA. This selective inhibition was due to the induction of 4-1BB exclusively on CD8(+ T cells of DNA-primed and protein-boosted mice following Ag85B protein stimulation. The 4-1BB-mediated IFN-gamma inhibition did not require soluble IL-10, TGF-beta, XCL-1 and MIP-1beta. In vivo Ag85B stimulation induced 4-1BB expression on CD8(+ T cells and in vivo 4-1BB ligation reduced the activation, IFN-gamma production and expansion of Ag85B-specific CD4(+ T cells of DNA-primed and protein-boosted mice. CONCLUSION/SIGNIFICANCE: Antigen-specific suppressor CD8(+ T cells are elicited through immunization with the mycobacterial antigen Ag85B. Ligation of 4-1BB receptor further enhanced their suppressive activity on IFN-gamma-secreting CD4(+ T cells. The selective

  14. Association of estrogen receptor α PvuII and XbaI polymorphisms with prostate cancer susceptibility and risk stratification: a meta-analysis from case-control studies

    Directory of Open Access Journals (Sweden)

    Zhao YN

    2017-06-01

    Full Text Available Yining Zhao,1,* Xi Zheng,2,* Lijie Zhang,3 Qiang Hu,3 Yitian Guo,3 Hua Jiang,3 Shennan Shi,4 Xiang Zhang1 1Department of Urology, Qilu Hospital of Shandong University, Jinan, 2Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 3Department of Urology, Affiliated Zhongda Hospital, Medical School, Southeast University, Nanjing, 4Department of General Surgery, Qilu Hospital of Shandong University, Jinan, People’s Republic of China *These authors contributed equally to this work Background: Studies on the association between two single nucleotide polymorphisms (SNPs in estrogen receptor α (ERα, PvuII (rs2234693 T>C and XbaI (rs9340799 A>G, and the prostate cancer risk are inconsistent. Therefore, we performed a meta-analysis to derive a more accurate estimation of this relationship. Methods: A literature search of PubMed, Embase, Web of Science databases until October 1, 2016, was conducted. Crude odds ratios (ORs with 95% confidence intervals (CIs were calculated to assess the strength of this association. Results: Eighteen case-control studies, with a total of 3,317 prostate cancer patients and 8,324 controls, were included. Results showed that both PvuII and XbaI polymorphisms were significantly associated with a higher prostate cancer risk in overall populations. To derive a more accurate estimation, subgroup analysis stratified by ethnicity revealed that this relationship existed only in Caucasians, but not in Asians. Furthermore, PvuII polymorphism was significantly associated with high Gleason grade (Gleason score ≥7 cancers. Conclusion: The current meta-analysis demonstrates that ERα PvuII and XbaI polymorphisms are associated with a higher prostate cancer risk in Caucasians, but not in Asians, and PvuII polymorphism is significantly associated with high Gleason grade tumors, indicating the probability of inherited susceptibility to prostate cancer arising from different genomic ERα SNPs

  15. Glutamate receptor agonists

    DEFF Research Database (Denmark)

    Vogensen, Stine Byskov; Greenwood, Jeremy R; Bunch, Lennart

    2011-01-01

    The neurotransmitter (S)-glutamate [(S)-Glu] is responsible for most of the excitatory neurotransmission in the central nervous system. The effect of (S)-Glu is mediated by both ionotropic and metabotropic receptors. Glutamate receptor agonists are generally a-amino acids with one or more...... stereogenic centers due to strict requirements in the agonist binding pocket of the activated state of the receptor. By contrast, there are many examples of achiral competitive antagonists. The present review addresses how stereochemistry affects the activity of glutamate receptor ligands. The review focuses...... mainly on agonists and discusses stereochemical and conformational considerations as well as biostructural knowledge of the agonist binding pockets, which is useful in the design of glutamate receptor agonists. Examples are chosen to demonstrate how stereochemistry not only determines how the agonist...

  16. AMPA receptor ligands

    DEFF Research Database (Denmark)

    Strømgaard, Kristian; Mellor, Ian

    2004-01-01

    Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPAR), subtype of the ionotropic glutamate receptors (IGRs), mediate fast synaptic transmission in the central nervous system (CNS), and are involved in many neurological disorders, as well as being a key player in the f......Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPAR), subtype of the ionotropic glutamate receptors (IGRs), mediate fast synaptic transmission in the central nervous system (CNS), and are involved in many neurological disorders, as well as being a key player...... in the formation of memory. Hence, ligands affecting AMPARs are highly important for the study of the structure and function of this receptor, and in this regard polyamine-based ligands, particularly polyamine toxins, are unique as they selectively block Ca2+ -permeable AMPARs. Indeed, endogenous intracellular...

  17. A2A-D2 receptor-receptor interaction modulates gliotransmitter release from striatal astrocyte processes.

    Science.gov (United States)

    Cervetto, Chiara; Venturini, Arianna; Passalacqua, Mario; Guidolin, Diego; Genedani, Susanna; Fuxe, Kjell; Borroto-Esquela, Dasiel O; Cortelli, Pietro; Woods, Amina; Maura, Guido; Marcoli, Manuela; Agnati, Luigi F

    2017-01-01

    Evidence for striatal A2A-D2 heterodimers has led to a new perspective on molecular mechanisms involved in schizophrenia and Parkinson's disease. Despite the increasing recognition of astrocytes' participation in neuropsychiatric disease vulnerability, involvement of striatal astrocytes in A2A and D2 receptor signal transmission has never been explored. Here, we investigated the presence of D2 and A2A receptors in isolated astrocyte processes prepared from adult rat striatum by confocal imaging; the effects of receptor activation were measured on the 4-aminopyridine-evoked release of glutamate from the processes. Confocal analysis showed that A2A and D2 receptors were co-expressed on the same astrocyte processes. Evidence for A2A-D2 receptor-receptor interactions was obtained by measuring the release of the gliotransmitter glutamate: D2 receptors inhibited the glutamate release, while activation of A2A receptors, per se ineffective, abolished the effect of D2 receptor activation. The synthetic D2 peptide VLRRRRKRVN corresponding to the receptor region involved in electrostatic interaction underlying A2A-D2 heteromerization abolished the ability of the A2A receptor to antagonize the D2 receptor-mediated effect. Together, the findings are consistent with heteromerization of native striatal astrocytic A2A-D2 receptors that via allosteric receptor-receptor interactions could play a role in the control of striatal glutamatergic transmission. These new findings suggest possible new pathogenic mechanisms and/or therapeutic approaches to neuropsychiatric disorders. © 2016 International Society for Neurochemistry.

  18. GABAA Receptor-Mediated Bidirectional Control of Synaptic Activity, Intracellular Ca2+, Cerebral Blood Flow, and Oxygen Consumption in Mouse Somatosensory Cortex In Vivo

    DEFF Research Database (Denmark)

    Jessen, Sanne Barsballe; Brazhe, Alexey; Lind, Barbara Lykke

    2015-01-01

    Neural activity regulates local increases in cerebral blood flow (ΔCBF) and the cortical metabolic rate of oxygen (ΔCMRO2) that constitutes the basis of BOLD functional neuroimaging signals. Glutamate signaling plays a key role in brain vascular and metabolic control; however, the modulatory effect...... of GABA is incompletely understood. Here we performed in vivo studies in mice to investigate how THIP (which tonically activates extrasynaptic GABAARs) and Zolpidem (a positive allosteric modulator of synaptic GABAARs) impact stimulation-induced ΔCBF, ΔCMRO2, local field potentials (LFPs), and fluorescent...... cytosolic Ca2+ transients in neurons and astrocytes. Low concentrations of THIP increased ΔCBF and ΔCMRO2 at low stimulation frequencies. These responses were coupled to increased synaptic activity as indicated by LFP responses, and to Ca2+ activities in neurons and astrocytes. Intermediate and high...

  19. Time-dependent effect of orchidectomy on vascular nitric oxide and thromboxane A2 release. Functional implications to control cell proliferation through activation of the epidermal growth factor receptor.

    Directory of Open Access Journals (Sweden)

    Marta del Campo

    Full Text Available This study analyzes whether the release of nitric oxide (NO and thromboxane A2 (TXA2 depends on the time lapsed since gonadal function is lost, and their correlation with the proliferation of vascular smooth muscle cells (VSMC mediated by the epidermal growth factor receptor (EGFR. For this purpose, aortic and mesenteric artery segments from control and 6-weeks or 5-months orchidectomized rats were used to measure NO and TXA2 release. The results showed that the basal and acetylcholine (ACh-induced NO release were decreased 6 weeks post-orchidectomy both in aorta and mesenteric artery, but were recovered 5 months thereafter up to levels similar to those found in arteries from control rats. The basal and ACh-induced TXA2 release increased in aorta and mesenteric artery 6 weeks post-orchidectomy, and was maintained at high levels 5 months thereafter. Since we previously observed that orchidectomy, which decreased testosterone level, enlarged the muscular layer of mesenteric arteries, the effect of testosterone on VSMC proliferation was analyzed. The results showed that treatment of cultured VSMC with testosterone downregulated mitogenic signaling pathways initiated by the ligand-dependent activation of the EGFR. In contrast, the EGFR pathways were constitutively active in mesenteric arteries of long-term orchidectomized rats. Thus, the exposure of mesenteric arteries from control rats to epidermal growth factor (EGF induced the activation of EGFR signaling pathways. However, the addition of EGF to arteries from orchidectomized rats failed to induce a further activation of these pathways. In conclusion, this study shows that the release of NO depends on the time lapsed since the gonadal function is lost, while the release of TXA2 is already increased after short periods post-orchidectomy. The alterations in these signaling molecules could contribute to the constitutive activation of the EGFR and its downstream signaling pathways after long period

  20. Tumour control probability derived from dose distribution in homogeneous and heterogeneous models: assuming similar pharmacokinetics, 125Sn–177Lu is superior to 90Y–177Lu in peptide receptor radiotherapy

    International Nuclear Information System (INIS)

    Walrand, Stephan; Hanin, François-Xavier; Pauwels, Stanislas; Jamar, François

    2012-01-01

    Clinical trials on 177 Lu– 90 Y therapy used empirical activity ratios. Radionuclides (RN) with larger beta maximal range could favourably replace 90 Y. Our aim is to provide RN dose-deposition kernels and to compare the tumour control probability (TCP) of RN combinations. Dose kernels were derived by integration of the mono-energetic beta-ray dose distributions (computed using Monte Carlo) weighted by their respective beta spectrum. Nine homogeneous spherical tumours (1–25 mm in diameter) and four spherical tumours including a lattice of cold, but alive, spheres (1, 3, 5, 7 mm in diameter) were modelled. The TCP for 93 Y, 90 Y and 125 Sn in combination with 177 Lu in variable proportions (that kept constant the renal cortex biological effective dose) were derived by 3D dose kernel convolution. For a mean tumour-absorbed dose of 180 Gy, 2 mm homogeneous tumours and tumours including 3 mm diameter cold alive spheres were both well controlled (TCP > 0.9) using a 75–25% combination of 177 Lu and 90 Y activity. However, 125 Sn– 177 Lu achieved a significantly better result by controlling 1 mm-homogeneous tumour simultaneously with tumours including 5 mm diameter cold alive spheres. Clinical trials using RN combinations should use RN proportions tuned to the patient dosimetry. 125 Sn production and its coupling to somatostatin analogue appear feasible. Assuming similar pharmacokinetics 125 Sn is the best RN for combination with 177 Lu in peptide receptor radiotherapy justifying pharmacokinetics studies in rodent of 125 Sn-labelled somatostatin analogues. (paper)

  1. Effectiveness of Sodium-Glucose Cotransporter-2 Inhibitor as an Add-on Drug to GLP-1 Receptor Agonists for Glycemic Control of a Patient with Prader-Willi Syndrome: A Case Report.

