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Sample records for hybrid receptor activation

  1. δ-Opioid receptor-stimulated Akt signaling in neuroblastoma x glioma (NG108-15) hybrid cells involves receptor tyrosine kinase-mediated PI3K activation

    International Nuclear Information System (INIS)

    Heiss, Anika; Ammer, Hermann; Eisinger, Daniela A.

    2009-01-01

    δ-Opioid receptor (DOR) agonists possess cytoprotective properties, an effect associated with activation of the 'pro-survival' kinase Akt. Here we delineate the signal transduction pathway by which opioids induce Akt activation in neuroblastoma x glioma (NG108-15) hybrid cells. Exposure of the cells to both [D-Pen 2,5 ]enkephalin and etorphine resulted in a time- and dose-dependent increase in Akt activity, as measured by means of an activation-specific antibody recognizing phosphoserine-473. DOR-mediated Akt signaling is blocked by the opioid antagonist naloxone and involves inhibitory G i/o proteins, because pre-treatment with pertussis toxin, but not over-expression of the G q/11 scavengers EBP50 and GRK2-K220R, prevented this effect. Further studies with Wortmannin and LY294002 revealed that phophoinositol-3-kinase (PI3K) plays a central role in opioid-induced Akt activation. Opioids stimulate Akt activity through transactivation of receptor tyrosine kinases (RTK), because pre-treatment of the cells with inhibitors for neurotrophin receptor tyrosine kinases (AG879) and the insulin-like growth factor receptor IGF-1 (AG1024), but not over-expression of the Gβγ scavenger phosducin, abolished this effect. Activated Akt translocates to the nuclear membrane, where it promotes GSK3 phosphorylation and prevents caspase-3 cleavage, two key events mediating inhibition of cell apoptosis and enhancement of cell survival. Taken together, these results demonstrate that in NG108-15 hybrid cells DOR agonists possess cytoprotective properties mediated by activation of the RTK/PI3K/Akt signaling pathway.

  2. {delta}-Opioid receptor-stimulated Akt signaling in neuroblastoma x glioma (NG108-15) hybrid cells involves receptor tyrosine kinase-mediated PI3K activation

    Energy Technology Data Exchange (ETDEWEB)

    Heiss, Anika; Ammer, Hermann [Institute of Pharmacology, Toxicology and Pharmacy Ludwig-Maximilians-University of Munich Koeniginstrasse 16 80539 Muenchen Federal Republic of Germany (Germany); Eisinger, Daniela A., E-mail: eisinger@pharmtox.vetmed.uni-muenchen.de [Institute of Pharmacology, Toxicology and Pharmacy Ludwig-Maximilians-University of Munich Koeniginstrasse 16 80539 Muenchen Federal Republic of Germany (Germany)

    2009-07-15

    {delta}-Opioid receptor (DOR) agonists possess cytoprotective properties, an effect associated with activation of the 'pro-survival' kinase Akt. Here we delineate the signal transduction pathway by which opioids induce Akt activation in neuroblastoma x glioma (NG108-15) hybrid cells. Exposure of the cells to both [D-Pen{sup 2,5}]enkephalin and etorphine resulted in a time- and dose-dependent increase in Akt activity, as measured by means of an activation-specific antibody recognizing phosphoserine-473. DOR-mediated Akt signaling is blocked by the opioid antagonist naloxone and involves inhibitory G{sub i/o} proteins, because pre-treatment with pertussis toxin, but not over-expression of the G{sub q/11} scavengers EBP50 and GRK2-K220R, prevented this effect. Further studies with Wortmannin and LY294002 revealed that phophoinositol-3-kinase (PI3K) plays a central role in opioid-induced Akt activation. Opioids stimulate Akt activity through transactivation of receptor tyrosine kinases (RTK), because pre-treatment of the cells with inhibitors for neurotrophin receptor tyrosine kinases (AG879) and the insulin-like growth factor receptor IGF-1 (AG1024), but not over-expression of the G{beta}{gamma} scavenger phosducin, abolished this effect. Activated Akt translocates to the nuclear membrane, where it promotes GSK3 phosphorylation and prevents caspase-3 cleavage, two key events mediating inhibition of cell apoptosis and enhancement of cell survival. Taken together, these results demonstrate that in NG108-15 hybrid cells DOR agonists possess cytoprotective properties mediated by activation of the RTK/PI3K/Akt signaling pathway.

  3. Effect of insulin analogues on insulin/IGF1 hybrid receptors: increased activation by glargine but not by its metabolites M1 and M2.

    Directory of Open Access Journals (Sweden)

    Cécile Pierre-Eugene

    Full Text Available BACKGROUND: In diabetic patients, the pharmacokinetics of injected human insulin does not permit optimal control of glycemia. Fast and slow acting insulin analogues have been developed, but they may have adverse properties, such as increased mitogenic or anti-apoptotic signaling. Insulin/IGF1 hybrid receptors (IR/IGF1R, present in most tissues, have been proposed to transmit biological effects close to those of IGF1R. However, the study of hybrid receptors is difficult because of the presence of IR and IGF1R homodimers. Our objective was to perform the first study on the pharmacological properties of the five marketed insulin analogues towards IR/IGF1R hybrids. METHODOLOGY: To study the effect of insulin analogues on IR/IGF1R hybrids, we used our previously developed Bioluminescence Resonance Energy Transfer (BRET assay that permits specific analysis of the pharmacological properties of hybrid receptors. Moreover, we have developed a new, highly sensitive BRET-based assay to monitor phophatidylinositol-3 phosphate (PIP(3 production in living cells. Using this assay, we performed a detailed pharmacological analysis of PIP(3 production induced by IGF1, insulin and insulin analogues in living breast cancer-derived MCF-7 and MDA-MB231 cells. RESULTS: Among the five insulin analogues tested, only glargine stimulated IR/IGF1R hybrids with an EC50 that was significantly lower than insulin and close to that of IGF1. Glargine more efficiently stimulated PIP(3 production in MCF-7 cells but not in MDA-MB231 cells as compared to insulin. In contrast, glargine metabolites M1 and M2 showed lower potency for hybrid receptors stimulation, PIP(3 production, Akt and Erk1/2 phosphorylation and DNA synthesis in MCF-7 cells, compared to insulin. CONCLUSION: Glargine, possibly acting through IR/IGF1R hybrids, displays higher potency, whereas its metabolites M1 and M2 display lower potency than insulin for the stimulation of proliferative/anti-apoptotic pathways in

  4. Active and Passive Hybrid Sensor

    Science.gov (United States)

    Carswell, James R.

    2010-01-01

    A hybrid ocean wind sensor (HOWS) can map ocean vector wind in low to hurricane-level winds, and non-precipitating and precipitating conditions. It can acquire active and passive measurements through a single aperture at two wavelengths, two polarizations, and multiple incidence angles. Its low profile, compact geometry, and low power consumption permits installation on air craft platforms, including high-altitude unmanned aerial vehicles (UAVs).

  5. Targeting Interleukin-4 Receptor Alpha by Hybrid Peptide for Novel Biliary Tract Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Kahori Seto

    2014-01-01

    Full Text Available It is known that the interleukin-4 receptor α (IL-4Rα is highly expressed on the surface of various human solid tumors. We previously designed novel IL-4Rα-lytic hybrid peptide composed of binding peptide to IL-4Rα and cell-lytic peptide and reported that the designed IL-4Rα-lytic hybrid peptide exhibited cytotoxic and antitumor activity both in vitro and in vivo against the human pancreatic cancer cells expressing IL-4Rα. Here, we evaluated the antitumor activity of the IL-4Rα-lytic hybrid peptide as a novel molecular targeted therapy for human biliary tract cancer (BTC. The IL-4Rα-lytic hybrid peptide showed cytotoxic activity in six BTC cell lines with a concentration that killed 50% of all cells (IC50 as low as 5 μM. We also showed that IL-4Rα-lytic hybrid peptide in combination with gemcitabine exhibited synergistic cytotoxic activity in vitro. In addition, intravenous administration of IL-4Rα-lytic hybrid peptide significantly inhibited tumor growth in a xenograft model of human BTC in vivo. Taken together, these results indicated that the IL-4Rα-lytic hybrid peptide is a potent agent that might provide a novel therapy for patients with BTC.

  6. DSP Control of Line Hybrid Active Filter

    DEFF Research Database (Denmark)

    Dan, Stan George; Benjamin, Doniga Daniel; Magureanu, R.

    2005-01-01

    Active Power Filters have been intensively explored in the past decade. Hybrid active filters inherit the efficiency of passive filters and the improved performance of active filters, and thus constitute a viable improved approach for harmonic compensation. In this paper a parallel hybrid filter...... is studied for current harmonic compensation. The hybrid filter is formed by a single tuned Le filter and a small-rated power active filter, which are directly connected in series without any matching transformer. Thus the required rating of the active filter is much smaller than a conventional standalone...... active filter. Simulation and experimental results obtained in laboratory confirmed the validity and effectiveness of the control....

  7. Nuclear receptor corepressor-dependent repression of peroxisome-proliferator-activated receptor delta-mediated transactivation

    DEFF Research Database (Denmark)

    Krogsdam, Anne-M; Nielsen, Curt A F; Neve, Søren

    2002-01-01

    delta-RXR alpha heterodimer bound to an acyl-CoA oxidase (ACO)-type peroxisome-proliferator response element recruited a glutathione S-transferase-NCoR fusion protein in a ligand-independent manner. Contrasting with most other nuclear receptors, PPAR delta was found to interact equally well......The nuclear receptor corepressor (NCoR) was isolated as a peroxisome-proliferator-activated receptor (PPAR) delta interacting protein using the yeast two-hybrid system. NCoR interacted strongly with the ligand-binding domain of PPAR delta, whereas interactions with the ligand-binding domains...

  8. Active Trimming of Hybrid Integrated Circuits

    OpenAIRE

    Németh, P.; Krémer, P.

    1984-01-01

    One of the more important fields of the microelectronics industry is the manufacturing of hybrid integrated circuits.An important part of the manufacturing process is concerned with the trimming of the hybrid integratedl circuits. This article deals with the basic principles of active trimming and introduces a microprocessor controlled trimming machine. By comparing active trimming with passive techniques, it can be shown that the active system has some advantages. This article outlines these...

  9. Retinoid X receptor and peroxisome proliferator-activated receptor activate an estrogen responsive gene independent of the estrogen receptor.

    Science.gov (United States)

    Nuñez, S B; Medin, J A; Braissant, O; Kemp, L; Wahli, W; Ozato, K; Segars, J H

    1997-03-14

    Estrogen receptors regulate transcription of genes essential for sexual development and reproductive function. Since the retinoid X receptor (RXR) is able to modulate estrogen responsive genes and both 9-cis RA and fatty acids influenced development of estrogen responsive tumors, we hypothesized that estrogen responsive genes might be modulated by RXR and the fatty acid receptor (peroxisome proliferator-activated receptor, PPAR). To test this hypothesis, transfection assays in CV-1 cells were performed with an estrogen response element (ERE) coupled to a luciferase reporter construct. Addition of expression vectors for RXR and PPAR resulted in an 11-fold increase in luciferase activity in the presence of 9-cis RA. Furthermore, mobility shift assays demonstrated binding of RXR and PPAR to the vitellogenin A2-ERE and an ERE in the oxytocin promoter. Methylation interference assays demonstrated that specific guanine residues required for RXR/PPAR binding to the ERE were similar to residues required for ER binding. Moreover, RXR domain-deleted constructs in transfection assays showed that activation required RXR since an RXR delta AF-2 mutant completely abrogated reporter activity. Oligoprecipitation binding studies with biotinylated ERE and (35)S-labeled in vitro translated RXR constructs confirmed binding of delta AF-2 RXR mutant to the ERE in the presence of baculovirus-expressed PPAR. Finally, in situ hybridization confirmed RXR and PPAR mRNA expression in estrogen responsive tissues. Collectively, these data suggest that RXR and PPAR are present in reproductive tissues, are capable of activating estrogen responsive genes and suggest that the mechanism of activation may involve direct binding of the receptors to estrogen response elements.

  10. CERAPP: Collaborative Estrogen Receptor Activity Prediction Project

    Data.gov (United States)

    U.S. Environmental Protection Agency — Data from a large-scale modeling project called CERAPP (Collaborative Estrogen Receptor Activity Prediction Project) demonstrating using predictive computational...