    Science.gov (United States)

    Horikawa, Yukio; Enya, Mayumi; Komagata, Makie; Hashimoto, Ken-Ichi; Kagami, Masayo; Fukami, Maki; Takeda, Jun

    2018-02-01

    Diabetes patients with Prader-Willi syndrome (PWS) are obese because of hyperphagia; weight control by dietary modification and medicine is required for glycemic control. There are several recent reports showing the effectiveness of GLP-1 receptor agonists (GLP-1RAs) for diabetes treatment in PWS. A 36-year-old Japanese male patient was diagnosed with PWS at 10 years of age. At age 16 years, he was diagnosed with diabetes and began to take several kinds of oral hypoglycemic agents. At age 29 years, his BMI was 39.1 kg/m 2 and he was referred to our department for diabetes and obesity treatment. In the present case, the HbA1c was not improved by GLP-1RAs despite a 28-kg BW reduction, which included a 9-kg loss of muscle. Apprehensive of further loss of muscle mass, basal insulin of insulin glargine was administered in addition to GLP-1RAs. Immediately after the addition of tofogliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, the patient's HbA1c decreased dramatically with only about an additional 3% BW reduction. We note an improvement in our case of lipid deposition in the pancreas confirmed by abdominal CT after the improvement of HbA1c. It is unknown whether this improvement of fatty pancreas was a cause or an effect of the improved glycemic control in the present case. This finding clearly supports the effectiveness of combining SGLT2 inhibitors with GLP-1RAs for treatment of patients with PWS and non-alcoholic fatty pancreas disease.

  2. Lipophorin Receptor: The Insect Lipoprotein Receptor

    Indian Academy of Sciences (India)

    IAS Admin

    Director of ... function of the Lp is to deliver lipids throughout the insect body for metabolism ... Lipid is used as a major energy source for development as well as other metabolic .... LpR4 receptor variant was expressed exclusively in the brain and.

  3. Developmental regulation of ecdysone receptor (EcR and EcR-controlled gene expression during pharate-adult development of honeybees (Apis mellifera.

    Directory of Open Access Journals (Sweden)

    Tathyana Rachel Palo Mello

    2014-12-01

    Full Text Available Major developmental transitions in multicellular organisms are driven by steroid hormones. In insects, these, together with juvenile hormone (JH, control development, metamorphosis, reproduction and aging, and are also suggested to play an important role in caste differentiation of social insects. Here, we aimed to determine how EcR transcription and ecdysteroid titers are related during honeybee postembryonic development and what may actually be the role of EcR in caste development of this social insect. In addition, we expected that knocking-down EcR gene expression would give us information on the participation of the respective protein in regulating downstream targets of EcR. We found that in Apis mellifera females, EcR-A is the predominantly expressed variant in postembryonic development, while EcR-B transcript levels are higher in embryos, indicating an early developmental switch in EcR function. During larval and pupal stages, EcR-B expression levels are very low, while EcR-A transcripts are more variable and abundant in workers compared to queens. Strikingly, these transcript levels are opposite to the ecdysteroid titer profile. 20-hydroxyecdysone (20E application experiments revealed that low 20E levels induce EcR expression during development, whereas high ecdysteroid titers seem to be repressive. By means of RNAi-mediated knockdown (KD of both EcR transcript variants we detected the differential expression of 234 poly-A+ transcripts encoding genes such as CYPs, MRJPs and certain hormone response genes (Kr-h1 and ftz-f1. EcR-KD also promoted the differential expression of 70 miRNAs, including highly conserved ones (e.g. miR-133 and miR-375, as well honeybee-specific ones (e.g. miR-3745 and miR-3761. Our results put in evidence a broad spectrum of EcR-controlled gene expression during postembryonic development of honeybees, revealing new facets of EcR biology in this social insect.

  4. Lack of association between peroxisome proliferator-activated receptors alpha and gamma2 polymorphisms and progressive liver damage in patients with non-alcoholic fatty liver disease: a case control study

    Directory of Open Access Journals (Sweden)

    Dongiovanni Paola

    2010-09-01

    Full Text Available Abstract Background Peroxisome proliferator-activated receptors (PPARs play key roles in the pathogenesis of nonalcoholic fatty liver disease (NAFLD. Aim to assess the effect of functional single nucleotide polymorphisms (SNPs of PPARα and PPARγ2, previously associated with insulin resistance and dyslipidemia, on liver damage in NAFLD, whose progression is influenced by metabolic abnormalities and inherited factors. Methods The Leu162Val PPARα and Pro12Ala PPARγ2 SNPs were evaluated by restriction analysis. We considered 202 Italian patients with biopsy-proven NAFLD. Results The frequency of the evaluated SNPs did not differ between patients and 346 healthy controls. The presence of the PPARα 162Val allele (prevalence 57%, but not of the PPARγ2 12Ala allele (prevalence 18%, was associated with higher insulin resistance (HOMA-IR index 4.71 ± 3.8 vs. 3.58 ± 2.7, p = 0.026, but not with hyperglycemia. The PPARα 162Val and PPARγ2 12Ala alleles were not associated with the severity of steatosis, necroinflammation, or fibrosis. Conclusions The presence of the PPARα 162Val allele was associated with insulin resistance, but not with liver damage in NAFLD. Because of the limited power of the present sample, larger studies are needed to exclude a minor effect of the PPARγ2 12Ala allele on necroinflammation/fibrosis in NAFLD.

  5. Association of vitamin D receptor BsmI, TaqI, FokI, and ApaI polymorphisms with susceptibility of chronic periodontitis: A systematic review and meta-analysis based on 38 case -control studies.

    Science.gov (United States)

    Mashhadiabbas, Fatemeh; Neamatzadeh, Hossein; Nasiri, Rezvan; Foroughi, Elnaz; Farahnak, Soudabeh; Piroozmand, Parisa; Mazaheri, Mahta; Zare-Shehneh, Masoud

    2018-01-01

    There has been increasing interest in the study of the association between Vitamin D receptor (VDR) gene polymorphisms and risk of chronic periodontitis. However, the results remain inconclusive. To better understand the roles of VDR polymorphisms (BsmI, TaqI, FokI, and ApaI) in chronic periodontitis susceptibility, we conducted this systematic review and meta-analysis. The PubMed, Google Scholar, and Web of Science database were systemically searched to determine all the eligible studies about VDR polymorphisms and risk of chronic periodontitis up to April 2017. Odds ratio (OR) and 95% confidence interval (CI) were used to evaluate the associations between VDR polymorphisms and chronic periodontitis risk. All the statistical analyses were performed by Comprehensive Meta-Analysis. All P values were two-tailed with a significant level at 0.05. Finally, a total of 38 case-control studies in 19 publications were identified which met our inclusion criteria. There are ten studies with 866 chronic periodontitis cases and 786 controls for BsmI, 16 studies with 1570 chronic periodontitis cases and 1676 controls for TaqI, five studies with 374 chronic periodontitis cases and 382 controls for FokI, and seven studies with 632 chronic periodontitis cases and 604 controls for ApaI. Overall, no significant association was observed between VDR gene BsmI, TaqI, FokI, and ApaI polymorphisms and risk of chronic periodontitis in any genetic model. Subgroup analysis stratified by ethnicity suggested a significant association between BsmI polymorphism and chronic periodontitis risk in the Caucasian subgroup under allele model (A vs. G: OR = 1.747, 95% CI = 1.099-2.778, P = 0.018). Further, no significant associations were observed when stratified by Hardy-Weinberg equilibrium status for BsmI, TaqI, and ApaI. Our results suggest that BsmI, TaqI, FokI, and ApaI polymorphisms in the VDR gene might not be associated with risk of chronic periodontitis in overall population.

  6. Beta adrenergic receptors in human cavernous tissue

    Energy Technology Data Exchange (ETDEWEB)

    Dhabuwala, C.B.; Ramakrishna, C.V.; Anderson, G.F.

    1985-04-01

    Beta adrenergic receptor binding was performed with /sup 125/I iodocyanopindolol on human cavernous tissue membrane fractions from normal tissue and transsexual procedures obtained postoperatively, as well as from postmortem sources. Isotherm binding studies on normal fresh tissues indicated that the receptor density was 9.1 fmoles/mg. with a KD of 23 pM. Tissue stored at room temperature for 4 to 6 hours, then at 4C in saline solution for 19 to 20 hours before freezing showed no significant changes in receptor density or affinity, and provided evidence for the stability of postmortem tissue obtained within the same time period. Beta receptor density of 2 cavernous preparations from transsexual procedures was not significantly different from normal control tissues, and showed that high concentrations of estrogen received by these patients had no effect on beta adrenergic receptor density. Displacement of /sup 125/iodocyanopindolol by 5 beta adrenergic agents demonstrated that 1-propranolol had the greatest affinity followed by ICI 118,551, zinterol, metoprolol and practolol. When the results of these displacement studies were subjected to Scatfit, non- linear regression line analysis, a single binding site was described. Based on the relative potency of the selective beta adrenergic agents it appears that these receptors were of the beta 2 subtype.

  7. Targeting the TAM Receptors in Leukemia.

    Science.gov (United States)

    Huey, Madeline G; Minson, Katherine A; Earp, H Shelton; DeRyckere, Deborah; Graham, Douglas K

    2016-11-08

    Targeted inhibition of members of the TAM (TYRO-3, AXL, MERTK) family of receptor tyrosine kinases has recently been investigated as a novel strategy for treatment of hematologic malignancies. The physiologic functions of the TAM receptors in innate immune control, natural killer (NK) cell differentiation, efferocytosis, clearance of apoptotic debris, and hemostasis have previously been described and more recent data implicate TAM kinases as important regulators of erythropoiesis and megakaryopoiesis. The TAM receptors are aberrantly or ectopically expressed in many hematologic malignancies including acute myeloid leukemia, B- and T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and multiple myeloma. TAM receptors contribute to leukemic phenotypes through activation of pro-survival signaling pathways and interplay with other oncogenic proteins such as FLT3, LYN, and FGFR3. The TAM receptors also contribute to resistance to both cytotoxic chemotherapeutics and targeted agents, making them attractive therapeutic targets. A number of translational strategies for TAM inhibition are in development, including small molecule inhibitors, ligand traps, and monoclonal antibodies. Emerging areas of research include modulation of TAM receptors to enhance anti-tumor immunity, potential roles for TYRO-3 in leukemogenesis, and the function of the bone marrow microenvironment in mediating resistance to TAM inhibition.

  8. Targeting the TAM Receptors in Leukemia

    Directory of Open Access Journals (Sweden)

    Madeline G. Huey

    2016-11-01

    Full Text Available Targeted inhibition of members of the TAM (TYRO-3, AXL, MERTK family of receptor tyrosine kinases has recently been investigated as a novel strategy for treatment of hematologic malignancies. The physiologic functions of the TAM receptors in innate immune control, natural killer (NK cell differentiation, efferocytosis, clearance of apoptotic debris, and hemostasis have previously been described and more recent data implicate TAM kinases as important regulators of erythropoiesis and megakaryopoiesis. The TAM receptors are aberrantly or ectopically expressed in many hematologic malignancies including acute myeloid leukemia, B- and T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and multiple myeloma. TAM receptors contribute to leukemic phenotypes through activation of pro-survival signaling pathways and interplay with other oncogenic proteins such as FLT3, LYN, and FGFR3. The TAM receptors also contribute to resistance to both cytotoxic chemotherapeutics and targeted agents, making them attractive therapeutic targets. A number of translational strategies for TAM inhibition are in development, including small molecule inhibitors, ligand traps, and monoclonal antibodies. Emerging areas of research include modulation of TAM receptors to enhance anti-tumor immunity, potential roles for TYRO-3 in leukemogenesis, and the function of the bone marrow microenvironment in mediating resistance to TAM inhibition.

  9. Serotonin Receptors in Hippocampus

    Science.gov (United States)

    Berumen, Laura Cristina; Rodríguez, Angelina; Miledi, Ricardo; García-Alcocer, Guadalupe

    2012-01-01

    Serotonin is an ancient molecular signal and a recognized neurotransmitter brainwide distributed with particular presence in hippocampus. Almost all serotonin receptor subtypes are expressed in hippocampus, which implicates an intricate modulating system, considering that they can be localized as autosynaptic, presynaptic, and postsynaptic receptors, even colocalized within the same cell and being target of homo- and heterodimerization. Neurons and glia, including immune cells, integrate a functional network that uses several serotonin receptors to regulate their roles in this particular part of the limbic system. PMID:22629209

  10. Evolutionary history of the somatostatin and somatostatin receptors

    Indian Academy of Sciences (India)

    Somatostatin and its receptors have a critical role in mammalian growth through their control pattern of secretion of growth hormone, but the evolutionary history of somatostatin and somatostatin receptors are ill defined. We used comparative whole genome analysis of Danio rerio, Carassius auratus, Xenopus tropicalis, ...

  11. Comparison between paricalcitol and active non-selective vitamin D receptor activator for secondary hyperparathyroidism in chronic kidney disease: a systematic review and meta-analysis of randomized controlled trials.

    Science.gov (United States)

    Cai, Panpan; Tang, Xiaohong; Qin, Wei; Ji, Ling; Li, Zi

    2016-04-01

    The goal of this systematic review is to evaluate the efficacy and safety of paricalcitol versus active non-selective vitamin D receptor activators (VDRAs) for secondary hyperparathyroidism (SHPT) management in chronic kidney disease (CKD) patients. PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), clinicaltrials.gov (inception to September 2015), and ASN Web site were searched for relevant studies. A meta-analysis of randomized controlled trials (RCTs) and quasi-RCTs that assessed the effects and adverse events of paricalcitol and active non-selective VDRA in adult CKD patients with SHPT was performed using Review Manager 5.2. A total of 10 trials involving 734 patients were identified for this review. The quality of included trials was limited, and very few trials reported all-cause mortality or cardiovascular calcification without any differences between two groups. Compared with active non-selective VDRAs, paricalcitol showed no significant difference in both PTH reduction (MD -7.78, 95% CI -28.59-13.03, P = 0.46) and the proportion of patients who achieved the target reduction of PTH (OR 1.27, 95% CI 0.87-1.85, P = 0.22). In addition, no statistical differences were found in terms of serum calcium, episodes of hypercalcemia, serum phosphorus, calcium × phosphorus products, and bone metabolism index. Current evidence is insufficient, showing paricalcitol is superior to active non-selective VDRAs in lowering PTH or reducing the burden of mineral loading. Further trials are required to prove the tissue-selective effect of paricalcitol and to overcome the limitation of current research.

  12. Control of leptin by metabolic state and its regulatory interactions with pituitary growth hormone and hepatic growth hormone receptors and insulin like growth factors in the tilapia (Oreochromis mossambicus).

    Science.gov (United States)

    Douros, Jonathan D; Baltzegar, David A; Mankiewicz, Jamie; Taylor, Jordan; Yamaguchi, Yoko; Lerner, Darren T; Seale, Andre P; Grau, E Gordon; Breves, Jason P; Borski, Russell J

    2017-01-01

    Leptin is an important cytokine for regulating energy homeostasis, however, relatively little is known about its function and control in teleost fishes or other ectotherms, particularly with regard to interactions with the growth hormone (GH)/insulin-like growth factors (IGFs) growth regulatory axis. Here we assessed the regulation of LepA, the dominant paralog in tilapia (Oreochromis mossambicus) and other teleosts under altered nutritional state, and evaluated how LepA might alter pituitary growth hormone (GH) and hepatic insulin-like growth factors (IGFs) that are known to be disparately regulated by metabolic state. Circulating LepA, and lepa and lepr gene expression increased after 3-weeks fasting and declined to control levels 10days following refeeding. This pattern of leptin regulation by metabolic state is similar to that previously observed for pituitary GH and opposite that of hepatic GHR and/or IGF dynamics in tilapia and other fishes. We therefore evaluated if LepA might differentially regulate pituitary GH, and hepatic GH receptors (GHRs) and IGFs. Recombinant tilapia LepA (rtLepA) increased hepatic gene expression of igf-1, igf-2, ghr-1, and ghr-2 from isolated hepatocytes following 24h incubation. Intraperitoneal rtLepA injection, on the other hand, stimulated hepatic igf-1, but had little effect on hepatic igf-2, ghr1, or ghr2 mRNA abundance. LepA suppressed GH accumulation and gh mRNA in pituitaries in vitro, but had no effect on GH release. We next sought to test if abolition of pituitary GH via hypophysectomy (Hx) affects the expression of hepatic lepa and lepr. Hypophysectomy significantly increases hepatic lepa mRNA abundance, while GH replacement in Hx fish restores lepa mRNA levels to that of sham controls. Leptin receptor (lepr) mRNA was unchanged by Hx. In in vitro hepatocyte incubations, GH inhibits lepa and lepr mRNA expression at low concentrations, while higher concentration stimulates lepa expression. Taken together, these findings

  13. Erythropoietin receptor signaling is membrane raft dependent

    NARCIS (Netherlands)

    K.L. McGraw (Kathy); G.M. Fuhler (Gwenny); J.O. Johnson (Joseph); J.A. Clark (Justine); G.C. Caceres (Gisela); L. Sokol (Lubomir); A.F. List (Alan)

    2012-01-01

    textabstractUpon erythropoietin (Epo) engagement, Epo-receptor (R) homodimerizes to activate JAK2 and Lyn, which phosphorylate STAT5. Although recent investigations have identified key negative regulators of Epo-R signaling, little is known about the role of membrane localization in controlling

  14. The CCK(-like) receptor in the animal kingdom: functions, evolution and structures.

    Science.gov (United States)

    Staljanssens, Dorien; Azari, Elnaz Karimian; Christiaens, Olivier; Beaufays, Jérôme; Lins, Laurence; Van Camp, John; Smagghe, Guy

    2011-03-01

    In this review, the cholecystokinin (CCK)(-like) receptors throughout the animal kingdom are compared on the level of physiological functions, evolutionary basis and molecular structure. In vertebrates, the CCK receptor is an important member of the G-protein coupled receptors as it is involved in the regulation of many physiological functions like satiety, gastrointestinal motility, gastric acid secretion, gall bladder contraction, pancreatic secretion, panic, anxiety and memory and learning processes. A homolog for this receptor is also found in nematodes and arthropods, called CK receptor and sulfakinin (SK) receptor, respectively. These receptors seem to have evolved from a common ancestor which is probably still closely related to the nematode CK receptor. The SK receptor is more closely related to the CCK receptor and seems to have similar functions. A molecular 3D-model for the CCK receptor type 1 has been built together with the docking of the natural ligands for the CCK and SK receptors in the CCK receptor type 1. These molecular models can help to study ligand-receptor interactions, that can in turn be useful in the development of new CCK(-like) receptor agonists and antagonists with beneficial health effects in humans or potential for pest control. Copyright © 2010 Elsevier Inc. All rights reserved.

  15. Purinergic receptors expressed in human skeletal muscle fibres

    DEFF Research Database (Denmark)

    Bornø, A; Ploug, Thorkil; Bune, L T

    2012-01-01

    distribution of purinergic receptors in skeletal muscle fibres. We speculate that the intracellular localization of purinergic receptors may reflect a role in regulation of muscle metabolism; further studies are nevertheless needed to determine the function of the purinergic system in skeletal muscle cells.......Purinergic receptors are present in most tissues and thought to be involved in various signalling pathways, including neural signalling, cell metabolism and local regulation of the microcirculation in skeletal muscles. The present study aims to determine the distribution and intracellular content...... of purinergic receptors in skeletal muscle fibres in patients with type 2 diabetes and age-matched controls. Muscle biopsies from vastus lateralis were obtained from six type 2 diabetic patients and seven age-matched controls. Purinergic receptors were analysed using light and confocal microscopy...