  11. Hybrid energy harvesting using active thermal backplane

    Science.gov (United States)

    Kim, Hyun-Wook; Lee, Dong-Gun

    2016-04-01

    In this study, we demonstrate the concept of a new hybrid energy harvesting system by combing solar cells with magneto-thermoelectric generator (MTG, i.e., thermal energy harvesting). The silicon solar cell can easily reach high temperature under normal operating conditions. Thus the heated solar cell becomes rapidly less efficient as the temperature of solar cell rises. To increase the efficiency of the solar cell, air or water-based cooling system is used. To surpass conventional cooling devices requiring additional power as well as large working space for air/water collectors, we develop a new technology of pairing an active thermal backplane (ATB) to solar cell. The ATB design is based on MTG technology utilizing the physics of the 2nd order phase transition of active ferromagnetic materials. The MTG is cost-effective conversion of thermal energy to electrical energy and is fundamentally different from Seebeck TEG devices. The ATB (MTG) is in addition to being an energy conversion system, a very good conveyor of heat through both conduction and convection. Therefore, the ATB can provide dual-mode for the proposed hybrid energy harvesting. One is active convective and conductive cooling for heated solar cell. Another is active thermal energy harvesting from heat of solar cell. These novel hybrid energy harvesting device have potentially simultaneous energy conversion capability of solar and thermal energy into electricity. The results presented can be used for better understanding of hybrid energy harvesting system that can be integrated into commercial applications.

  12. Chapter 8. Activation mechanisms of chemokine receptors

    DEFF Research Database (Denmark)

    Jensen, Pia C; Rosenkilde, Mette M

    2009-01-01

    binding. Attempts to unravel the activation mechanism of 7TM receptors have led to the conclusion that activation involves movements of the transmembrane segments VI and VII in particular, as recently gathered in the Global Toggle Switch Model. However, to understand the activation mechanism completely......, more research has to be done in this field. Chemokine receptors are interesting tools in this matter. First, the chemokine system has a high degree of promiscuity that allows several chemokines to target one receptor in different ways, as well as a single chemokine ligand to target several receptors...

  13. Molecular characterization of a novel human hybrid-type receptor that binds the alpha2-macroglobulin receptor-associated protein

    DEFF Research Database (Denmark)

    Jacobsen, Linda; Madsen, P; Moestrup, S K

    1996-01-01

    the corresponding cDNA. The gene, designated SORL1, maps to chromosome 11q 23/24 and encodes a 2214-residue type 1 receptor containing a furin cleavage site immediately preceding the N terminus determined in the purified protein. The receptor, designated sorLA-1, has a short cytoplasmic tail containing a tyrosine...... density lipoprotein receptor gene family receptors, and 3) six tandemly arranged fibronectin type III repeats also found in certain neural adhesion proteins. sorLA-1 may therefore be classified as a hybrid receptor. Northern blotting revealed specific mRNA transcripts in brain, spinal cord, and testis......The 39-40-kDa receptor-associated protein (RAP) binds to the members of the low density lipoprotein receptor gene family and functions as a specialized endoplasmic reticulum/Golgi chaperone. Using RAP affinity chromatography, we have purified a novel approximately 250-kDa brain protein and isolated...

  14. Active flywheel control for hybrid vehicle; Compensation active des pulsations de couple dans un vehicule hybride

    Energy Technology Data Exchange (ETDEWEB)

    Tnani, S.; Coirault, P.; Champenois, G. [Ecole Superieure d' Ingenieurs, Lab. d' Automatique et d' Informatique Industrielle, 86 - Poitiers (France)

    2005-01-01

    In the paper, the authors propose a novel control strategy of torque ripple on hybrid vehicle. The combustion engine ripple's are reduced by using an active filter and an AC machine which is mounted on the crank-shaft to generate on inverse torque sequence. The control strategy is based on a multi-objectives state feedback synthesis. A complete modelling of the hybrid propulsion of the vehicle is achieved. Simulation results highlight the interest of the control scheme. (authors)

  15. Novel nuclear localization and potential function of insulin-like growth factor-1 receptor/insulin receptor hybrid in corneal epithelial cells.

    Directory of Open Access Journals (Sweden)

    Yu-Chieh Wu

    Full Text Available BACKGROUND: Type I insulin-like growth factor receptor (IGF-1R and insulin receptor (INSR are highly homologous molecules, which can heterodimerize to form an IGF-1R/INSR hybrid (Hybrid-R. The presence and biological significance of the Hybrid-R in human corneal epithelium has not yet been established. In addition, while nuclear localization of IGF-1R was recently reported in cancer cells and human corneal epithelial cells, the function and profile of nuclear IGF-1R is unknown. In this study, we characterized the nuclear localization and function of the Hybrid-R and the role of IGF-1/IGF-1R and Hybrid-R signaling in the human corneal epithelium. METHODOLOGY/PRINCIPLE FINDINGS: IGF-1-mediated signaling and cell growth were examined in a human telomerized corneal epithelial (hTCEpi cell line using co-immunoprecipitation, immunoblotting and cell proliferation assays. The presence of Hybrid-R in hTCEpi and primary cultured human corneal epithelial cells was confirmed by immunofluorescence and reciprocal immunoprecipitation of whole cell lysates. We found that IGF-1 stimulated Akt and promoted cell growth through IGF-1R activation, which was independent of the Hybrid-R. The presence of Hybrid-R, but not IGF-1R/IGF-1R, was detected in nuclear extracts. Knockdown of INSR by small interfering RNA resulted in depletion of the INSR/INSR and preferential formation of Hybrid-R. Chromatin-immunoprecipitation sequencing assay with anti-IGF-1R or anti-INSR was subsequently performed to identify potential genomic targets responsible for critical homeostatic regulatory pathways. CONCLUSION/SIGNIFICANCE: In contrast to previous reports on nuclear localized IGF-1R, this is the first report identifying the nuclear localization of Hybrid-R in an epithelial cell line. The identification of a nuclear Hybrid-R and novel genomic targets suggests that IGF-1R traffics to the nucleus as an IGF-1R/INSR heterotetrameric complex to regulate corneal epithelial homeostatic

  16. Rotor Vibration Reduction via Active Hybrid Bearings

    DEFF Research Database (Denmark)

    Nicoletti, Rodrigo; Santos, Ilmar

    2002-01-01

    The use of fluid power to reduce and control rotor vibration in rotating machines is investigated. An active hybrid bearing is studied, whose main objective is to reduce wear and vibration between rotating and stationary machinery parts. By injecting pressurised oil into the oil film, through...... orifices machined in the bearing pads, one can alter the machine dynamic characteristics, thus enhancing its operational range. A mathematical model of the rotor-bearing system, as well as of the hydraulic system, is presented. Numerical results of the system frequency response show good agreement...

  17. 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

  18. Localization of insulin receptor mRNA in rat brain by in situ hybridization

    International Nuclear Information System (INIS)

    Marks, J.L.; Porte, D. Jr.; Stahl, W.L.; Baskin, D.G.

    1990-01-01

    Insulin receptor mRNA was demonstrated in rat brain slices by in situ hybridization with three 35 S-oligonucleotide probes and contact film autoradiography. Specificity was confirmed by showing that (a) excess unlabeled probe abolished the signal, (b) an oligonucleotide probe for rat neuropeptide Y mRNA showed a different distribution of hybridization signal, and (c) the distribution of insulin receptor binding was consistent with the distribution of insulin receptor mRNA. Insulin receptor mRNA was most abundant in the granule cell layers of the olfactory bulb, cerebellum and dentate gyrus, in the pyramidal cell body layers of the pyriform cortex and hippocampus, in the choroid plexus and in the arcuate nucleus of the hypothalamus

  19. Neurokinin-1 receptor activation in globus pallidus

    Directory of Open Access Journals (Sweden)

    Lei Chen

    2009-10-01

    Full Text Available The undecapeptide substance P has been demonstrated to modulate neuronal activity in a number of brain regions by acting on neurokinin-1 receptors. Anatomical studies revealed a moderate level of neurokinin-1 receptor in rat globus pallidus. To determine the electrophysiological effects of neurokinin-1 receptor activation in globus pallidus, whole-cell patch-clamp recordings were performed in the present study. Under current-clamp recordings, neurokinin-1 receptor agonist, [Sar9, Met(O211] substance P (SM-SP at 1 μM, depolarized globus pallidus neurons and increased their firing rate. Consistently, SM-SP induced an inward current under voltage-clamp recording. The depolarization evoked by SM-SP persisted in the presence of tetrodotoxin, glutamate and GABA receptor antagonists, indicating its direct postsynaptic effects. The neurokinin-1 receptor antagonist, SR140333B, could block SM-SP-induced depolarization. Further experiments showed that suppression of potassium conductance was the predominant ionic mechanism of SM-SP-induced depolarization. To determine if neurokinin-1 receptor activation exerts any effects on GABAergic and glutamatergic neurotransmission, the action of SM-SP on synaptic currents was studied. SM-SP significantly increased the frequency of spontaneous inhibitory postsynaptic currents, but only induced a transient increase in the frequency of miniature inhibitory postsynaptic currents. No change was observed in both spontaneous and miniature excitatory postsynaptic currents. Based on the direct excitatory effects of SM-SP on pallidal neurons, we hypothesize that neurokinin-1 receptor activation in globus pallidus may be involved in the beneficial effect of substance P in Parkinson’s disease.

  20. Gonadal expression of aromatase and estrogen receptor alpha genes in two races of Tunisian mice and their hypofertile hybrids.

    Science.gov (United States)

    Saïd, Lamia; Delalande, Christelle; Britton-Davidian, Janice; Saïd, Khaled; Saad, Ali; Carreau, Serge

    2007-07-01

    House mice (Mus musculus domesticus) in Tunisia consists of two races, one carries the 40-acrocentric standard karyotypes and the other one is a robertsonian race (2n=22) homozygous for nine centric fusions (Rb). The F1 hybrids between the two chromosomal races showed a significant decrease in reproductive success and litter size. Such results can be related to the formation of meiotic trivalent in the hybrids leading to the production of viable aneuploid gametes and post-zygotic elimination of embryos due to chromosomal non disjunction events at meiosis. Moreover, testicular histology of F1 and backcross males showed in some cases a breakdown in spermatogenesis. In both females and males, androgens but also estrogens play an important role in gametogenesis. In this study, we have studied aromatase and estrogen receptor alpha (ERalpha) gene expression in the gonads of the two parental races and their chromosomal hybrids. The results showed that aromatase and ERalpha mRNAs are expressed in hybrid males of inter-racial crosses (female22Rb x male40Std and female40Std x male22Rb) and in hybrid females of inter-racial crosses (female22Rb x male40Std) as in the two parental races. However, in hybrid females of inter-racial crosses (female40Std x male22Rb) the amount of aromatase transcripts decreased sharply suggesting that this gene is involved in the breakdown of hybrid fertility in females, but not in males. However, in hybrid males, a putative post-translational modification of this enzyme, in terms of activity, should be verified.