  16. Nuclear receptors in control of cholesterol transport

    NARCIS (Netherlands)

    van der Veen, Jelske Nynke

    2007-01-01

    Cholesterol is een structurele component van celmembranen en een grondstof voor de aanmaak van steroïde hormonen en galzouten en vervult dus een aantal essentiële fysiologische functies. Een goede balans van cholesterol opname, synthese, afbraak en uitscheiding is noodzakelijk, omdat verhoogde

  17. Dark chocolate receptors: epicatechin-induced cardiac protection is dependent on delta-opioid receptor stimulation.

    Science.gov (United States)

    Panneerselvam, Mathivadhani; Tsutsumi, Yasuo M; Bonds, Jacqueline A; Horikawa, Yousuke T; Saldana, Michelle; Dalton, Nancy D; Head, Brian P; Patel, Piyush M; Roth, David M; Patel, Hemal H

    2010-11-01

    Epicatechin, a flavonoid, is a well-known antioxidant linked to a variety of protective effects in both humans and animals. In particular, its role in protection against cardiovascular disease has been demonstrated by epidemiologic studies. Low-dose epicatechin, which does not have significant antioxidant activity, is also protective; however, the mechanism by which low-dose epicatechin induces this effect is unknown. Our laboratory tested the hypothesis that low-dose epicatechin mediates cardiac protection via opioid receptor activation. C57BL/6 mice were randomly assigned to 1 of 10 groups: control, epicatechin, naloxone (nonselective opioid receptor antagonist), epicatechin + naloxone, naltrindole (δ-specific opioid receptor antagonist), epicatechin + naltrindole, norbinaltorphimine (nor-BNI, κ-specific opioid receptor antagonist), epicatechin + nor-BNI, 5-hydroxydecanoic acid [5-HD, ATP-sensitive potassium channel antagonist], and epicatechin + 5-HD. Epicatechin (1 mg/kg) or other inhibitors (5 mg/kg) were administered by oral gavage or intraperitoneal injection, respectively, daily for 10 days. Mice were subjected to 30 min coronary artery occlusion followed by 2 h of reperfusion, and infarct size was determined via planimetry. Whole heart homogenates were assayed for downstream opioid receptor signaling targets. Infarct size was significantly reduced in epicatechin- and epicatechin + nor-BNI-treated mice compared with control mice. This protection was blocked by naloxone, naltrindole, and 5-HD. Epicatechin and epicatechin + nor-BNI increased the phosphorylation of Src, Akt, and IκBα, while simultaneously decreasing the expression of c-Jun NH(2)-terminal kinase and caspase-activated DNase. All signaling effects are consistent with opioid receptor stimulation and subsequent cardiac protection. Naloxone, naltrindole, and 5-HD attenuated these effects. In conclusion, epicatechin acts via opioid receptors and more specifically through the δ-opioid receptor to

  18. Epidermal Growth Factor Receptor Mutation Is Associated With Longer Local Control After Definitive Chemoradiotherapy in Patients With Stage III Nonsquamous Non–Small-Cell Lung Cancer

    International Nuclear Information System (INIS)

    Yagishita, Shigehiro; Horinouchi, Hidehito; Katsui Taniyama, Tomoko; Nakamichi, Shinji; Kitazono, Satoru; Mizugaki, Hidenori; Kanda, Shintaro; Fujiwara, Yutaka; Nokihara, Hiroshi; Yamamoto, Noboru; Sumi, Minako; Shiraishi, Kouya; Kohno, Takashi; Furuta, Koh; Tsuta, Koji; Tamura, Tomohide

    2015-01-01

    Purpose: To determine the frequency and clinical significance of epidermal growth factor receptor (EGFR) mutations in patients with potentially curable stage III non–small-cell lung cancer (NSCLC) who are eligible for definitive chemoradiotherapy (CRT). Patients and Methods: Between January 2001 and December 2010, we analyzed the EGFR mutational status in consecutive NSCLC patients who were treated by CRT. The response rate, relapse-free survival, 2-year relapse-free rate, initial relapse sites, and overall survival of the patients were investigated. Results: A total of 528 patients received CRT at our hospital during the study period. Of these, 274 were diagnosed as having nonsquamous NSCLC. Sufficient specimens for mutational analyses could be obtained from 198 of these patients. The proportion of patients with EGFR activating mutations was 17%. In addition to the well-known characteristics of patients carrying EGFR mutations (female, adenocarcinoma, and never/light smoker), the proportion of cases with smaller primary lesions (T1/2) was found to be higher in patients with EGFR mutations than in those with wild-type EGFR. Patients with EGFR mutations showed similar response rate, relapse-free survival, and 2-year relapse-free rates as compared to patients with wild-type EGFR. Local relapses as the site of initial relapse occurred significantly less frequently in patients with EGFR mutation (4% vs 21%; P=.045). Patients with EGFR mutations showed longer local control (adjusted hazard ratio 0.49; P=.043). After disease progression, a majority of the patients with EGFR mutations received EGFR tyrosine kinase inhibitors (62%), and these patients showed longer postprogression survival than those with wild-type EGFR. Conclusions: Our study is the first to show radiosensitive biology of EGFR-mutated tumors in definitive CRT with curative intent. This finding could serve as a credible baseline estimate of EGFR-mutated population in stage III nonsquamous NSCLC

  19. Design and rationale of a prospective, collaborative meta-analysis of all randomized controlled trials of angiotensin receptor antagonists in Marfan syndrome, based on individual patient data: A report from the Marfan Treatment Trialists' Collaboration

    Science.gov (United States)

    Pitcher, Alex; Emberson, Jonathan; Lacro, Ronald V.; Sleeper, Lynn A.; Stylianou, Mario; Mahony, Lynn; Pearson, Gail D.; Groenink, Maarten; Mulder, Barbara J.; Zwinderman, Aeilko H.; De Backer, Julie; De Paepe, Anne M.; Arbustini, Eloisa; Erdem, Guliz; Jin, Xu Yu; Flather, Marcus D.; Mullen, Michael J.; Child, Anne H.; Forteza, Alberto; Evangelista, Arturo; Chiu, Hsin-Hui; Wu, Mei-Hwan; Sandor, George; Bhatt, Ami B.; Creager, Mark A.; Devereux, Richard B.; Loeys, Bart; Forfar, J. Colin; Neubauer, Stefan; Watkins, Hugh; Boileau, Catherine; Jondeau, Guillaume; Dietz, Harry C.; Baigent, Colin

    2015-01-01

    Rationale A number of randomized trials are underway, which will address the effects of angiotensin receptor blockers (ARBs) on aortic root enlargement and a range of other end points in patients with Marfan syndrome. If individual participant data from these trials were to be combined, a meta-analysis of the resulting data, totaling approximately 2,300 patients, would allow estimation across a number of trials of the treatment effects both of ARB therapy and of β-blockade. Such an analysis would also allow estimation of treatment effects in particular subgroups of patients on a range of end points of interest and would allow a more powerful estimate of the effects of these treatments on a composite end point of several clinical outcomes than would be available from any individual trial. Design A prospective, collaborative meta-analysis based on individual patient data from all randomized trials in Marfan syndrome of (i) ARBs versus placebo (or open-label control) and (ii) ARBs versus β-blockers will be performed. A prospective study design, in which the principal hypotheses, trial eligibility criteria, analyses, and methods are specified in advance of the unblinding of the component trials, will help to limit bias owing to data-dependent emphasis on the results of particular trials. The use of individual patient data will allow for analysis of the effects of ARBs in particular patient subgroups and for time-to-event analysis for clinical outcomes. The meta-analysis protocol summarized in this report was written on behalf of the Marfan Treatment Trialists' Collaboration and finalized in late 2012, without foreknowledge of the results of any component trial, and will be made available online (http://www.ctsu.ox.ac.uk/research/meta-trials). PMID:25965707

  20. Epidermal Growth Factor Receptor Mutation Is Associated With Longer Local Control After Definitive Chemoradiotherapy in Patients With Stage III Nonsquamous Non–Small-Cell Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Yagishita, Shigehiro [Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo (Japan); Horinouchi, Hidehito, E-mail: hhorinou@ncc.go.jp [Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo (Japan); Katsui Taniyama, Tomoko; Nakamichi, Shinji; Kitazono, Satoru; Mizugaki, Hidenori; Kanda, Shintaro; Fujiwara, Yutaka; Nokihara, Hiroshi; Yamamoto, Noboru [Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo (Japan); Sumi, Minako [Department of Radiation Oncology, National Cancer Center Hospital, Tokyo (Japan); Shiraishi, Kouya; Kohno, Takashi [Division of Genome Biology, National Cancer Center Research Institute, Tokyo (Japan); Furuta, Koh [Department of Clinical Laboratories, National Cancer Center Hospital, Tokyo (Japan); Tsuta, Koji [Department of Pathology, National Cancer Center Hospital, Tokyo (Japan); Tamura, Tomohide [Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo (Japan)

    2015-01-01

    Purpose: To determine the frequency and clinical significance of epidermal growth factor receptor (EGFR) mutations in patients with potentially curable stage III non–small-cell lung cancer (NSCLC) who are eligible for definitive chemoradiotherapy (CRT). Patients and Methods: Between January 2001 and December 2010, we analyzed the EGFR mutational status in consecutive NSCLC patients who were treated by CRT. The response rate, relapse-free survival, 2-year relapse-free rate, initial relapse sites, and overall survival of the patients were investigated. Results: A total of 528 patients received CRT at our hospital during the study period. Of these, 274 were diagnosed as having nonsquamous NSCLC. Sufficient specimens for mutational analyses could be obtained from 198 of these patients. The proportion of patients with EGFR activating mutations was 17%. In addition to the well-known characteristics of patients carrying EGFR mutations (female, adenocarcinoma, and never/light smoker), the proportion of cases with smaller primary lesions (T1/2) was found to be higher in patients with EGFR mutations than in those with wild-type EGFR. Patients with EGFR mutations showed similar response rate, relapse-free survival, and 2-year relapse-free rates as compared to patients with wild-type EGFR. Local relapses as the site of initial relapse occurred significantly less frequently in patients with EGFR mutation (4% vs 21%; P=.045). Patients with EGFR mutations showed longer local control (adjusted hazard ratio 0.49; P=.043). After disease progression, a majority of the patients with EGFR mutations received EGFR tyrosine kinase inhibitors (62%), and these patients showed longer postprogression survival than those with wild-type EGFR. Conclusions: Our study is the first to show radiosensitive biology of EGFR-mutated tumors in definitive CRT with curative intent. This finding could serve as a credible baseline estimate of EGFR-mutated population in stage III nonsquamous NSCLC.

  1. BsmI, ApaI and TaqI Polymorphisms in the Vitamin D Receptor Gene (VDR and Association with Lumbar Spine Pathologies: An Italian Case-Control Study.

    Directory of Open Access Journals (Sweden)

    Alessandra Colombini

    Full Text Available Three adjacent single nucleotide polymorphisms of the vitamin D receptor gene (VDR BsmI (rs1544410, ApaI (rs7975232, and TaqI (rs731236 are commonly studied in several pathologies. We aimed to evaluate the distribution of VDR BsmI, ApaI, and TaqI allele, genotype, and haplotype frequencies in an Italian cohort of 266 patients with lumbar spine disorders assessed by Magnetic Resonance Imaging and 252 asymptomatic controls. The exposure to putative risk factors was evaluated by a questionnaire. Polymorphisms were detected by PCR-RFLP and TaqMan® SNP Genotyping Assay. The results were statistically adjusted for the identified conventional risk factors. The three SNPs were in linkage disequilibrium. For all cases BbAaTT was a 3-fold risk factor OR = 3.38, whereas bbAATT (OR = 0.22, and bbaaTT (OR = 0.47 genotypes were found to be protective. Specifically, for patients affected by disc herniation only (n = 88 and all lumbar pathologies excluding stenosis and/or spondylolistesis (n = 215 B allele, Bb, Aa, and BbAaTT genotypes were risky, whereas b allele, bb, aa, and bbaaTT genotypes were protective. In patients affected by osteochondrosis with or without disc hernation (n = 50, T allele, Aa, and bbAaTT genotypes were risky, whereas t allele, AA, tt genotypes were protective. In patients affected by stenosis and/or spondylolistesis (n = 51 no significant associations were found. This is the first study showing an association of the three genetic VDR variants BsmI, ApaI, and TaqI and lumbar spine pathologies. Our study contributes to delineate genetic risk factors for specific subgroups of patients with lumbar spine pathologies highlighting the importance of haplotype analysis, and of detailed clinical evaluation of the patients for identification of genetic biomarkers.

  2. A preliminary study measuring the number of T-cell receptor-rearrangement excision circles (TRECs) in peripheral blood T-cell populations of A-bomb survivors and control populations

    International Nuclear Information System (INIS)

    Kubo, Yoshiko; Yamaoka, Mika; Kusunoki, Yoichiro

    2006-01-01

    More than a half century after damage of the immune systems by the radiation from A-bomb, we can still observe significant decreases in the percentages of naieve CD4 and CD8 T cells among the survivors. To investigate whether the observed decreases in the naieve T-cell populations may have resulted from reduction in thymic T-cell production ability of survivors, we established a real-time polymerase chain reaction (PCR) method to examine the number of T-cell receptor-rearrangement excision circles (TRECs) in peripheral blood CD4 and CD8 T-cell populations. The real-time PCR quantitatively detected TREC sequences with a good reproducibility in human laboratory controls. In the 445 survivors so far been examined, multiple regression analysis indicated that the number of TRECs in the CD4 T-cell fraction was significantly higher in females than in males and decreased significantly with age in both males and females. This analysis also suggested a possible dose-dependent decrease in the number of TRECs in the CD4 T-cell fraction of the survivors who were less than 20 years of age at the time of bombing (p=0.09). A similar statistically significant trend for gender difference or age was observed in the CD8 T-cell fraction of the survivors. However, there was no effect of radiation exposure on the number of TRECs in the CD8-T cell fraction. The results indicate the possibility that A-bomb radiation exposure may have induced a long-term impairment in thymic CD4 T-cell production. Further investigations in a larger study population are necessary to test this hypothesis. (author)

  3. Inhibitors for Androgen Receptor Activation Surfaces

    Science.gov (United States)

    2007-09-01

    times and the electron-rich iodine groups of Triac representing particularly good markers. Control soaks with solvent ( DMSO ) reveal no similar...electron-rich iodine groups of Triac represent particu- larly good markers. Control soaks with solvent ( DMSO ) reveal no similar effects on coregulator...3-(dibutylamino)-1-(4-hexylphenyl)propan-1-one DMSO , dimethylsulfoxide DTT, dithiothreitol ER, estrogen receptor GST, glutathione S-transferase

  4. Cell surface receptors for signal transduction and ligand transport: a design principles study.

    Directory of Open Access Journals (Sweden)

    Harish Shankaran

    2007-06-01

    Full Text Available Receptors constitute the interface of cells to their external environment. These molecules bind specific ligands involved in multiple processes, such as signal transduction and nutrient transport. Although a variety of cell surface receptors undergo endocytosis, the systems-level design principles that govern the evolution of receptor trafficking dynamics are far from fully understood. We have constructed a generalized mathematical model of receptor-ligand binding and internalization to understand how receptor internalization dynamics encodes receptor function and regulation. A given signaling or transport receptor system represents a particular implementation of this module with a specific set of kinetic parameters. Parametric analysis of the response of receptor systems to ligand inputs reveals that receptor systems can be characterized as being: i avidity-controlled where the response control depends primarily on the extracellular ligand capture efficiency, ii consumption-controlled where the ability to internalize surface-bound ligand is the primary control parameter, and iii dual-sensitivity where both the avidity and consumption parameters are important. We show that the transferrin and low-density lipoprotein receptors are avidity-controlled, the vitellogenin receptor is consumption-controlled, and the epidermal growth factor receptor is a dual-sensitivity receptor. Significantly, we show that ligand-induced endocytosis is a mechanism to enhance the accuracy of signaling receptors rather than merely serving to attenuate signaling. Our analysis reveals that the location of a receptor system in the avidity-consumption parameter space can be used to understand both its function and its regulation.

  5. Ionotropic crustacean olfactory receptors.

    Directory of Open Access Journals (Sweden)

    Elizabeth A Corey

    Full Text Available The nature of the olfactory receptor in crustaceans, a major group of arthropods, has remained elusive. We report that spiny lobsters, Panulirus argus, express ionotropic receptors (IRs, the insect chemosensory variants of ionotropic glutamate receptors. Unlike insects IRs, which are expressed in a specific subset of olfactory cells, two lobster IR subunits are expressed in most, if not all, lobster olfactory receptor neurons (ORNs, as confirmed by antibody labeling and in situ hybridization. Ligand-specific ORN responses visualized by calcium imaging are consistent with a restricted expression pattern found for other potential subunits, suggesting that cell-specific expression of uncommon IR subunits determines the ligand sensitivity of individual cells. IRs are the only type of olfactory receptor that we have detected in spiny lobster olfactory tissue, suggesting that they likely mediate olfactory signaling. Given long-standing evidence for G protein-mediated signaling in activation of lobster ORNs, this finding raises the interesting specter that IRs act in concert with second messenger-mediated signaling.

  6. Semiotic Selection of Mutated or Misfolded Receptor Proteins

    DEFF Research Database (Denmark)

    Giorgi, Franco; Bruni, Luis Emilio; Maggio, Roberto

    2013-01-01

    contention that the plasma membrane acts as the locus where several contextual cues may be integrated. As such it allows the semiotic selection of those receptor configurations that provide cells with the minimum essential requirements for agency. The occurrence of protein misfolding makes it impossible...... focused on the significance and semiotic nature of the interplay between membrane receptors and the epigenetic control of gene expression, as mediated by the control of mismatched repairing and protein folding mechanisms....

  7. Muscarinic receptor compensation in hippocampus of alzheimer patients. [Autoradiography

    Energy Technology Data Exchange (ETDEWEB)

    Nordberg, A; Larsson, C; Adolfsson, R; Alafuzoff, I; Winblad, B [Uppsala Univ. (Sweden)

    1983-01-01

    The activity of the acetylcholine synthesizing enzyme choline acetyltransferase (ChAT) (presynaptic marker) and number of muscarine-like receptor binding sites have been measured in the hippocampus from eight individuals with senile dementia of Alzheimer type (SDAT) and ten controls. A negative correlation (r=0.80; p<0.05) was found between the ChAT activity and the number of muscarine-like receptors in the SDAT group but not in the controls. The findings might indicate an ongoing compensatory receptor mechanism as a response to changes in presynaptic cholinergic activity.

  8. The Efficacy of Single-Agent Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy in Biologically Selected Patients with Non-Small-Cell Lung Cancer: A Meta-Analysis of 19 Randomized Controlled Trials.

    Science.gov (United States)

    Li, Guifang; Gao, Shunji; Sheng, Zhixin; Li, Bin

    2016-01-01

    To determine the efficacy of first-generation single-agent epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy in advanced non-small-cell lung cancer patients with known EGFR mutation status, we undertook this pooled analysis. We searched for randomized controlled trials (RCTs) in Medline, Embase, the Cochrane Controlled Trials Register, the Science Citation Index, and the American Society of Clinical Oncology annual meetings. Out of 2,129 retrieved articles, 19 RCTs enrolling 2,016 patients with wild-type EGFR tumors and 1,034 patients with mutant EGFR tumors were identified. For these EGFR mutant patients, single-agent EGFR-TKI therapy improved progression-free survival (PFS) over chemotherapy: the summary hazard ratios (HRs) were 0.41 (p well as chemotherapy in the first-line setting (HR = 1.65, p = 0.03) and in the second-/third-line setting (HR = 1.27, p = 0.006). No statistically significant difference was observed in terms of overall survival (OS). Using platinum-based doublet chemotherapy as a common comparator, indirect comparison showed the superior efficacy of single-agent EGFR-TKI therapy over EGFR-TKIs added to chemotherapy in PFS [HR = 1.35 (1.03, 1.77), p = 0.03]. Additionally, a marginal trend towards the same direction was found in the OS analysis [HR = 1.16 (0.99, 1.35), p = 0.06]. Interestingly, for those EGFR wild-type tumors, single-agent EGFR-TKI therapy was inferior to EGFR-TKIs added to chemotherapy in PFS [HR = 0.38 (0.33, 0.44), p chemotherapy. However, single-agent EGFR-TKI therapy was inferior to chemotherapy in PFS for those EGFR wild-type patients. Single-agent EGFR-TKI therapy could improve PFS over the combination of EGFR-TKIs and chemotherapy in these EGFR mutant patients. However, EGFR-TKIs combined with chemotherapy could provide additive PFS and OS benefit over single-agent EGFR-TKI therapy in those EGFR wild-type patients. © 2016 S. Karger AG, Basel.

  9. Molecular alteration of a muscarinic acetylcholine receptor system during synaptogenesis

    International Nuclear Information System (INIS)

    Large, T.H.; Cho, N.J.; De Mello, F.G.; Klein, W.L.