  1. CINPA1 Is an Inhibitor of Constitutive Androstane Receptor That Does Not Activate Pregnane X Receptor

    Science.gov (United States)

    Cherian, Milu T; Lin, Wenwei; Wu, Jing

    2015-01-01

    Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are xenobiotic sensors that enhance the detoxification and elimination of xenobiotics and endobiotics by modulating the expression of genes encoding drug-metabolizing enzymes and transporters. Elevated levels of drug-metabolizing enzymes and efflux transporters, resulting from CAR activation in various cancers, promote the elimination of chemotherapeutic agents, leading to reduced therapeutic effectiveness and acquired drug resistance. CAR inhibitors, in combination with existing chemotherapeutics, could therefore be used to attenuate multidrug resistance in cancers. Interestingly, all previously reported CAR inverse-agonists are also activators of PXR, rendering them mechanistically counterproductive in tissues where both these xenobiotic receptors are present and active. We used a directed high-throughput screening approach, followed by subsequent mechanistic studies, to identify novel, potent, and specific small-molecule CAR inhibitors that do not activate PXR. We describe here one such inhibitor, CINPA1 (CAR inhibitor not PXR activator 1), capable of reducing CAR-mediated transcription with an IC50 of ∼70 nM. CINPA1 1) is a specific xenobiotic receptor inhibitor and has no cytotoxic effects up to 30 µM; 2) inhibits CAR-mediated gene expression in primary human hepatocytes, where CAR is endogenously expressed; 3) does not alter the protein levels or subcellular localization of CAR; 4) increases corepressor and reduces coactivator interaction with the CAR ligand-binding domain in mammalian two-hybrid assays; and 5) disrupts CAR binding to the promoter regions of target genes in chromatin immunoprecipitation assays. CINPA1 could be used as a novel molecular tool for understanding CAR function. PMID:25762023

  2. CINPA1 is an inhibitor of constitutive androstane receptor that does not activate pregnane X receptor.

    Science.gov (United States)

    Cherian, Milu T; Lin, Wenwei; Wu, Jing; Chen, Taosheng

    2015-05-01

    Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are xenobiotic sensors that enhance the detoxification and elimination of xenobiotics and endobiotics by modulating the expression of genes encoding drug-metabolizing enzymes and transporters. Elevated levels of drug-metabolizing enzymes and efflux transporters, resulting from CAR activation in various cancers, promote the elimination of chemotherapeutic agents, leading to reduced therapeutic effectiveness and acquired drug resistance. CAR inhibitors, in combination with existing chemotherapeutics, could therefore be used to attenuate multidrug resistance in cancers. Interestingly, all previously reported CAR inverse-agonists are also activators of PXR, rendering them mechanistically counterproductive in tissues where both these xenobiotic receptors are present and active. We used a directed high-throughput screening approach, followed by subsequent mechanistic studies, to identify novel, potent, and specific small-molecule CAR inhibitors that do not activate PXR. We describe here one such inhibitor, CINPA1 (CAR inhibitor not PXR activator 1), capable of reducing CAR-mediated transcription with an IC50 of ∼70 nM. CINPA1 1) is a specific xenobiotic receptor inhibitor and has no cytotoxic effects up to 30 µM; 2) inhibits CAR-mediated gene expression in primary human hepatocytes, where CAR is endogenously expressed; 3) does not alter the protein levels or subcellular localization of CAR; 4) increases corepressor and reduces coactivator interaction with the CAR ligand-binding domain in mammalian two-hybrid assays; and 5) disrupts CAR binding to the promoter regions of target genes in chromatin immunoprecipitation assays. CINPA1 could be used as a novel molecular tool for understanding CAR function. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  3. Hybrid Synthetic Receptors on MOSFET Devices for Detection of Prostate Specific Antigen in Human Plasma.

    Science.gov (United States)

    Tamboli, Vibha K; Bhalla, Nikhil; Jolly, Pawan; Bowen, Chris R; Taylor, John T; Bowen, Jenna L; Allender, Chris J; Estrela, Pedro

    2016-12-06

    The study reports the use of extended gate field-effect transistors (FET) for the label-free and sensitive detection of prostate cancer (PCa) biomarkers in human plasma. The approach integrates for the first time hybrid synthetic receptors comprising of highly selective aptamer-lined pockets (apta-MIP) with FETs for sensitive detection of prostate specific antigen (PSA) at clinically relevant concentrations. The hybrid synthetic receptors were constructed by immobilizing an aptamer-PSA complex on gold and subjecting it to 13 cycles of dopamine electropolymerization. The polymerization resulted in the creation of highly selective polymeric cavities that retained the ability to recognize PSA post removal of the protein. The hybrid synthetic receptors were subsequently used in an extended gate FET setup for electrochemical detection of PSA. The sensor was reported to have a limit of detection of 0.1 pg/mL with a linear detection range from 0.1 pg/mL to 1 ng/mL PSA. Detection of 1-10 pg/mL PSA was also achieved in diluted human plasma. The present apta-MIP sensor developed in conjunction with FET devices demonstrates the potential for clinical application of synthetic hybrid receptors for the detection of clinically relevant biomarkers in complex samples.

  4. A muscle model for hybrid muscle activation

    Directory of Open Access Journals (Sweden)

    Klauer Christian

    2015-09-01

    Full Text Available To develop model-based control strategies for Functional Electrical Stimulation (FES in order to support weak voluntary muscle contractions, a hybrid model for describing joint motions induced by concurrent voluntary-and FES induced muscle activation is proposed. It is based on a Hammerstein model – as commonly used in feedback controlled FES – and exemplarily applied to describe the shoulder abduction joint angle. Main component of a Hammerstein muscle model is usually a static input nonlinearity depending on the stimulation intensity. To additionally incorporate voluntary contributions, we extended the static non-linearity by a second input describing the intensity of the voluntary contribution that is estimated by electromyography (EMG measurements – even during active FES. An Artificial Neural Network (ANN is used to describe the static input non-linearity. The output of the ANN drives a second-order linear dynamical system that describes the combined muscle activation and joint angle dynamics. The tunable parameters are adapted to the individual subject by a system identification approach using previously recorded I/O-data. The model has been validated in two healthy subjects yielding RMS values for the joint angle error of 3.56° and 3.44°, respectively.

  5. Hybrid active pixel sensors in infrared astronomy

    International Nuclear Information System (INIS)

    Finger, Gert; Dorn, Reinhold J.; Meyer, Manfred; Mehrgan, Leander; Stegmeier, Joerg; Moorwood, Alan

    2005-01-01

    Infrared astronomy is currently benefiting from three main technologies providing high-performance hybrid active pixel sensors. In the near infrared from 1 to 5 μm two technologies, both aiming for buttable 2Kx2K mosaics, are competing, namely InSb and HgCdTe grown by LPE or MBE on Al 2 O 3 , Si or CdZnTe substrates. Blocked impurity band Si:As arrays cover the mid infrared spectral range from 8 to 28 μm. Adaptive optics combined with multiple integral field units feeding high-resolution spectrographs drive the requirements for the array format of infrared sensors used at ground-based infrared observatories. The pixel performance is now approaching fundamental limits. In view of this development, a detection limit for the photon flux of the ideal detector will be derived, depending only on the temperature and the impedance of the detector. It will be shown that this limit is approximated by state of the art infrared arrays for long on-chip integrations. Different detector materials are compared and strategies to populate large focal planes are discussed. The need for the development of small-format low noise sensors for adaptive optics and interferometry will be pointed out

  6. Fatty acids activate a chimera of the clofibric acid-activated receptor and the glucocorticoid receptor.

    Science.gov (United States)

    Göttlicher, M; Widmark, E; Li, Q; Gustafsson, J A

    1992-01-01

    Peroxisome proliferators such as clofibric acid, nafenopin, and WY-14,643 have been shown to activate PPAR (peroxisome proliferator-activated receptor), a member of the steroid nuclear receptor superfamily. We have cloned the cDNA from the rat that is homologous to that from the mouse [Issemann, I. & Green, S. (1990) Nature (London) 347, 645-650], which encodes a 97% similar protein with a particularly well-conserved putative ligand-binding domain. To search for physiologically occurring activators, we established a transcriptional transactivation assay by stably expressing in CHO cells a chimera of rat PPAR and the human glucocorticoid receptor that activates expression of the placental alkaline phosphatase reporter gene under the control of the mouse mammary tumor virus promoter. Testing of compounds related to lipid metabolism or peroxisomal proliferation revealed that 150 microM concentrations of arachidonic or linoleic acid but not of dehydroepiandrosterone, cholesterol, or 25-hydroxy-cholesterol, activate the receptor chimera. In addition, saturated fatty acids induce the reporter gene. Shortening the chain length to n = 6 or introduction of an omega-terminal carboxylic group abolished the activation potential of the fatty acid. In conclusion, the present results indicate that fatty acids can regulate gene expression mediated by a member of the steroid nuclear receptor superfamily. Images PMID:1316614

  7. Exploratory Topology Modelling of Form-Active Hybrid Structures

    DEFF Research Database (Denmark)

    Holden Deleuran, Anders; Pauly, Mark; Tamke, Martin

    2016-01-01

    The development of novel form-active hybrid structures (FAHS) is impeded by a lack of modelling tools that allow for exploratory topology modelling of shaped assemblies. We present a flexible and real-time computational design modelling pipeline developed for the exploratory modelling of FAHS...... that enables designers and engineers to iteratively construct and manipulate form-active hybrid assembly topology on the fly. The pipeline implements Kangaroo2's projection-based methods for modelling hybrid structures consisting of slender beams and cable networks. A selection of design modelling sketches...

  8. CERAPP: Collaborative estrogen receptor activity prediction project

    DEFF Research Database (Denmark)

    Mansouri, Kamel; Abdelaziz, Ahmed; Rybacka, Aleksandra

    2016-01-01

    ). Risk assessors need tools to prioritize chemicals for evaluation in costly in vivo tests, for instance, within the U.S. EPA Endocrine Disruptor Screening Program. oBjectives: We describe a large-scale modeling project called CERAPP (Collaborative Estrogen Receptor Activity Prediction Project...... States and Europe to predict ER activity of a common set of 32,464 chemical structures. Quantitative structure-activity relationship models and docking approaches were employed, mostly using a common training set of 1,677 chemical structures provided by the U.S. EPA, to build a total of 40 categorical......: Individual model scores ranged from 0.69 to 0.85, showing high prediction reliabilities. Out of the 32,464 chemicals, the consensus model predicted 4,001 chemicals (12.3%) as high priority actives and 6,742 potential actives (20.8%) to be considered for further testing. conclusion: This project demonstrated...

  9. Structural basis for activation of G-protein-coupled receptors

    DEFF Research Database (Denmark)

    Gether, Ulrik; Asmar, Fazila; Meinild, Anne Kristine

    2002-01-01

    into conformational changes accompanying GPCR activation and the underlying molecular mechanism governing transition of the receptor between its active and inactive states. Using the beta2-adrenergic receptor as a model system we have obtained evidence for an evolutionary conserved activation mechanism where...... changes and receptor activation. At the current stage we are exploring the possibility of reaching this goal by direct in situ labeling of the beta2-adrenergic receptor in Xenopus laevis oocytes with conformationally sensitive fluorescent probes and parallel detection of receptor activation by co...

  10. Expression and localization of ionotropic glutamate receptor subunits in the goldfish retina--an in situ hybridization and immunocytochemical study

    NARCIS (Netherlands)

    Vandenbranden, C. A.; Kamphuis, W.; Nunes Cardozo, B.; Kamermans, M.

    2000-01-01

    The expression and distribution of AMPA, kainate and NMDA glutamate receptor subunits was studied in the goldfish retina. For the immunocytochemical localization of the AMPA receptor antisera against GluR2, GluR2/3 and GluR4 were used, and for in situ hybridization rat specific probes for GluR1 and

  11. Protease activated receptors (PARS) mediation in gyroxin biological activity

    International Nuclear Information System (INIS)

    Silva, Jose Alberto Alves da

    2009-01-01

    Gyroxin is a serine protease enzyme from the South American rattlesnake (Crotalus durissus terrificus) venom; it is only partially characterized and has multiple activities. Gyroxin induces blood coagulation, blood pressure decrease and a neurotoxic behavior named barrel rotation. The mechanisms involved in this neurotoxic activity are not known. Whereas gyroxin is a member of enzymes with high potential to become a new drug with clinical applications such as thrombin, batroxobin, ancrod, tripsyn and kalicrein, it is important to find out how gyroxin works. The analysis on agarose gel electrophoresis and circular dichroism confirmed the molecules' integrity and purity. The gyroxin intravenous administration in mice proved its neurotoxicity (barrel rotation). In vivo studies employing intravital microscopy proved that gyroxin induces vasodilation with the participation of protease activated receptors (PARs), nitric oxide and Na+K+ATPase. The leukocytes' adherence and rolling counting indicated that gyroxin has no pro inflammatory activity. Gyroxin induced platelet aggregation, which was blocked by inhibitors of PAR1 and PAR4 receptors (SCH 79797 and tcY-NH 2 , respectively). Finally, it was proved that the gyroxin temporarily alter the permeability of the blood brain barrier (BBB). Our study has shown that both the protease-activated receptors and nitric oxide are mediators involved in the biological activities of gyroxin. (author)

  12. Folding and activity of hybrid sequence, disulfide-stabilized peptides

    Energy Technology Data Exchange (ETDEWEB)

    Pease, J.H.B.; Storrs, R.W.; Wemmer, D.E. (Univ. of California, Berkeley (USA))

    1990-08-01

    Peptides have been synthesized that have hybrid sequences, partially derived from the bee venom peptide apamin and partially from the S peptide of ribonuclease A. The hybrid peptides were demonstrated by NMR spectroscopy to fold, forming the same disulfides and basic three-dimensional structure as native apamin, containing a {beta}-turn and an {alpha}-helix. These hybrids were active in complementing S protein, reactivating nuclease activity. In addition, the hybrid peptide was effective in inducing antibodies that cross-react with the RNase, without conjugation to a carrier protein. The stability of the folded structure of this peptide suggests that it should be possible to elicit antibodies that will react not only with a specific sequence, but also with a specific secondary structure. Hybrid sequence peptides also provide opportunities to study separately nucleation and propagation steps in formation of secondary structure. The authors show that in S peptide the {alpha}-helix does not end abruptly but rather terminates gradually over four or five residues. In general, these hybrid sequence peptides, which fold predictably because of disulfide bond formation, can provide opportunities for examining structure - function relationships for many biologically active sequences.