    1985-01-01

    Biochemical properties of the muscarinic acetylcholine receptor system of the avian retina were found to change during the period when synapses form in ovo. Comparison of ligand binding to membranes obtained before and after synaptogenesis showed a significant increase in the affinity, but not proportion, of the high affinity agonist-binding state. There was no change in receptor sensitivity to antagonists during this period. Pirenzepine binding, which can discriminate muscarinic receptor subtypes, showed the presence of a single population of low affinity sites (M2) before and after synaptogenesis. The change in agonist binding was not due to the late development of receptor function. However, detergent-solubilization of membranes eliminated differences in agonist binding between receptors from embryos and hatched chicks, suggesting a developmental change in interactions of the receptor with functionally related membrane components. A possible basis for altered interactions was obtained from isoelectric point data showing that the muscarinic receptor population underwent a transition from a predominantly low pI form (4.25) in 13 day embryos to a predominantly high pI form (4.50) in newly hatched chicks. The possibility that biochemical changes in the muscarinic receptor play a role in differentiation of the system by controlling receptor position on the surface of nerve cells is discussed

  10. NR4A nuclear receptors are orphans but not lonesome.

    Science.gov (United States)

    Kurakula, Kondababu; Koenis, Duco S; van Tiel, Claudia M; de Vries, Carlie J M

    2014-11-01

    The NR4A subfamily of nuclear receptors consists of three mammalian members: Nur77, Nurr1, and NOR-1. The NR4A receptors are involved in essential physiological processes such as adaptive and innate immune cell differentiation, metabolism and brain function. They act as transcription factors that directly modulate gene expression, but can also form trans-repressive complexes with other transcription factors. In contrast to steroid hormone nuclear receptors such as the estrogen receptor or the glucocorticoid receptor, no ligands have been described for the NR4A receptors. This lack of known ligands might be explained by the structure of the ligand-binding domain of NR4A receptors, which shows an active conformation and a ligand-binding pocket that is filled with bulky amino acid side-chains. Other mechanisms, such as transcriptional control, post-translational modifications and protein-protein interactions therefore seem to be more important in regulating the activity of the NR4A receptors. For Nur77, over 80 interacting proteins (the interactome) have been identified so far, and roughly half of these interactions has been studied in more detail. Although the NR4As show some overlap in interacting proteins, less information is available on the interactome of Nurr1 and NOR-1. Therefore, the present review will describe the current knowledge on the interactomes of all three NR4A nuclear receptors with emphasis on Nur77. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. [Effects of Electroacupunctrue Combined with Dietary Control on Peroxisome Proliferator-activa- ted Receptor-α, and Liver Fatty Acid-binding Protein Levels in Non-alcoholic Fatty Liver Disease Rats].

    Science.gov (United States)

    Zhang, Yi; Tang, Cheng-lin; Tian, Yuan; Yuan, Hai-zhou; Yang, Hui; Tang, Nian-zhen; Gao, Rui-qi; Cao, Jing

    2015-10-01

    To observe the effect of electroacupunctrue (EA) intervention or EA combined with dietary control on peroxisome proliferator-activated receptor (PPAR)-α, and liver fatty acid-binding protein (L-FABP) levels in non-alcoholic fatty liver disease (NAFLD) rats, so as to reveal its mechanism underlying improvement of NAFLD. Sixty SD male rats were randomly divided into common diet (control) group (n = 10) and high-fat diet group (n = 45). The NAFLD model was established by feeding the animals with high-fat forage (HFF, including cholesterol, sodium cholate, propylthiouracil, sucrose, lard and common forage) for 5 weeks. Forty NAFLD rats were then randomized into model, EA + HFF, low-fat forage (LFF) and EA+ LFF groups (n = 10 rats in each group). EA (4 Hz/20 Hz, 3 mA) was applied to ipsilateral "Zusanli" (ST 36),"Sanyinjiao" (SP 6) and "Taichong" (LR 3) for 20 min, once daily for 4 weeks. The pathologic changes of the hepatic tissue were detected by H. E. staining. Serum total cholesterol (TC) and triglyceride (TG) contents were determined by using enzymatic methods, serum free fat acids (FFA) content was detected by colorimetry. The expression levels of PPAR-α and L-FABP protein and gene of the liver tissue were determined by Western blot and RT-PCR, respectively. H. E. staining showed that the hepatocytes presented moderate or severe bullous adipose degeneration in rats of the model group, vesicular steatosis in the EA + HFF and LFF groups, turned to almost normal but with small amount of lipid droplets in the EA + LFF group. The contents of serum TC, TG and FFA were significantly higher in the model group than in the control group (P < 0.05), and were obviously decreased in the EA + HFF, LFF and EA + LFF groups in comparison with the model group (P < 0.05). Compared to the control group, hepatic PPAR-α protein and mRNA were markedly down-regulated in the model group, and hepatic L-FABP protein and mRNA considerably up-regulated in the model group (P < 0

  12. Erythropoietin Receptor Signaling Is Membrane Raft Dependent

    Science.gov (United States)

    McGraw, Kathy L.; Fuhler, Gwenny M.; Johnson, Joseph O.; Clark, Justine A.; Caceres, Gisela C.; Sokol, Lubomir; List, Alan F.

    2012-01-01

    Upon erythropoietin (Epo) engagement, Epo-receptor (R) homodimerizes to activate JAK2 and Lyn, which phosphorylate STAT5. Although recent investigations have identified key negative regulators of Epo-R signaling, little is known about the role of membrane localization in controlling receptor signal fidelity. Here we show a critical role for membrane raft (MR) microdomains in creation of discrete signaling platforms essential for Epo-R signaling. Treatment of UT7 cells with Epo induced MR assembly and coalescence. Confocal microscopy showed that raft aggregates significantly increased after Epo stimulation (mean, 4.3±1.4(SE) vs. 25.6±3.2 aggregates/cell; p≤0.001), accompanied by a >3-fold increase in cluster size (p≤0.001). Raft fraction immunoblotting showed Epo-R translocation to MR after Epo stimulation and was confirmed by fluorescence microscopy in Epo stimulated UT7 cells and primary erythroid bursts. Receptor recruitment into MR was accompanied by incorporation of JAK2, Lyn, and STAT5 and their activated forms. Raft disruption by cholesterol depletion extinguished Epo induced Jak2, STAT5, Akt and MAPK phosphorylation in UT7 cells and erythroid progenitors. Furthermore, inhibition of the Rho GTPases Rac1 or RhoA blocked receptor recruitment into raft fractions, indicating a role for these GTPases in receptor trafficking. These data establish a critical role for MR in recruitment and assembly of Epo-R and signal intermediates into discrete membrane signaling units. PMID:22509308

  13. Efficacy and safety of once-weekly GLP-1 receptor agonist albiglutide (HARMONY 2): 52 week primary endpoint results from a randomised, placebo-controlled trial in patients with type 2 diabetes mellitus inadequately controlled with diet and exercise.

    Science.gov (United States)

    Nauck, Michael A; Stewart, Murray W; Perkins, Christopher; Jones-Leone, Angela; Yang, Fred; Perry, Caroline; Reinhardt, Rickey R; Rendell, Marc

    2016-02-01

    Additional safe and effective therapies for type 2 diabetes are needed, especially ones that do not cause weight gain and have a low risk of hypoglycaemia. The present study evaluated albiglutide as monotherapy. In this placebo-controlled study, 309 patients (aged ≥ 18 years) with type 2 diabetes inadequately controlled by diet and exercise and who were not using a glucose-lowering agent (HbA1c 7.0-10.0% [53.00-85.79 mmol/mol], body mass index 20-45 kg/m(2), and fasting C-peptide ≥ 0.26 nmol/l) were randomised (1:1:1 on a fixed randomisation schedule using an interactive voice response system) to receive once-weekly albiglutide 30 mg (n = 102) or 50 mg (n = 102) or matching placebo (n = 105). The study treatments were blinded to both patients and study personnel. All study data were collected at individual patient clinic visits. The primary efficacy endpoint was change in HbA1c from baseline to week 52. The primary analysis was applied to the intent-to-treat population. Additional efficacy and safety endpoints were assessed. At week 52, both albiglutide 30 mg and 50 mg were superior to placebo in reducing HbA1c. The least-squares means treatment difference from placebo was -0.84% (95% CI -1.11%, -0.58%; p < 0.0001) with albiglutide 30 mg and -1.04% (-1.31%, -0.77%; p < 0.0001) with albiglutide 50 mg. Injection-site reactions were reported more frequently with albiglutide (30 mg: 17.8%; 50 mg: 22.2%) than with placebo (9.9%). Other commonly reported adverse events included nausea, diarrhoea, vomiting and hypoglycaemia; the incidences of these were generally similar across treatment groups. Albiglutide is safe and effective as monotherapy and significantly lowered HbA1c levels over 52 weeks, did not cause weight gain, and had good gastrointestinal tolerability and a low rate of hypoglycaemia compared with placebo. Trial registration ClinicalTrials.gov NCT00849017 Funding This study was sponsored by GlaxoSmithKline.

  14. HBA1C CONTROL AND COST-EFFECTIVENESS IN PATIENTS WITH TYPE 2 DIABETES MELLITUS INITIATED ON CANAGLIFLOZIN OR A GLUCAGON-LIKE PEPTIDE 1 RECEPTOR AGONIST IN A REAL-WORLD SETTING.

    Science.gov (United States)

    Wysham, Carol H; Pilon, Dominic; Ingham, Mike; Lafeuille, Marie-Hélène; Emond, Bruno; Kamstra, Rhiannon; Pfeifer, Michael; Lefebvre, Patrick

    2018-03-01

    To compare glycated hemoglobin (HbA1c) control and medication costs between patients with type 2 diabetes mellitus (T2DM) treated with canagliflozin 300 mg (CANA) or a glucagon-like peptide 1 receptor agonist (GLP-1 RA) in a real-world setting. Adults with T2DM newly initiated on CANA or a GLP-1 RA (index date) were identified from IQVIA ™ Real-World Data Electronic Medical Records U.S. database (March 29, 2012-April 30, 2016). Inverse probability of treatment weighting accounted for differences in baseline characteristics. HbA1c levels at 3-month intervals were compared using generalized estimating equations. Medication costs used wholesale acquisition costs. For both cohorts (CANA: n = 11,435; GLP-1 RA: n = 11,582), HbA1c levels decreased at 3 months postindex and remained lower through 30 months. Absolute changes in mean HbA1c from index to 3 months postindex for CANA and GLP-1 RA were -1.16% and -1.21% (patients with baseline HbA1c ≥7% [53 mmol/mol]); -1.54% and -1.51% (patients with baseline HbA1c ≥8% [64 mmol/mol]); and -2.13% and -1.99% (patients with baseline HbA1c ≥9% [75 mmol/mol]), respectively. Postindex, CANA patients with baseline HbA1c ≥7% had similar HbA1c levels at each interval versus GLP-1 RA patients, except 9 months (mean HbA1c, 7.75% [61 mmol/mol] vs. 7.86% [62 mmol/mol]; P = .0305). CANA patients with baseline HbA1c ≥8% and ≥9% had consistently lower HbA1c numerically versus GLP-1 RA patients and statistically lower HbA1c at 9 (baseline HbA1c ≥8% or ≥9%), 27, and 30 months (baseline HbA1c ≥9%). Continuous 12-month medication cost $3,326 less for CANA versus GLP-1 RA. This retrospective study demonstrated a similar evolution of HbA1c levels among CANA and GLP-1 RA patients in a real-world setting. Lower medication costs suggest CANA is economically dominant over GLP-1 RA (similar effectiveness, lower cost). AHA = antihyperglycemic agent BMI = body mass index CANA = canagliflozin 300 mg DCSI = diabetes complications severity

  15. Assays for calcitonin receptors

    International Nuclear Information System (INIS)

    Teitelbaum, A.P.; Nissenson, R.A.; Arnaud, C.D.

    1985-01-01

    The assays for calcitonin receptors described focus on their use in the study of the well-established target organs for calcitonin, bone and kidney. The radioligand used in virtually all calcitonin binding studies is 125 I-labelled salmon calcitonin. The lack of methionine residues in this peptide permits the use of chloramine-T for the iodination reaction. Binding assays are described for intact bone, skeletal plasma membranes, renal plasma membranes, and primary kidney cell cultures of rats. Studies on calcitonin metabolism in laboratory animals and regulation of calcitonin receptors are reviewed

  16. Toll-like receptor 2 or toll-like receptor 4 deficiency does not modify lupus in MRLlpr mice.

    Directory of Open Access Journals (Sweden)

    Simon J Freeley

    Full Text Available Systemic lupus erythematosus is an autoimmune disease with a high morbidity and nephritis is a common manifestation. Previous studies in murine lupus models have suggest a role for Toll-like receptor 2 and 4. We examined the role of these molecules in MRL lpr mice which is one of the most established and robust murine models. We compared disease parameters in Toll-like receptor 2 or Toll-like receptor 4 deficient mice with their littermate controls. We found no difference in the severity of glomerulonephritis as assessed by histology, serum creatinine and albuminuria when Toll-like receptor 2 or Toll-like receptor 4 deficient MRLlpr mice were compared with Toll-like receptor sufficient controls. We also found similar levels of anti-dsDNA and anti-ssDNA antibodies. These results show that Toll-like receptor 2 and Toll-like receptor 4 do not play a significant role in MRLlpr mice, and therefore they may not be important in human lupus.

  17. Angiotensin type 2 receptor (AT2R) and receptor Mas

    DEFF Research Database (Denmark)

    Villela, Daniel; Leonhardt, Julia; Patel, Neal

    2015-01-01

    The angiotensin type 2 receptor (AT2R) and the receptor Mas are components of the protective arms of the renin-angiotensin system (RAS), i.e. they both mediate tissue protective and regenerative actions. The spectrum of actions of these two receptors and their signalling mechanisms display striki...

  18. Type I interferon production during herpes simplex virus infection is controlled by cell-type-specific viral recognition through Toll-like receptor 9, the mitochondrial antiviral signaling protein pathway, and novel recognition systems

    DEFF Research Database (Denmark)

    Rasmussen, Simon Brandtoft; Sørensen, Louise Nørgaard; Malmgaard, Lene

    2007-01-01

    Recognition of viruses by germ line-encoded pattern recognition receptors of the innate immune system is essential for rapid production of type I interferon (IFN) and early antiviral defense. We investigated the mechanisms of viral recognition governing production of type I IFN during herpes...... simplex virus (HSV) infection. We show that early production of IFN in vivo is mediated through Toll-like receptor 9 (TLR9) and plasmacytoid dendritic cells, whereas the subsequent alpha/beta IFN (IFN-alpha/beta) response is derived from several cell types and induced independently of TLR9...

  19. Treatment of antipsychotic-associated obesity with a GLP-1 receptor agonist--protocol for an investigator-initiated prospective, randomised, placebo-controlled, double-blinded intervention study

    DEFF Research Database (Denmark)

    Ishøy, Pelle L; Knop, Filip K; Broberg, Brian V

    2014-01-01

    -associated obesity are limited and insufficient. Glucagon-like peptide-1 (GLP-1) receptor agonists are approved for the treatment of type 2 diabetes, but their bodyweight-lowering effects have also been recognised in patients with non-diabetes. The primary endpoint of this trial is weight loss after 3 months...... of treatment with a GLP-1 receptor agonist (exenatide once weekly) in patients with non-diabetic schizophrenia with antipsychotic-associated obesity. Secondary endpoints include physiological and metabolic measurements, various psychopathological and cognitive measures, and structural and functional brain MRI....

  20. TLX: An elusive receptor.

    Science.gov (United States)

    Benod, Cindy; Villagomez, Rosa; Webb, Paul

    2016-03-01

    TLX (tailless receptor) is a member of the nuclear receptor superfamily and belongs to a class of nuclear receptors for which no endogenous or synthetic ligands have yet been identified. TLX is a promising therapeutic target in neurological disorders and brain tumors. Thus, regulatory ligands for TLX need to be identified to complete the validation of TLX as a useful target and would serve as chemical probes to pursue the study of this receptor in disease models. It has recently been proved that TLX is druggable. However, to identify potent and specific TLX ligands with desirable biological activity, a deeper understanding of where ligands bind, how they alter TLX conformation and of the mechanism by which TLX mediates the transcription of its target genes is needed. While TLX is in the process of escaping from orphanhood, future ligand design needs to progress in parallel with improved understanding of (i) the binding cavity or surfaces to target with small molecules on the TLX ligand binding domain and (ii) the nature of the TLX coregulators in particular cell and disease contexts. Both of these topics are discussed in this review. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. Glutamate receptor ligands

    DEFF Research Database (Denmark)

    Guldbrandt, Mette; Johansen, Tommy N; Frydenvang, Karla Andrea

    2002-01-01

    Homologation and substitution on the carbon backbone of (S)-glutamic acid [(S)-Glu, 1], as well as absolute stereochemistry, are structural parameters of key importance for the pharmacological profile of (S)-Glu receptor ligands. We describe a series of methyl-substituted 2-aminoadipic acid (AA...

  2. Ginkgolides and glycine receptors

    DEFF Research Database (Denmark)

    Jaracz, Stanislav; Nakanishi, Koji; Jensen, Anders A.

    2004-01-01

    Ginkgolides from the Ginkgo biloba tree are diterpenes with a cage structure consisting of six five-membered rings and a unique tBu group. They exert a variety of biological properties. In addition to being antagonists of the platelet activating factor receptor (PAFR), it has recently been shown ...

  3. adrenergic receptor with preeclampsia

    African Journals Online (AJOL)

    User

    2011-05-09

    May 9, 2011 ... due to a post- receptor defect (Karadas et al., 2007). Several polymorphisms have ... the detection of the Arg16Gly polymorphism, overnight digestion at. 37°C with 10 U ..... DW, Wood AJ, Stein CM (2004). Beta2-adrenoceptor ...

  4. Serotonin type-1A receptor imaging in depression

    International Nuclear Information System (INIS)

    Drevets, Wayne C.; Frank, Ellen; Price, Julie C.; Kupfer, David J.; Greer, Phil J.; Mathis, Chester

    2000-01-01

    Regional 5-hydroxytryptamine 1A (5-HT 1A ) receptor binding potential (BP) of depressed subjects with primary, recurrent, familial mood disorders was compared to that of healthy controls by using positron emission tomography and [carbonyl- 11 C]WAY-100635 {[ 11 C]N-(2-(4-(2-methoxyphenyl)-1-piperazin-1-yl)ethyl)-N-(2-pyridyl) cyclohexanecarboxamide}. The mean 5-HT 1A receptor BP was reduced 42% in the midbrain raphe and 25-33% in limbic and neocortical areas in the mesiotemporal, occipital, and parietal cortex. The magnitude of these abnormalities was most prominent in bipolar depressives and unipolar depressives who had bipolar relatives. These abnormal reductions in 5-HT 1A receptor BP are consistent with in vivo evidence that 5-HT 1A receptor sensitivity is reduced in major depressive disorder and postmortem data showing a widespread deficit of 5-HT 1A receptor expression in primary mood disorders

  5. Palmitoylation as a Functional Regulator of Neurotransmitter Receptors

    Directory of Open Access Journals (Sweden)

    Vladimir S. Naumenko

    2018-01-01

    Full Text Available The majority of neuronal proteins involved in cellular signaling undergo different posttranslational modifications significantly affecting their functions. One of these modifications is a covalent attachment of a 16-C palmitic acid to one or more cysteine residues (S-palmitoylation within the target protein. Palmitoylation is a reversible modification, and repeated cycles of palmitoylation/depalmitoylation might be critically involved in the regulation of multiple signaling processes. Palmitoylation also represents a common posttranslational modification of the neurotransmitter receptors, including G protein-coupled receptors (GPCRs and ligand-gated ion channels (LICs. From the functional point of view, palmitoylation affects a wide span of neurotransmitter receptors activities including their trafficking, sorting, stability, residence lifetime at the cell surface, endocytosis, recycling, and synaptic clustering. This review summarizes the current knowledge on the palmitoylation of neurotransmitter receptors and its role in the regulation of receptors functions as well as in the control of different kinds of physiological and pathological behavior.

  6. Human epidermal growth factor receptor 2 assessment in a case-control study: comparison of fluorescence in situ hybridization and quantitative reverse transcription polymerase chain reaction performed by central laboratories.

    Science.gov (United States)

    Baehner, Frederick L; Achacoso, Ninah; Maddala, Tara; Shak, Steve; Quesenberry, Charles P; Goldstein, Lynn C; Gown, Allen M; Habel, Laurel A

    2010-10-01

    The optimal method to assess human epidermal growth factor receptor 2 (HER2) status remains highly controversial. Before reporting patient HER2 results, American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines mandate that laboratories demonstrate ≥ 95% concordance to another approved laboratory or methodology. Here, we compare central laboratory HER2 assessed by fluorescence in situ hybridization (FISH) and quantitative reverse transcriptase polymerase chain reaction (RT-PCR) using Oncotype DX in lymph node-negative, chemotherapy-untreated patients from a large Kaiser Permanente case-control study. Breast cancer specimens from the Kaiser-Genomic Health study were examined. Central FISH assessment of HER2 amplification and polysomy 17 was conducted by PhenoPath Laboratories (ratios > 2.2, 1.8 to 2.2, and < 1.8 define HER2 positive, HER2 equivocal, and HER2 negative, respectively). HER2 expression by RT-PCR was conducted using Oncotype DX by Genomic Health (normalized expression units ≥ 11.5, 10.7 to < 11.5, and < 10.7 define HER2 positive, HER2 equivocal, and HER2 negative, respectively). Concordance analyses followed ASCO/CAP guidelines. HER2 concordance by central FISH and central RT-PCR was 97% (95% CI, 96% to 99%). Twelve percent (67 of 568 patients) and 11% (60 of 568 patients) of patients were HER2 positive by RT-PCR and FISH, respectively. HER2-positive patients had increased odds of dying from breast cancer compared with HER2-negative patients. Polysomy 17 was demonstrated in 12.5% of all patients and 33% of FISH-positive patients. Nineteen of 20 FISH-positive patients with polysomy 17 were also RT-PCR HER2 positive. Although not statistically significantly different, HER2-positive/polysomy 17 patients tended to have the worst prognosis, followed by HER2-positive/eusomic, HER2-negative/polysomy 17, and HER2-negative/eusomic patients. There is a high degree of concordance between central FISH and quantitative RT

  7. Impact of an exercise program on muscular and functional performance and plasma levels of interleukin 6 and soluble receptor tumor necrosis factor in prefrail community-dwelling older women: a randomized controlled trial.