  13. Folding and activity of hybrid sequence, disulfide-stabilized peptides

    International Nuclear Information System (INIS)

    Pease, J.H.B.; Storrs, R.W.; Wemmer, D.E.

    1990-01-01

    Peptides have been synthesized that have hybrid sequences, partially derived from the bee venom peptide apamin and partially from the S peptide of ribonuclease A. The hybrid peptides were demonstrated by NMR spectroscopy to fold, forming the same disulfides and basic three-dimensional structure as native apamin, containing a β-turn and an α-helix. These hybrids were active in complementing S protein, reactivating nuclease activity. In addition, the hybrid peptide was effective in inducing antibodies that cross-react with the RNase, without conjugation to a carrier protein. The stability of the folded structure of this peptide suggests that it should be possible to elicit antibodies that will react not only with a specific sequence, but also with a specific secondary structure. Hybrid sequence peptides also provide opportunities to study separately nucleation and propagation steps in formation of secondary structure. The authors show that in S peptide the α-helix does not end abruptly but rather terminates gradually over four or five residues. In general, these hybrid sequence peptides, which fold predictably because of disulfide bond formation, can provide opportunities for examining structure - function relationships for many biologically active sequences

  14. Shunt hybrid active power filter for harmonic mitigation: A practical ...

    Indian Academy of Sciences (India)

    The increasing importance of Power Quality problems has been responsible for several improvements in Active Power Filter (APF) typologies in the last decade. The increased cost and switching losses make a pure shunt APF economically impractical for high power applications. In higher power levels shunt Hybrid Active ...

  15. Recruitment of activation receptors at inhibitory NK cell immune synapses.

    Directory of Open Access Journals (Sweden)

    Nicolas Schleinitz

    2008-09-01

    Full Text Available Natural killer (NK cell activation receptors accumulate by an actin-dependent process at cytotoxic immune synapses where they provide synergistic signals that trigger NK cell effector functions. In contrast, NK cell inhibitory receptors, including members of the MHC class I-specific killer cell Ig-like receptor (KIR family, accumulate at inhibitory immune synapses, block actin dynamics, and prevent actin-dependent phosphorylation of activation receptors. Therefore, one would predict inhibition of actin-dependent accumulation of activation receptors when inhibitory receptors are engaged. By confocal imaging of primary human NK cells in contact with target cells expressing physiological ligands of NK cell receptors, we show here that this prediction is incorrect. Target cells included a human cell line and transfected Drosophila insect cells that expressed ligands of NK cell activation receptors in combination with an MHC class I ligand of inhibitory KIR. The two NK cell activation receptors CD2 and 2B4 accumulated and co-localized with KIR at inhibitory immune synapses. In fact, KIR promoted CD2 and 2B4 clustering, as CD2 and 2B4 accumulated more efficiently at inhibitory synapses. In contrast, accumulation of KIR and of activation receptors at inhibitory synapses correlated with reduced density of the integrin LFA-1. These results imply that inhibitory KIR does not prevent CD2 and 2B4 signaling by blocking their accumulation at NK cell immune synapses, but by blocking their ability to signal within inhibitory synapses.

  16. The WSXWS motif in cytokine receptors is a molecular switch involved in receptor activation

    DEFF Research Database (Denmark)

    Dagil, Robert; Knudsen, Maiken J.; Olsen, Johan Gotthardt

    2012-01-01

    The prolactin receptor (PRLR) is activated by binding of prolactin in a 2:1 complex, but the activation mechanism is poorly understood. PRLR has a conserved WSXWS motif generic to cytokine class I receptors. We have determined the nuclear magnetic resonance solution structure of the membrane...

  17. Hybrid Active-Passive Radiation Shielding System

    Data.gov (United States)

    National Aeronautics and Space Administration — A radiation shielding system is proposed that integrates active magnetic fields with passive shielding materials. The objective is to increase the shielding...

  18. Activation of glucocorticoid receptors increases 5-HT2A receptor levels

    DEFF Research Database (Denmark)

    Trajkovska, Viktorija; Kirkegaard, Lisbeth; Krey, Gesa

    2009-01-01

    an effect of GR activation on 5-HT2A levels, mature organotypic hippocampal cultures were exposed to corticosterone with or without GR antagonist mifepristone and mineralocorticoid receptor (MR) antagonist spironolactone. In GR under-expressing mice, hippocampal 5-HT2A receptor protein levels were decreased......Major depression is associated with both dysregulation of the hypothalamic pituitary adrenal axis and serotonergic deficiency, not the least of the 5-HT2A receptor. However, how these phenomena are linked to each other, and whether a low 5-HT2A receptor level is a state or a trait marker...... of depression is unknown. In mice with altered glucocorticoid receptor (GR) expression we investigated 5-HT2A receptor levels by Western blot and 3H-MDL100907 receptor binding. Serotonin fibre density was analyzed by stereological quantification of serotonin transporter immunopositive fibers. To establish...

  19. Redox-active Hybrid Materials for Pseudocapacitive Energy Storage

    Science.gov (United States)

    Boota, Muhammad

    Organic-inorganic hybrid materials show a great promise for the purpose of manufacturing high performance electrode materials for electrochemical energy storage systems and beyond. Molecular level combination of two best suited components in a hybrid material leads to new or sometimes exceptional sets of physical, chemical, mechanical and electrochemical properties that makes them attractive for broad ranges of applications. Recently, there has been growing interest in producing redox-active hybrid nanomaterials for energy storage applications where generally the organic component provides high redox capacitance and the inorganic component offers high conductivity and robust support. While organic-inorganic hybrid materials offer tremendous opportunities for electrochemical energy storage applications, the task of matching the right organic material out of hundreds of natural and nearly unlimited synthetic organic molecules to appropriate nanostructured inorganic support hampers their electrochemical energy storage applications. We aim to present the recent development of redox-active hybrid materials for pseudocapacitive energy storage. We will show the impact of combination of suitable organic materials with distinct carbon nanostructures and/or highly conductive metal carbides (MXenes) on conductivity, charge storage performance, and cyclability. Combined experimental and molecular simulation results will be discussed to shed light on the interfacial organic-inorganic interactions, pseudocapacitive charge storage mechanisms, and likely orientations of organic molecules on conductive supports. Later, the concept of all-pseudocapacitive organic-inorganic asymmetric supercapacitors will be highlighted which open up new avenues for developing inexpensive, sustainable, and high energy density aqueous supercapacitors. Lastly, future challenges and opportunities to further tailor the redox-active hybrids will be highlighted.

  20. Modulating Estrogen Receptor-related ReceptorActivity Inhibits Cell Proliferation*

    OpenAIRE

    Bianco, Stéphanie; Lanvin, Olivia; Tribollet, Violaine; Macari, Claire; North, Sophie; Vanacker, Jean-Marc

    2009-01-01

    High expression of the estrogen receptor-related receptor (ERR)-α in human tumors is correlated to a poor prognosis, suggesting an involvement of the receptor in cell proliferation. In this study, we show that a synthetic compound (XCT790) that modulates the activity of ERRα reduces the proliferation of various cell lines and blocks the G1/S transition of the cell cycle in an ERR...

  1. Novel Platinum (Pt)-Vandetanib Hybrid Compounds: Design, Synthesis and Investigation of Anti-cancer Activity and Mechanism of Action

    Science.gov (United States)

    Fei, Rong

    Purpose: Lung cancer is one of the most common cancers and non-small cell lung cancer (NSCLC) accounts for 80-85% of lung cancers. 70% of individuals with NSCLC harboring somatic mutations in exons of the epidermal growth factor receptor (EGFR) gene that encode tyrosine kinase domain. EGFR tyrosine kinase inhibitors (TKIs) are promising molecular targeted therapy for NSCLC with sensitizing EGFR mutations. However, secondary mutation of EGFR after treatment of TKIs develops resistance. Vandetanib is introduced to overcome erlotinib resistance as a multi-targeted TKI. However, its anticancer effect is still compromised by EGFR T790M mutation. Therefore, new molecular anticancer strategies are necessarily needed. In this study, vandetanib is incorporated with Pt-based anticancer agents as hybrid compounds, aiming to circumvent TKI resistance. Furthermore, hybrid compounds are investigated in cisplatin resistant problem to expect to overcome resistance by introduction of vandetanib. Methods: Three novel Pt-vandetanib hybrid compounds were synthesized and its physicochemical properties were characterized. Anticancer activity and cytotoxicity were evaluated by sulforhodamine B assay and lactate dehydrogenase release. Docking simulation was performed to investigate the interaction of compounds with EGFR harboring different mutations. Inhibition efficacy of hybrids to kinases was evaluated by kinase inhibition profiling service and cell-free kinase inhibition assay. Mechanistic studies on cytotoxicity activity of the hybrid compounds were carried out. DNA damage response of hybrid compounds was further investigated in KB cells. The cytotoxicity of hybrids was tested in cisplatin resistant KB CP20 cells. Mechanistic of anticancer activity was studied to test inhibition on oncoprotein CIP2Aand DNA damage. Results: Platinum-vandetanib hybrid compounds were synthesized and test to be stable under extracellular condition. Hybrids reacted with 5'-GMP2- and glutathione, and both

  2. The Orphan Nuclear Receptor TR4 Is a Vitamin A-activated Nuclear Receptor

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, X. Edward; Suino-Powell, Kelly M.; Xu, Yong; Chan, Cee-Wah; Tanabe, Osamu; Kruse, Schoen W.; Reynolds, Ross; Engel, James Douglas; Xu, H. Eric (Michigan-Med); (Van Andel)

    2015-11-30

    Testicular receptors 2 and 4 (TR2/4) constitute a subgroup of orphan nuclear receptors that play important roles in spermatogenesis, lipid and lipoprotein regulation, and the development of the central nervous system. Currently, little is known about the structural features and the ligand regulation of these receptors. Here we report the crystal structure of the ligand-free TR4 ligand binding domain, which reveals an autorepressed conformation. The ligand binding pocket of TR4 is filled by the C-terminal half of helix 10, and the cofactor binding site is occupied by the AF-2 helix, thus preventing ligand-independent activation of the receptor. However, TR4 exhibits constitutive transcriptional activity on multiple promoters, which can be further potentiated by nuclear receptor coactivators. Mutations designed to disrupt cofactor binding, dimerization, or ligand binding substantially reduce the transcriptional activity of this receptor. Importantly, both retinol and retinoic acid are able to promote TR4 to recruit coactivators and to activate a TR4-regulated reporter. These findings demonstrate that TR4 is a ligand-regulated nuclear receptor and suggest that retinoids might have a much wider regulatory role via activation of orphan receptors such as TR4.

  3. Family C 7TM receptor dimerization and activation

    DEFF Research Database (Denmark)

    Bonde, Marie Mi; Sheikh, Søren P; Hansen, Jakob Lerche

    2006-01-01

    The family C seven transmembrane (7TM) receptors constitutes a small and especially well characterized subfamily of the large 7TM receptor superfamily. Approximately 50% of current prescription drugs target 7TM receptors, this biologically important family represents the largest class of drug...... to be fully defined. This review presents the biochemical support for family C 7TM receptor dimerization and discusses its importance for receptor biosynthesis, surface expression, ligand binding and activation, since lessons learnt here may well be applicable to the whole superfamily of 7TM receptors.......-targets today. It is well established that family C 7TM receptors form homo- or hetero-dimers on the cell surface of living cells. The large extra-cellular domains (ECD) have been crystallized as a dimer in the presence and absence of agonist. Upon agonist binding, the dimeric ECD undergoes large conformational...

  4. Interaction of chemokines with their receptors--from initial chemokine binding to receptor activating steps

    DEFF Research Database (Denmark)

    Thiele, Stefanie; Rosenkilde, Mette Marie

    2014-01-01

    and surveillance. Chemokines are a group of 8-12 kDa large peptides with a secondary structure consisting of a flexible N-terminus and a core-domain usually stabilized by two conserved disulfide bridges. They mainly interact with the extracellular domains of their cognate 7TM receptors. Affinityand activity......-contributing interactions are attributed to different domains and known to occur in two steps. Here, knowledge on chemokine and receptor domains involved in the first binding-step and the second activation-step is reviewed. A mechanism comprising at least two steps seems consistent; however, several intermediate...... interactions possibly occur, resulting in a multi-step process, as recently proposed for other 7TM receptors. Overall, the N-terminus of chemokine receptors is pivotal for binding of all chemokines. During receptor activation, differences between the two major chemokine subgroups occur, as CC-chemokines mainly...

  5. Design and control of hybrid active power filters

    CERN Document Server

    Lam, Chi-Seng

    2014-01-01

    Design and Control of Hybrid Active Power Filters presents an overview of the current quality problems and their compensators. To get a balance between the system cost and performance, hybrid active power filters (HAPFs) are valuable. The book presents the coverage of resonance phenomena prevention capability, filtering performance and system robustness analysis of HAPF; nonlinear inverter current slope characteristics and their linear operation region requirement analysis of the hysteresis PWM for the HAPF; minimum inverter capacity design procedure of HAPF, adaptive dc-link voltage controller for the HAPF and the real design example of a 220V 10kVA HAPF, in which the system performance analysis method, minimum dc voltage deduction concept and adaptive dc voltage idea can be further extended into the other active compensators, such as APF, static synchronous compensator STATCOM, etc. This book will benefit researchers, graduate students, and electrical power engineers in the field of power-quality compensati...

  6. Synthesis, Docking and Biological Activities of Novel Hybrids Celecoxib and Anthraquinone Analogs as Potent Cytotoxic Agents

    Directory of Open Access Journals (Sweden)

    Maha S. Almutairi

    2014-12-01

    Full Text Available Herein, novel hybrid compounds of celecoxib and 2-aminoanthraquinone derivatives have been synthesized using condensation reactions of celecoxib with 2-aminoanthraquinone derivatives or 2-aminoanthraquinon with celecoxib derivatives. Celecoxib was reacted with different acid chlorides, 2-chloroethylisocyanate and bis (2-chloroethyl amine hydrochloride. These intermediates were then reacted with 2-aminoanthraquinone. Also the same different acid chlorides and 2-chloroethylisocyanate were reacted with 2-aminoanthraquinone and the resulting intermediates were reacted with celecoxib to give isomers for the previous compounds. The antitumor activities against hepatic carcinoma tumor cell line (HEPG2 have been investigated in vitro, and all these compounds showed promising activities, especially compound 3c, 7, and 12. Flexible docking studies involving AutoDock 4.2 was investigated to identify the potential binding affinities and the mode of interaction of the hybrid compounds into two protein tyrosine kinases namely, SRC (Pp60v-src and platelet-derived growth factor receptor, PDGFR (c-Kit. The compounds in this study have a preferential affinity for the c-Kit PDGFR PTK over the non-receptor tyrosine kinase SRC (Pp60v-src.

  7. Synthesis, Docking and Biological Activities of Novel Hybrids Celecoxib and Anthraquinone Analogs as Potent Cytotoxic Agents

    Science.gov (United States)

    Almutairi, Maha S.; Hegazy, Gehan H.; Haiba, Mogedda E.; Ali, Hamed I.; Khalifa, Nagy M.; Soliman, Abd El-mohsen M.

    2014-01-01

    Herein, novel hybrid compounds of celecoxib and 2-aminoanthraquinone derivatives have been synthesized using condensation reactions of celecoxib with 2-aminoanthraquinone derivatives or 2-aminoanthraquinon with celecoxib derivatives. Celecoxib was reacted with different acid chlorides, 2-chloroethylisocyanate and bis (2-chloroethyl) amine hydrochloride. These intermediates were then reacted with 2-aminoanthraquinone. Also the same different acid chlorides and 2-chloroethylisocyanate were reacted with 2-aminoanthraquinone and the resulting intermediates were reacted with celecoxib to give isomers for the previous compounds. The antitumor activities against hepatic carcinoma tumor cell line (HEPG2) have been investigated in vitro, and all these compounds showed promising activities, especially compound 3c, 7, and 12. Flexible docking studies involving AutoDock 4.2 was investigated to identify the potential binding affinities and the mode of interaction of the hybrid compounds into two protein tyrosine kinases namely, SRC (Pp60v-src) and platelet-derived growth factor receptor, PDGFR (c-Kit). The compounds in this study have a preferential affinity for the c-Kit PDGFR PTK over the non-receptor tyrosine kinase SRC (Pp60v-src). PMID:25490139

  8. WC1 is a hybrid γδ TCR coreceptor and pattern recognition receptor for pathogenic bacteria.

    Science.gov (United States)

    Hsu, Haoting; Chen, Chuang; Nenninger, Ariel; Holz, Lauren; Baldwin, Cynthia L; Telfer, Janice C

    2015-03-01

    WC1 proteins are uniquely expressed on γδ T cells and belong to the scavenger receptor cysteine-rich (SRCR) superfamily. While present in variable, and sometimes high, numbers in the genomes of mammals and birds, in cattle there are 13 distinct genes (WC1-1 to WC1-13). All bovine WC1 proteins can serve as coreceptors for the TCR in a tyrosine phosphorylation dependent manner, and some are required for the γδ T cell response to Leptospira. We hypothesized that individual WC1 receptors encode Ag specificity via coligation of bacteria with the γδ TCR. SRCR domain binding was directly correlated with γδ T cell response, as WC1-3 SRCR domains from Leptospira-responsive cells, but not WC1-4 SRCR domains from Leptospira-nonresponsive cells, bound to multiple serovars of two Leptospira species, L. borgpetersenii, and L. interrogans. Three to five of eleven WC1-3 SRCR domains, but none of the eleven WC1-4 SRCR domains, interacted with Leptospira spp. and Borrelia burgdorferi, but not with Escherichia coli or Staphylococcus aureus. Mutational analysis indicated that the active site for bacterial binding in one of the SRCR domains is composed of amino acids in three discontinuous regions. Recombinant WC1 SRCR domains with the ability to bind leptospires inhibited Leptospira growth. Our data suggest that WC1 gene arrays play a multifaceted role in the γδ T cell response to bacteria, including acting as hybrid pattern recognition receptors and TCR coreceptors, and they may function as antimicrobials. Copyright © 2015 by The American Association of Immunologists, Inc.

  9. Hybrid Particle Swarm Optimization for Hybrid Flowshop Scheduling Problem with Maintenance Activities

    Science.gov (United States)

    Li, Jun-qing; Pan, Quan-ke; Mao, Kun

    2014-01-01

    A hybrid algorithm which combines particle swarm optimization (PSO) and iterated local search (ILS) is proposed for solving the hybrid flowshop scheduling (HFS) problem with preventive maintenance (PM) activities. In the proposed algorithm, different crossover operators and mutation operators are investigated. In addition, an efficient multiple insert mutation operator is developed for enhancing the searching ability of the algorithm. Furthermore, an ILS-based local search procedure is embedded in the algorithm to improve the exploitation ability of the proposed algorithm. The detailed experimental parameter for the canonical PSO is tuning. The proposed algorithm is tested on the variation of 77 Carlier and Néron's benchmark problems. Detailed comparisons with the present efficient algorithms, including hGA, ILS, PSO, and IG, verify the efficiency and effectiveness of the proposed algorithm. PMID:24883414

  10. Hybrid Particle Swarm Optimization for Hybrid Flowshop Scheduling Problem with Maintenance Activities

    Directory of Open Access Journals (Sweden)

    Jun-qing Li

    2014-01-01

    Full Text Available A hybrid algorithm which combines particle swarm optimization (PSO and iterated local search (ILS is proposed for solving the hybrid flowshop scheduling (HFS problem with preventive maintenance (PM activities. In the proposed algorithm, different crossover operators and mutation operators are investigated. In addition, an efficient multiple insert mutation operator is developed for enhancing the searching ability of the algorithm. Furthermore, an ILS-based local search procedure is embedded in the algorithm to improve the exploitation ability of the proposed algorithm. The detailed experimental parameter for the canonical PSO is tuning. The proposed algorithm is tested on the variation of 77 Carlier and Néron’s benchmark problems. Detailed comparisons with the present efficient algorithms, including hGA, ILS, PSO, and IG, verify the efficiency and effectiveness of the proposed algorithm.

  11. Hybrid particle swarm optimization for hybrid flowshop scheduling problem with maintenance activities.

    Science.gov (United States)

    Li, Jun-qing; Pan, Quan-ke; Mao, Kun

    2014-01-01

    A hybrid algorithm which combines particle swarm optimization (PSO) and iterated local search (ILS) is proposed for solving the hybrid flowshop scheduling (HFS) problem with preventive maintenance (PM) activities. In the proposed algorithm, different crossover operators and mutation operators are investigated. In addition, an efficient multiple insert mutation operator is developed for enhancing the searching ability of the algorithm. Furthermore, an ILS-based local search procedure is embedded in the algorithm to improve the exploitation ability of the proposed algorithm. The detailed experimental parameter for the canonical PSO is tuning. The proposed algorithm is tested on the variation of 77 Carlier and Néron's benchmark problems. Detailed comparisons with the present efficient algorithms, including hGA, ILS, PSO, and IG, verify the efficiency and effectiveness of the proposed algorithm.

  12. Encompassing receptor flexibility in virtual screening using ensemble docking-based hybrid QSAR: discovery of novel phytochemicals for BACE1 inhibition.

    Science.gov (United States)

    Chakraborty, Sandipan; Ramachandran, Balaji; Basu, Soumalee

    2014-10-01

    Mimicking receptor flexibility during receptor-ligand binding is a challenging task in computational drug design since it is associated with a large increase in the conformational search space. In the present study, we have devised an in silico design strategy incorporating receptor flexibility in virtual screening to identify potential lead compounds as inhibitors for flexible proteins. We have considered BACE1 (β-secretase), a key target protease from a therapeutic perspective for Alzheimer's disease, as the highly flexible receptor. The protein undergoes significant conformational transitions from open to closed form upon ligand binding, which makes it a difficult target for inhibitor design. We have designed a hybrid structure-activity model containing both ligand based descriptors and energetic descriptors obtained from molecular docking based on a dataset of structurally diverse BACE1 inhibitors. An ensemble of receptor conformations have been used in the docking study, further improving the prediction ability of the model. The designed model that shows significant prediction ability judged by several statistical parameters has been used to screen an in house developed 3-D structural library of 731 phytochemicals. 24 highly potent, novel BACE1 inhibitors with predicted activity (Ki) ≤ 50 nM have been identified. Detailed analysis reveals pharmacophoric features of these novel inhibitors required to inhibit BACE1.

  13. Bonding techniques for hybrid active pixel sensors (HAPS)

    Energy Technology Data Exchange (ETDEWEB)

    Bigas, M. [Centre Nacional de Microelectronica, CNM-IMB (CSIC), Campus Universitat Autonoma de Barcelona, 08193 Bellaterra, Barcelona (Spain)]. E-mail: Marc.Bigas@cnm.es; Cabruja, E. [Centre Nacional de Microelectronica, CNM-IMB (CSIC), Campus Universitat Autonoma de Barcelona, 08193 Bellaterra, Barcelona (Spain)]. E-mail: Enric.Cabruja@cnm.es; Lozano, M. [Centre Nacional de Microelectronica, CNM-IMB (CSIC), Campus Universitat Autonoma de Barcelona, 08193 Bellaterra, Barcelona (Spain)

    2007-05-01

    A hybrid active pixel sensor (HAPS) consists of an array of sensing elements which is connected to an electronic read-out unit. The most used way to connect these two different devices is bump bonding. This interconnection technique is very suitable for these systems because it allows a very fine pitch and a high number of I/Os. However, there are other interconnection techniques available such as direct bonding. This paper, as a continuation of a review [M. Lozano, E. Cabruja, A. Collado, J. Santander, M. Ullan, Nucl. Instr. and Meth. A 473 (1-2) (2001) 95-101] published in 2001, presents an update of the different advanced bonding techniques available for manufacturing a hybrid active pixel detector.