    Science.gov (United States)

    Lustosa, Lygia Paccini; Máximo Pereira, Leani Souza; Coelho, Fernanda Matos; Pereira, Daniele Sirineu; Silva, Juscélio Pereira; Parentoni, Adriana Netto; Dias, Rosângela Correa; Domingues Dias, João Marcos

    2013-04-01

    To examine the impact of a muscle resistance program (MRP) on muscular and functional performance and on interleukin 6 (IL-6) and soluble tumor necrosis factor receptor-1 (sTNFr1) plasma levels in prefrail community-dwelling women. Randomized controlled trial crossover design with a postintervention and short-term follow-up. University hospital. Prefrail community-dwelling women (N=32; ≥65y). The MRP was designed based on the exercise at 75% of each participant's maximum load (10wk, 3 times/wk). Plasma concentrations of IL-6 and sTNFr1 (high-sensitivity enzyme-linked immunosorbent assay kits), muscle strength of the knee extensors (isokinetic), and functional performance (Timed Up & Go [TUG] test and 10-meter walk test [10MWT]). There were significant differences in functional and muscular performance between the pre-MRP, post-MRP, and 10-week follow-up period. After the MRP, both functional (TUG, pre-MRP=11.1s vs post-MRP=10.4s, P=.00; 10MWT, pre-MRP=4.9s vs post-MRP, 4.4s, P=.00) and muscular performances (pre-MRP=77.8% and post-MRP=83.1%, P=.02) improved. After cessation of the MRP (follow-up period), sTNFr1 plasma levels increased by 21.4% at 10-week follow-up (post-MRP, 406.4pg/mL; 10-week follow-up, 517.0pg/mL; P=.03). There were significant differences in sTNFr1 (P=.01). The MRP was effective in improving functional and muscular performances, although alterations in plasma levels of IL-6 and sTNFr1 could not be identified after the MRP. Cessation of the MRP after 10 weeks resulted in increased plasma levels of sTNFr1. Copyright © 2013 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

  8. Comprehensive proteome analysis of nasal lavage samples after controlled exposure to welding nanoparticles shows an induced acute phase and a nuclear receptor, LXR/RXR, activation that influence the status of the extracellular matrix.

    Science.gov (United States)

    Ali, Neserin; Ljunggren, Stefan; Karlsson, Helen M; Wierzbicka, Aneta; Pagels, Joakim; Isaxon, Christina; Gudmundsson, Anders; Rissler, Jenny; Nielsen, Jörn; Lindh, Christian H; Kåredal, Monica

    2018-01-01

    Epidemiological studies have shown that many welders experience respiratory symptoms. During the welding process a large number of airborne nanosized particles are generated, which might be inhaled and deposited in the respiratory tract. Knowledge of the underlying mechanisms behind observed symptoms is still partly lacking, although inflammation is suggested to play a central role. The aim of this study was to investigate the effects of welding fume particle exposure on the proteome expression level in welders suffering from respiratory symptoms, and changes in protein mediators in nasal lavage samples were analyzed. Such mediators will be helpful to clarify the pathomechanisms behind welding fume particle-induced effects. In an exposure chamber, 11 welders with work-related symptoms in the lower airways during the last month were exposed to mild-steel welding fume particles (1 mg/m 3 ) and to filtered air, respectively, in a double-blind manner. Nasal lavage samples were collected before, immediately after, and the day after exposure. The proteins in the nasal lavage were analyzed with two different mass spectrometry approaches, label-free discovery shotgun LC-MS/MS and a targeted selected reaction monitoring LC-MS/MS analyzing 130 proteins and four in vivo peptide degradation products. The analysis revealed 30 significantly changed proteins that were associated with two main pathways; activation of acute phase response signaling and activation of LXR/RXR, which is a nuclear receptor family involved in lipid signaling. Connective tissue proteins and proteins controlling the degradation of such tissues, including two different matrix metalloprotease proteins, MMP8 and MMP9, were among the significantly changed enzymes and were identified as important key players in the pathways. Exposure to mild-steel welding fume particles causes measurable changes on the proteome level in nasal lavage matrix in exposed welders, although no clinical symptoms were manifested. The

  9. Randomized controlled trial of toremifene 120 mg compared with exemestane 25 mg after prior treatment with a non-steroidal aromatase inhibitor in postmenopausal women with hormone receptor-positive metastatic breast cancer.

    Science.gov (United States)

    Yamamoto, Yutaka; Ishikawa, Takashi; Hozumi, Yasuo; Ikeda, Masahiko; Iwata, Hiroji; Yamashita, Hiroko; Toyama, Tatsuya; Chishima, Takashi; Saji, Shigehira; Yamamoto-Ibusuki, Mutsuko; Iwase, Hirotaka

    2013-05-16

    After the failure of a non-steroidal aromatase inhibitor (nsAI) for postmenopausal patients with metastatic breast cancer (mBC), it is unclear which of various kinds of endocrine therapy is the most appropriate. A randomized controlled trial was performed to compare the efficacy and safety of daily toremifene 120 mg (TOR120), a selective estrogen receptor modulator, and exemestane 25 mg (EXE), a steroidal aromatase inhibitor. The primary end point was the clinical benefit rate (CBR). The secondary end points were objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and toxicity. Initially, a total of 91 women was registered in the study and randomly assigned to either TOR120 (n = 46) or EXE (n = 45) from October 2008 to November 2011. Three of the 46 patients in the TOR120 arm were not received treatment, 2 patients having withdrawn from the trial by their preference and one having been dropped due to administration of another SERM. When analyzed after a median observation period of 16.9 months, the intention-to-treat analysis showed that there were no statistical difference between TOR120 (N = 46) and EXE (n = 45) in terms of CBR (41.3% vs. 26.7%; P = 0.14), ORR (10.8% vs. 2.2%; P = 0.083), and OS (Hazard ratio, 0.60; P = 0.22). The PFS of TOR120 was longer than that of EXE, the difference being statistically significant (Hazard ratio, 0.61, P = 0.045). The results in treatment-received cohort (N = 88) were similar to those in ITT cohort. Both treatments were well-tolerated with no severe adverse events, although the treatment of 3 of 43 women administered TOR120 was stopped after a few days because of nausea, general fatigue, hot flush and night sweating. TOR120, as a subsequent endocrine therapy for mBC patients who failed non-steroidal AI treatment, could potentially be more beneficial than EXE. UMIN000001841.

  10. Randomized controlled trial of toremifene 120 mg compared with exemestane 25 mg after prior treatment with a non-steroidal aromatase inhibitor in postmenopausal women with hormone receptor-positive metastatic breast cancer

    International Nuclear Information System (INIS)

    Yamamoto, Yutaka; Yamamoto-Ibusuki, Mutsuko; Iwase, Hirotaka; Ishikawa, Takashi; Hozumi, Yasuo; Ikeda, Masahiko; Iwata, Hiroji; Yamashita, Hiroko; Toyama, Tatsuya; Chishima, Takashi; Saji, Shigehira

    2013-01-01

    After the failure of a non-steroidal aromatase inhibitor (nsAI) for postmenopausal patients with metastatic breast cancer (mBC), it is unclear which of various kinds of endocrine therapy is the most appropriate. A randomized controlled trial was performed to compare the efficacy and safety of daily toremifene 120 mg (TOR120), a selective estrogen receptor modulator, and exemestane 25 mg (EXE), a steroidal aromatase inhibitor. The primary end point was the clinical benefit rate (CBR). The secondary end points were objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and toxicity. Initially, a total of 91 women was registered in the study and randomly assigned to either TOR120 (n = 46) or EXE (n = 45) from October 2008 to November 2011. Three of the 46 patients in the TOR120 arm were not received treatment, 2 patients having withdrawn from the trial by their preference and one having been dropped due to administration of another SERM. When analyzed after a median observation period of 16.9 months, the intention-to-treat analysis showed that there were no statistical difference between TOR120 (N = 46) and EXE (n = 45) in terms of CBR (41.3% vs. 26.7%; P = 0.14), ORR (10.8% vs. 2.2%; P = 0.083), and OS (Hazard ratio, 0.60; P = 0.22). The PFS of TOR120 was longer than that of EXE, the difference being statistically significant (Hazard ratio, 0.61, P = 0.045). The results in treatment-received cohort (N = 88) were similar to those in ITT cohort. Both treatments were well-tolerated with no severe adverse events, although the treatment of 3 of 43 women administered TOR120 was stopped after a few days because of nausea, general fatigue, hot flush and night sweating. TOR120, as a subsequent endocrine therapy for mBC patients who failed non-steroidal AI treatment, could potentially be more beneficial than EXE. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function

  11. Olfactory Receptor Database: a sensory chemoreceptor resource

    OpenAIRE

    Skoufos, Emmanouil; Marenco, Luis; Nadkarni, Prakash M.; Miller, Perry L.; Shepherd, Gordon M.

    2000-01-01

    The Olfactory Receptor Database (ORDB) is a WWW-accessible database that has been expanded from an olfactory receptor resource to a chemoreceptor resource. It stores data on six classes of G-protein-coupled sensory chemoreceptors: (i) olfactory receptor-like proteins, (ii) vomeronasal receptors, (iii) insect olfactory receptors, (iv) worm chemoreceptors, (v) taste papilla receptors and (vi) fungal pheromone receptors. A complementary database of the ligands of these receptors (OdorDB) has bee...

  12. Renal effects of DPP-4 inhibitor sitagliptin or GLP-1 receptor agonist liraglutide in overweight patients with type 2 diabetes : A 12-week, randomized, double-blind, placebo-controlled trial

    NARCIS (Netherlands