  14. Architecture for Collaborative Learning Activities in Hybrid Learning Environments

    OpenAIRE

    Ibáñez, María Blanca; Maroto, David; García Rueda, José Jesús; Leony, Derick; Delgado Kloos, Carlos

    2012-01-01

    3D virtual worlds are recognized as collaborative learning environments. However, the underlying technology is not sufficiently mature and the virtual worlds look cartoonish, unlinked to reality. Thus, it is important to enrich them with elements from the real world to enhance student engagement in learning activities. Our approach is to build learning environments where participants can either be in the real world or in its mirror world while sharing the same hybrid space in a collaborative ...

  15. Phenobarbital indirectly activates the constitutive active androstane receptor (CAR) by inhibition of epidermal growth factor receptor signaling.

    Science.gov (United States)

    Mutoh, Shingo; Sobhany, Mack; Moore, Rick; Perera, Lalith; Pedersen, Lee; Sueyoshi, Tatsuya; Negishi, Masahiko

    2013-05-07

    Phenobarbital is a central nervous system depressant that also indirectly activates nuclear receptor constitutive active androstane receptor (CAR), which promotes drug and energy metabolism, as well as cell growth (and death), in the liver. We found that phenobarbital activated CAR by inhibiting epidermal growth factor receptor (EGFR) signaling. Phenobarbital bound to EGFR and potently inhibited the binding of EGF, which prevented the activation of EGFR. This abrogation of EGFR signaling induced the dephosphorylation of receptor for activated C kinase 1 (RACK1) at Tyr(52), which then promoted the dephosphorylation of CAR at Thr(38) by the catalytic core subunit of protein phosphatase 2A. The findings demonstrated that the phenobarbital-induced mechanism of CAR dephosphorylation and activation is mediated through its direct interaction with and inhibition of EGFR.

  16. Quinoline hybrids and their antiplasmodial and antimalarial activities.

    Science.gov (United States)

    Hu, Yuan-Qiang; Gao, Chuan; Zhang, Shu; Xu, Lei; Xu, Zhi; Feng, Lian-Shun; Wu, Xiang; Zhao, Feng

    2017-10-20

    Malaria, in particular infection with P. falciparum (the most lethal of the human malaria parasite species, responsible for nearly one million deaths every year), is one of the most devastating and common infectious disease throughout the world. Beginning with quinine, quinoline containing compounds have long been used in clinical treatment of malaria and remained the mainstays of chemotherapy against malaria. The emergence of P. falciparum strains resistant to almost all antimalarials prompted medicinal chemists and biologists to study their effective replacement with an alternative mechanism of action and new molecules. Combination with variety of quinolines and other active moieties may increase the antiplasmodial and antimalarial activities and reduce the side effects. Thus, hybridization is a very attractive strategy to develop novel antimalarials. This review aims to summarize the recent advances towards the discovery of antiplasmodial and antimalarial hybrids including quinoline skeleton to provide an insight for rational designs of more active and less toxic quinoline hybrids antimalarials. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  17. Differential trafficking of AMPA receptors following activation of NMDA receptors and mGluRs

    Directory of Open Access Journals (Sweden)

    Sanderson Thomas M

    2011-07-01

    Full Text Available Abstract The removal of AMPA receptors from synapses is a major component of long-term depression (LTD. How this occurs, however, is still only partially understood. To investigate the trafficking of AMPA receptors in real-time we previously tagged the GluA2 subunit of AMPA receptors with ecliptic pHluorin and studied the effects of NMDA receptor activation. In the present study we have compared the effect of NMDA receptor and group I mGluR activation, using GluA2 tagged with super ecliptic pHluorin (SEP-GluA2 expressed in cultured hippocampal neurons. Surprisingly, agonists of the two receptors, which are both able to induce chemical forms of LTD, had clearly distinct effects on AMPA receptor trafficking. In agreement with our previous work we found that transient NMDA receptor activation results in an initial decrease in surface GluA2 from extrasynaptic sites followed by a delayed reduction in GluA2 from puncta (putative synapses. In contrast, transient activation of group I mGluRs, using DHPG, led to a pronounced but more delayed decrease in GluA2 from the dendritic shafts. Surprisingly, there was no average change in the fluorescence of the puncta. Examination of fluorescence at individual puncta, however, indicated that alterations did take place, with some puncta showing an increase and others a decrease in fluorescence. The effects of DHPG were, like DHPG-induced LTD, prevented by treatment with a protein tyrosine phosphatase (PTP inhibitor. The electrophysiological correlate of the effects of DHPG in the SEP-GluA2 infected cultures was a reduction in mEPSC frequency with no change in amplitude. The implications of these findings for the initial mechanisms of expression of both NMDA receptor- and mGluR-induced LTD are discussed.

  18. Transcriptional peroxisome proliferator-activated receptor γ ...

    African Journals Online (AJOL)

    user

    regulates slow fiber type formation during the transformation of muscle fiber type in S. prenanti. Key words: PGC-1ɑ, ... a master regulator of energy metabolism. PGC-1ɑ is identified ..... which is involved in hormone receptor families, such as ...

  19. Enhanced supercapacitance of activated vertical graphene nanosheets in hybrid electrolyte

    Science.gov (United States)

    Ghosh, Subrata; Sahoo, Gopinath; Polaki, S. R.; Krishna, Nanda Gopala; Kamruddin, M.; Mathews, Tom

    2017-12-01

    Supercapacitors are becoming the workhorse for emerging energy storage applications due to their higher power density and superior cycle life compared to conventional batteries. The performance of supercapacitors depends on the electrode material, type of electrolyte, and interaction between them. Owing to the beneficial interconnected porous structure with multiple conducting channels, vertical graphene nanosheets (VGN) have proved to be leading supercapacitor electrode materials. Herein, we demonstrate a novel approach based on the combination of surface activation and a new organo-aqueous hybrid electrolyte, tetraethylammonium tetrafluoroborate in H2SO4, to achieve significant enhancement in supercapacitor performance of VGN. As-synthesized VGN exhibits an excellent supercapacitance of 0.64 mF/cm2 in H2SO4. However, identification of a novel electrolyte for performance enhancement is the subject of current research. The present manuscript demonstrates the potential of the hybrid electrolyte in enhancing the areal capacitance (1.99 mF/cm2) with excellent retention (only 5.4% loss after 5000 cycles) and Coulombic efficiency (93.1%). In addition, a five-fold enhancement in the capacitance of VGNs (0.64 to 3.31 mF/cm2) with a reduced internal resistance is achieved by the combination of KOH activation and the hybrid electrolyte.

  20. Helix 11 Dynamics is Critical for Constitutive Androstane Receptor Activity

    OpenAIRE

    Wright, Edward; Busby, Scott A.; Wisecarver, Sarah; Vincent, Jeremy; Griffin, Patrick R.; Fernandez, Elias J.

    2011-01-01

    The constitutive androstane receptor (CAR) transactivation can occur in the absence of exogenous ligand and this activity is enhanced by agonists TCPOBOP and meclizine. We use biophysical and cell-based assays to show that increased activity of CAR(TCPOBOP) relative to CAR(meclizine) corresponds to a higher affinity of CAR(TCPOBOP) for the steroid receptor coactivator-1. Additionally, steady-state fluorescence spectra suggest conformational differences between CAR(TCPOBOP):RXR and CAR(meclizi...

  1. Mincle suppresses Toll-like receptor 4 activation.

    Science.gov (United States)

    Greco, Stephanie H; Mahmood, Syed Kashif; Vahle, Anne-Kristin; Ochi, Atsuo; Batel, Jennifer; Deutsch, Michael; Barilla, Rocky; Seifert, Lena; Pachter, H Leon; Daley, Donnele; Torres-Hernandez, Alejandro; Hundeyin, Mautin; Mani, Vishnu R; Miller, George

    2016-07-01

    Regulation of Toll-like receptor responses is critical for limiting tissue injury and autoimmunity in both sepsis and sterile inflammation. We found that Mincle, a C-type lectin receptor, regulates proinflammatory Toll-like receptor 4 signaling. Specifically, Mincle ligation diminishes Toll-like receptor 4-mediated inflammation, whereas Mincle deletion or knockdown results in marked hyperresponsiveness to lipopolysaccharide in vitro, as well as overwhelming lipopolysaccharide-mediated inflammation in vivo. Mechanistically, Mincle deletion does not up-regulate Toll-like receptor 4 expression or reduce interleukin 10 production after Toll-like receptor 4 ligation; however, Mincle deletion decreases production of the p38 mitogen-activated protein kinase-dependent inhibitory intermediate suppressor of cytokine signaling 1, A20, and ABIN3 and increases expression of the Toll-like receptor 4 coreceptor CD14. Blockade of CD14 mitigates the increased sensitivity of Mincle(-/-) leukocytes to Toll-like receptor 4 ligation. Collectively, we describe a major role for Mincle in suppressing Toll-like receptor 4 responses and implicate its importance in nonmycobacterial models of inflammation. © Society for Leukocyte Biology.

  2. Active graphene-silicon hybrid diode for terahertz waves.

    Science.gov (United States)

    Li, Quan; Tian, Zhen; Zhang, Xueqian; Singh, Ranjan; Du, Liangliang; Gu, Jianqiang; Han, Jiaguang; Zhang, Weili

    2015-05-11

    Controlling the propagation properties of the terahertz waves in graphene holds great promise in enabling novel technologies for the convergence of electronics and photonics. A diode is a fundamental electronic device that allows the passage of current in just one direction based on the polarity of the applied voltage. With simultaneous optical and electrical excitations, we experimentally demonstrate an active diode for the terahertz waves consisting of a graphene-silicon hybrid film. The diode transmits terahertz waves when biased with a positive voltage while attenuates the wave under a low negative voltage, which can be seen as an analogue of an electronic semiconductor diode. Here, we obtain a large transmission modulation of 83% in the graphene-silicon hybrid film, which exhibits tremendous potential for applications in designing broadband terahertz modulators and switchable terahertz plasmonic and metamaterial devices.

  3. Tyrosinase Inhibitor Activity of Coumarin-Resveratrol Hybrids

    Directory of Open Access Journals (Sweden)

    Giovanna Delogu

    2009-07-01

    Full Text Available In the present work we report on the contribution of the coumarin moiety to tyrosinase inhibition. Coumarin-resveratrol hybrids 1-8 have been resynthesized to investigate the structure-activity relationships and the IC50 values of these compounds were measured. The results showed that these compounds exhibited tyrosinase inhibitory activity. Compound 3-(3’,4’,5’-trihydroxyphenyl-6,8-dihydroxycoumarin (8is the most potentcompound (0.27 mM, more so than umbelliferone (0.42 mM, used as reference compound. The kinetic studies revealed that compound 8 caused non-competitive tyrosinase inhibition.

  4. Tyrosinase inhibitor activity of coumarin-resveratrol hybrids.

    Science.gov (United States)

    Fais, Antonella; Corda, Marcella; Era, Benedetta; Fadda, M Benedetta; Matos, Maria Joao; Quezada, Elias; Santana, Lourdes; Picciau, Carmen; Podda, Gianni; Delogu, Giovanna

    2009-07-13

    In the present work we report on the contribution of the coumarin moiety to tyrosinase inhibition. Coumarin-resveratrol hybrids 1-8 have been resynthesized to investigate the structure-activity relationships and the IC(50) values of these compounds were measured. The results showed that these compounds exhibited tyrosinase inhibitory activity. Compound 3-(3',4',5'-trihydroxyphenyl)-6,8-dihydroxycoumarin (8)is the most potentcompound (0.27 mM), more so than umbelliferone (0.42 mM), used as reference compound. The kinetic studies revealed that compound 8 caused non-competitive tyrosinase inhibition.

  5. The Tower: Modelling, Analysis and Construction of Bending Active Tensile Membrane Hybrid Structures

    DEFF Research Database (Denmark)

    Holden Deleuran, Anders; Schmeck, Michel; Charles Quinn, Gregory

    2015-01-01

    The project is the result of an interdisciplinary research collaboration between CITA, KET and Fibrenamics exploring the design of integrated hybrid structures employing bending active elements and tensile membranes with bespoke material properties and detailing. Hybrid structures are defined her...

  6. Yeast two-hybrid screening of proteins interacting with plasmin receptor subunit: C-terminal fragment of annexin A2.

    Science.gov (United States)

    Li, Qun; Laumonnier, Yves; Syrovets, Tatiana; Simmet, Thomas

    2011-11-01

    To identify proteins that interact with the C-terminal fragment of annexin A2 (A2IC), generated by plasmin cleavage of the plasmin receptor, a heterotetramer (AA2t) containing annexin A2. The gene that encodes the A2IC fragment was obtained from PCR-amplified cDNA isolated from human monocytes, and was ligated into the pBTM116 vector using a DNA ligation kit. The resultant plasmid (pBTM116-A2IC) was sequenced with an ABI PRISM 310 Genetic Analyzer. The expression of an A2IC bait protein fused with a LexA-DNA binding domain (BD) was determined using Western blot analysis. The identification of proteins that interact with A2IC and are encoded in a human monocyte cDNA library was performed using yeast two-hybrid screening. The DNA sequences of the relevant cDNAs were determined using an ABI PRISM BigDye terminator cycle sequencing ready reaction kit. Nucleotide sequence databases were searched for homologous sequences using BLAST search analysis (http://www.ncbi.nlm.nih.gov). Confirmation of the interaction between the protein LexA-A2IC and each of cathepsin S and SNX17 was conducted using a small-scale yeast transformation and X-gal assay. The yeast transformed with plasmids encoding the bait proteins were screened with a human monocyte cDNA library by reconstituting full-length transcription factors containing the GAL4-active domain (GAL4-AD) as the prey in a yeast two-hybrid approach. After screening 1×10(7) clones, 23 independent β-Gal-positive clones were identified. Sequence analysis and a database search revealed that 15 of these positive clones matched eight different proteins (SNX17, ProCathepsin S, RPS2, ZBTB4, OGDH, CCDC32, PAPD4, and actin which was already known to interact with annexin A2). A2IC A2IC interacts with various proteins to form protein complexes, which may contribute to the molecular mechanism of monocyte activation induced by plasmin. The yeast two-hybrid system is an efficient approach for investigating protein interactions.

  7. Natural Cinnamic Acids, Synthetic Derivatives and Hybrids with Antimicrobial Activity

    Directory of Open Access Journals (Sweden)

    Juan David Guzman

    2014-11-01

    Full Text Available Antimicrobial natural preparations involving cinnamon, storax and propolis have been long used topically for treating infections. Cinnamic acids and related molecules are partly responsible for the therapeutic effects observed in these preparations. Most of the cinnamic acids, their esters, amides, aldehydes and alcohols, show significant growth inhibition against one or several bacterial and fungal species. Of particular interest is the potent antitubercular activity observed for some of these cinnamic derivatives, which may be amenable as future drugs for treating tuberculosis. This review intends to summarize the literature data on the antimicrobial activity of the natural cinnamic acids and related derivatives. In addition, selected hybrids between cinnamic acids and biologically active scaffolds with antimicrobial activity were also included. A comprehensive literature search was performed collating the minimum inhibitory concentration (MIC of each cinnamic acid or derivative against the reported microorganisms. The MIC data allows the relative comparison between series of molecules and the derivation of structure-activity relationships.

  8. Differential ontogenetic patterns of levocabastine-sensitive neurotensin NT2 receptors and of NT1 receptors in the rat brain revealed by in situ hybridization.

    Science.gov (United States)

    Lépée-Lorgeoux, I; Betancur, C; Rostène, W; Pélaprat, D

    1999-03-12

    The postnatal ontogeny of the levocabastine-sensitive neurotensin receptor (NT2) mRNA was studied by in situ hybridization in the rat brain and compared with the distribution of the levocabastine-insensitive NT1 receptor. NT2 receptor mRNA was absent at birth from all brain structures except the ependymal cell layer lining the ventricles. The development of NT2 receptor mRNA followed three ontogenetic patterns. The first pattern, involving the majority of the cerebral gray matter, was characterized by a continuous increase from postnatal day 5 (P5) to P30. The second one, involving regions rich in myelinated fibers such as the corpus callosum and lacunosum moleculare layer of the hippocampus, exhibited a pronounced increase between P5 and P10, peaked at P15 and was followed by a plateau or a slight decrease. The third pattern was observed in the ependymal cell layer lining the olfactory and lateral ventricles, where the high labeling already present at birth continued to increase during development. These different developmental patterns could reflect the variety of cells expressing NT2 receptor mRNA, including neurons, protoplasmic astrocytes in gray matter, fibrous astrocytes present in myelinated fibers tracts, and ependymal cells. In contrast, NT1 receptor mRNA, which seems to be associated only with neurons, was highly and transiently expressed during the perinatal period in the cerebral cortex, hippocampus and striatal neuroepithelium. Other regions, notably the ventral tegmental area and substantia nigra compacta, exhibited a gradual increase in NT1 receptor signal, reaching adult levels by P21. Both the differential localization and ontogenetic profiles of NT1 and NT2 receptor mRNAs suggest different involvement of these two receptors in brain functions and development. Copyright 1999 Elsevier Science B.V.

  9. 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

  10. Modulation of β-catenin signaling by glucagon receptor activation.

    Directory of Open Access Journals (Sweden)

    Jiyuan Ke

    Full Text Available The glucagon receptor (GCGR is a member of the class B G protein-coupled receptor family. Activation of GCGR by glucagon leads to increased glucose production by the liver. Thus, glucagon is a key component of glucose homeostasis by counteracting the effect of insulin. In this report, we found that in addition to activation of the classic cAMP/protein kinase A (PKA pathway, activation of GCGR also induced β-catenin stabilization and activated β-catenin-mediated transcription. Activation of β-catenin signaling was PKA-dependent, consistent with previous reports on the parathyroid hormone receptor type 1 (PTH1R and glucagon-like peptide 1 (GLP-1R receptors. Since low-density-lipoprotein receptor-related protein 5 (Lrp5 is an essential co-receptor required for Wnt protein mediated β-catenin signaling, we examined the role of Lrp5 in glucagon-induced β-catenin signaling. Cotransfection with Lrp5 enhanced the glucagon-induced β-catenin stabilization and TCF promoter-mediated transcription. Inhibiting Lrp5/6 function using Dickkopf-1(DKK1 or by expression of the Lrp5 extracellular domain blocked glucagon-induced β-catenin signaling. Furthermore, we showed that Lrp5 physically interacted with GCGR by immunoprecipitation and bioluminescence resonance energy transfer assays. Together, these results reveal an unexpected crosstalk between glucagon and β-catenin signaling, and may help to explain the metabolic phenotypes of Lrp5/6 mutations.

  11. CINPA1 Is an Inhibitor of Constitutive Androstane Receptor That Does Not Activate Pregnane X Receptor

    OpenAIRE

    Cherian, Milu T; Lin, Wenwei; Wu, Jing; Chen, Taosheng

    2015-01-01

    Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are xenobiotic sensors that enhance the detoxification and elimination of xenobiotics and endobiotics by modulating the expression of genes encoding drug-metabolizing enzymes and transporters. Elevated levels of drug-metabolizing enzymes and efflux transporters, resulting from CAR activation in various cancers, promote the elimination of chemotherapeutic agents, leading to reduced therapeutic effectiveness and acquired drug ...

  12. Pharmacological characterization of receptor-activity-modifying proteins (RAMPs) and the human calcitonin receptor.

    Science.gov (United States)

    Armour, S L; Foord, S; Kenakin, T; Chen, W J

    1999-12-01

    Receptor-activity-modifying proteins (RAMPs) are a family of single transmembrane domain proteins shown to be important for the transport and ligand specificity of the calcitonin gene-related peptide (CGRP) receptor. In this report, we describe the analysis of pharmacological properties of the human calcitonin receptor (hCTR) coexpressed with different RAMPs with the use of the Xenopus laevis melanophore expression system. We show that coexpression of RAMP3 with human calcitonin receptor changed the relative potency of hCTR to human calcitonin (hCAL) and rat amylin. RAMP1 and RAMP2, in contrast, had little effect on the change of hCTR potency to hCAL or rat amylin. When coexpressed with RAMP3, hCTR reversed the relative potency by a 3.5-fold loss in sensitivity to hCAL and a 19-fold increase in sensitivity to rat amylin. AC66, an inverse agonist, produced apparent simple competitive antagonism of hCAL and rat amylin, as indicated by linear Schild regressions. The potency of AC66 was changed in the blockade of rat amylin but not hCAL responses with RAMP3 coexpression. The mean pK(B) for AC66 to hCAL was 9.4 +/- 0.3 without RAMP3 and 9.45 +/- 0.07 with RAMP3. For the antagonism of AC66 to rat amylin, the pK(B) was 9.25 +/- 0.15 without RAMP3 and 8.2 +/- 0.35 with RAMP3. The finding suggests that RAMP3 might modify the active states of calcitonin receptor in such a way as to create a new receptor phenotype that is "amylin-like." Irrespective of the physiological association of the new receptor species, the finding that a coexpressed membrane protein can completely change agonist and antagonist affinities for a receptor raises implications for screening in recombinant receptor systems.

  13. Dynamic regulation of Drosophila nuclear receptor activity in vivo.

    Science.gov (United States)

    Palanker, Laura; Necakov, Aleksandar S; Sampson, Heidi M; Ni, Ruoyu; Hu, Chun; Thummel, Carl S; Krause, Henry M

    2006-09-01

    Nuclear receptors are a large family of transcription factors that play major roles in development, metamorphosis, metabolism and disease. To determine how, where and when nuclear receptors are regulated by small chemical ligands and/or protein partners, we have used a 'ligand sensor' system to visualize spatial activity patterns for each of the 18 Drosophila nuclear receptors in live developing animals. Transgenic lines were established that express the ligand binding domain of each nuclear receptor fused to the DNA-binding domain of yeast GAL4. When combined with a GAL4-responsive reporter gene, the fusion proteins show tissue- and stage-specific patterns of activation. We show that these responses accurately reflect the presence of endogenous and exogenously added hormone, and that they can be modulated by nuclear receptor partner proteins. The amnioserosa, yolk, midgut and fat body, which play major roles in lipid storage, metabolism and developmental timing, were identified as frequent sites of nuclear receptor activity. We also see dynamic changes in activation that are indicative of sweeping changes in ligand and/or co-factor production. The screening of a small compound library using this system identified the angular psoralen angelicin and the insect growth regulator fenoxycarb as activators of the Ultraspiracle (USP) ligand-binding domain. These results demonstrate the utility of this system for the functional dissection of nuclear receptor pathways and for the development of new receptor agonists and antagonists that can be used to modulate metabolism and disease and to develop more effective means of insect control.

  14. Opportunistic activation of TRP receptors by endogenous lipids: exploiting lipidomics to understand TRP receptor cellular communication.

    Science.gov (United States)

    Bradshaw, Heather B; Raboune, Siham; Hollis, Jennifer L

    2013-03-19

    Transient receptor potential channels (TRPs) form a large family of ubiquitous non-selective cation channels that function as cellular sensors and in many cases regulate intracellular calcium. Identification of the endogenous ligands that activate these TRP receptors is still under intense investigation with the majority of these channels still remaining "orphans." That these channels respond to a variety of external stimuli (e.g. plant-derived lipids, changes in temperature, and changes in pH) provides a framework for their abilities as cellular sensors, however, the mechanism of direct activation is still under much debate and research. In the cases where endogenous ligands (predominately lipids) have shown direct activation of a channel, multiple ligands have been shown to activate the same channel suggesting that these receptors are "promiscuous" in nature. Lipidomics of a growing class of endogenous lipids, N-acyl amides, the most famous of which is N-arachidonoyl ethanolamine (the endogenous cannabinoid, Anandamide) is providing a novel set of ligands that have been shown to activate some members of the TRP family and have the potential to deorphanize many more. Here it is argued that activation of TRPV receptors, a subset of the larger family of TRPs, by multiple endogenous lipids that are structurally analogous is a model system to drive our understanding that many TRP receptors are not promiscuous, but are more characteristically "opportunistic" in nature; exploiting the structural similarity and biosynthesis of a narrow range of analogous endogenous lipids. In addition, this manuscript will compare the activation properties of TRPC5 to the activity profile of an "orphan" lipid, N-palmitoyl glycine; further demonstrating that lipidomics aimed at expanding our knowledge of the family of N-acyl amides has the potential to provide novel avenues of research for TRP receptors. Copyright © 2012 Elsevier Inc. All rights reserved.

  15. Activation of Adenylyl Cyclase Causes Stimulation of Adenosine Receptors

    Directory of Open Access Journals (Sweden)

    Thomas Pleli

    2018-03-01

    Full Text Available Background/Aims: Signaling of Gs protein-coupled receptors (GsPCRs is accomplished by stimulation of adenylyl cyclase, causing an increase of the intracellular cAMP concentration, activation of the intracellular cAMP effectors protein kinase A (PKA and Epac, and an efflux of cAMP, the function of which is still unclear. Methods: Activation of adenylyl cyclase by GsPCR agonists or cholera toxin was monitored by measurement of the intracellular cAMP concentration by ELISA, anti-phospho-PKA substrate motif phosphorylation by immunoblotting, and an Epac-FRET assay in the presence and absence of adenosine receptor antagonists or ecto-nucleotide phosphodiesterase/pyrophosphatase2 (eNPP2 inhibitors. The production of AMP from cAMP by recombinant eNPP2 was measured by HPLC. Extracellular adenosine was determined by LC-MS/MS, extracellular ATP by luciferase and LC-MS/MS. The expression of eNPP isoenzymes 1-3 was examined by RT-PCR. The expression of multidrug resistance protein 4 was suppressed by siRNA. Results: Here we show that the activation of GsPCRs and the GsPCRs-independent activation of Gs proteins and adenylyl cyclase by cholera toxin induce stimulation of cell surface adenosine receptors (A2A or A2B adenosine receptors. In PC12 cells stimulation of adenylyl cyclase by GsPCR or cholera toxin caused activation of A2A adenosine receptors by an autocrine signaling pathway involving cAMP efflux through multidrug resistance protein 4 and hydrolysis of released cAMP to AMP by eNPP2. In contrast, in PC3 cells cholera toxin- and GsPCR-induced stimulation of adenylyl cyclase resulted in the activation of A2B adenosine receptors. Conclusion: Our findings show that stimulation of adenylyl cyclase causes a remarkable activation of cell surface adenosine receptors.

  16. Flavonoids with M1 Muscarinic Acetylcholine Receptor Binding Activity

    Directory of Open Access Journals (Sweden)

    Meyyammai Swaminathan

    2014-06-01

    Full Text Available Muscarinic acetylcholine receptor-active compounds have potential for the treatment of Alzheimer’s disease. In this study, a series of natural and synthetic flavones and flavonols was assayed in vitro for their ability to inhibit radioligand binding at human cloned M1 muscarinic receptors. Several compounds were found to possess competitive binding affinity (Ki = 40–110 µM, comparable to that of acetylcholine (Ki = 59 µM. Despite the fact that these compounds lack a positively-charged ammonium group under physiological conditions, molecular modelling studies suggested that they bind to the orthosteric site of the receptor, mainly through non-polar interactions.

  17. Assembly and activation of neurotrophic factor receptor complexes.

    Science.gov (United States)

    Simi, Anastasia; Ibáñez, Carlos F

    2010-04-01

    Neurotrophic factors play important roles in the development and function of both neuronal and glial elements of the central and peripheral nervous systems. Their functional diversity is in part based on their ability to interact with alternative complexes of receptor molecules. This review focuses on our current understanding of the mechanisms that govern the assembly and activation of neurotrophic factor receptor complexes. The realization that many, if not the majority, of these complexes exist in a preassembled form at the plasma membrane has forced the revision of classical ligand-mediated oligomerization models, and led to the discovery of novel mechanisms of receptor activation and generation of signaling diversity which are likely to be shared by many different classes of receptors.

  18. Active diagnosis of hybrid systems - A model predictive approach

    DEFF Research Database (Denmark)

    Tabatabaeipour, Seyed Mojtaba; Ravn, Anders P.; Izadi-Zamanabadi, Roozbeh

    2009-01-01

    A method for active diagnosis of hybrid systems is proposed. The main idea is to predict the future output of both normal and faulty model of the system; then at each time step an optimization problem is solved with the objective of maximizing the difference between the predicted normal and fault...... can be used as a test signal for sanity check at the commissioning or for detection of faults hidden by regulatory actions of the controller. The method is tested on the two tank benchmark example. ©2009 IEEE....

  19. Calibrated and Interactive Modelling of Form-Active Hybrid Structures

    DEFF Research Database (Denmark)

    Quinn, Gregory; Holden Deleuran, Anders; Piker, Daniel

    2016-01-01

    Form-active hybrid structures (FAHS) couple two or more different structural elements of low self weight and low or negligible bending flexural stiffness (such as slender beams, cables and membranes) into one structural assembly of high global stiffness. They offer high load-bearing capacity...... software packages which introduce interruptions and data exchange issues in the modelling pipeline. The mechanical precision, stability and open software architecture of Kangaroo has facilitated the development of proof-of-concept modelling pipelines which tackle this challenge and enable powerful...... materially-informed sketching. Making use of a projection-based dynamic relaxation solver for structural analysis, explorative design has proven to be highly effective....

  20. Localization of glucocorticoid receptor mRNA in the male rat brain by in situ hybridization

    International Nuclear Information System (INIS)

    Aronsson, M.; Fuxe, K.; Dong, Y.; Agnati, L.F.; Okret, S.; Gustafsson, J.A.

    1988-01-01

    The localization and distribution of mRNA encoding the glucocorticoid receptor (GR) was investigated in tissue sections of the adult male rat brain by in situ hybridization and RNA blot analysis. GR mRNA levels were measured by quantitative autoradiography with 35S- and 32P-labeled RNA probes, respectively. Strong labeling was observed within the pyramidal nerve cells of the CA1 and CA2 areas of the hippocampal formation, in the granular cells of the dentate gyrus, in the parvocellular nerve cells of the paraventricular hypothalamic nucleus, and in the cells of the arcuate nucleus, especially the parvocellular part. Moderate labeling of a large number of nerve cells was observed within layers II, III, and VI of the neocortex and in many thalamic nuclei, especially the anterior and ventral nuclear groups as well as several midline nuclei. Within the cerebellar cortex, strong labeling was observed all over the granular layer. In the lower brainstem, strong labeling was found within the entire locus coeruleus and within the mesencephalic raphe nuclei rich in noradrenaline and 5-hydroxytryptamine cell bodies, respectively. A close correlation was found between the distribution of GR mRNA and the distribution of previously described GR immunoreactivity. These studies open the possibility of obtaining additional information on in vivo regulation of GR synthesis and how the brain may alter its sensitivity to circulating glucocorticoids

  1. Quantum chemical study of agonist-receptor vibrational interactions for activation of the glutamate receptor.

    Science.gov (United States)

    Kubo, M; Odai, K; Sugimoto, T; Ito, E

    2001-06-01

    To understand the mechanism of activation of a receptor by its agonist, the excitation and relaxation processes of the vibrational states of the receptor should be examined. As a first approach to this problem, we calculated the normal vibrational modes of agonists (glutamate and kainate) and an antagonist (6-cyano-7-nitroquinoxaline-2,3-dione: CNQX) of the glutamate receptor, and then investigated the vibrational interactions between kainate and the binding site of glutamate receptor subunit GluR2 by use of a semiempirical molecular orbital method (MOPAC2000-PM3). We found that two local vibrational modes of kainate, which were also observed in glutamate but not in CNQX, interacted through hydrogen bonds with the vibrational modes of GluR2: (i) the bending vibration of the amine group of kainate, interacting with the stretching vibration of the carboxyl group of Glu705 of GluR2, and (ii) the symmetric stretching vibration of the carboxyl group of kainate, interacting with the bending vibration of the guanidinium group of Arg485. We also found collective modes with low frequency at the binding site of GluR2 in the kainate-bound state. The vibrational energy supplied by an agonist may flow from the high-frequency local modes to the low-frequency collective modes in a receptor, resulting in receptor activation.

  2. Peroxisome Proliferator-Activated Receptor and Vitamin D Receptor Signaling Pathways in Cancer Cells

    Directory of Open Access Journals (Sweden)

    Yasuko Kitagishi

    2013-10-01

    Full Text Available Peroxisome proliferator-activated receptors (PPARs are members of the superfamily of nuclear hormone receptors, which respond to specific ligands such as polyunsaturated fatty acids by altering gene expression. Three subtypes of this receptor have been discovered, each evolving to achieve different biological functions. Like other nuclear receptors, the transcriptional activity of PPARs is affected not only by ligand-stimulation, but also by cross-talk with other molecules. For example, both PPARs and the RXRs are ligand-activated transcription factors that coordinately regulate gene expression. In addition, PPARs and vitamin D receptor (VDR signaling pathways regulate a multitude of genes that are of importance for cellular functions including cell proliferation and cell differentiation. Interaction of the PPARs and VDR signaling pathways has been shown at the level of molecular cross-regulation of their transcription factor. A variety of ligands influencing the PPARs and VDR signaling pathways have been shown to reveal chemopreventive potential by mediating tumor suppressive activities in human cancers. Use of these compounds may represent a potential novel strategy to prevent cancers. This review summarizes the roles of the PPARs and the VDR in pathogenesis and progression of cancer.

  3. Peroxisome Proliferator-Activated Receptor and Vitamin D Receptor Signaling Pathways in Cancer Cells

    Energy Technology Data Exchange (ETDEWEB)

    Matsuda, Satoru, E-mail: smatsuda@cc.nara-wu.ac.jp; Kitagishi, Yasuko [Department of Food Science and Nutrition, Nara Women’s University, Kita-Uoya Nishimachi, Nara 630-8506 (Japan)

    2013-10-21

    Peroxisome proliferator-activated receptors (PPARs) are members of the superfamily of nuclear hormone receptors, which respond to specific ligands such as polyunsaturated fatty acids by altering gene expression. Three subtypes of this receptor have been discovered, each evolving to achieve different biological functions. Like other nuclear receptors, the transcriptional activity of PPARs is affected not only by ligand-stimulation, but also by cross-talk with other molecules. For example, both PPARs and the RXRs are ligand-activated transcription factors that coordinately regulate gene expression. In addition, PPARs and vitamin D receptor (VDR) signaling pathways regulate a multitude of genes that are of importance for cellular functions including cell proliferation and cell differentiation. Interaction of the PPARs and VDR signaling pathways has been shown at the level of molecular cross-regulation of their transcription factor. A variety of ligands influencing the PPARs and VDR signaling pathways have been shown to reveal chemopreventive potential by mediating tumor suppressive activities in human cancers. Use of these compounds may represent a potential novel strategy to prevent cancers. This review summarizes the roles of the PPARs and the VDR in pathogenesis and progression of cancer.

  4. Peroxisome Proliferator-Activated Receptor and Vitamin D Receptor Signaling Pathways in Cancer Cells

    International Nuclear Information System (INIS)

    Matsuda, Satoru; Kitagishi, Yasuko

    2013-01-01

    Peroxisome proliferator-activated receptors (PPARs) are members of the superfamily of nuclear hormone receptors, which respond to specific ligands such as polyunsaturated fatty acids by altering gene expression. Three subtypes of this receptor have been discovered, each evolving to achieve different biological functions. Like other nuclear receptors, the transcriptional activity of PPARs is affected not only by ligand-stimulation, but also by cross-talk with other molecules. For example, both PPARs and the RXRs are ligand-activated transcription factors that coordinately regulate gene expression. In addition, PPARs and vitamin D receptor (VDR) signaling pathways regulate a multitude of genes that are of importance for cellular functions including cell proliferation and cell differentiation. Interaction of the PPARs and VDR signaling pathways has been shown at the level of molecular cross-regulation of their transcription factor. A variety of ligands influencing the PPARs and VDR signaling pathways have been shown to reveal chemopreventive potential by mediating tumor suppressive activities in human cancers. Use of these compounds may represent a potential novel strategy to prevent cancers. This review summarizes the roles of the PPARs and the VDR in pathogenesis and progression of cancer

  5. Neurotrophin receptors expression and JNK pathway activation in human astrocytomas

    International Nuclear Information System (INIS)

    Assimakopoulou, Martha; Kondyli, Maria; Gatzounis, George; Maraziotis, Theodore; Varakis, John

    2007-01-01

    Neurotrophins are growth factors that regulate cell growth, differentiation and apoptosis in the nervous system. Their diverse actions are mediated through two different transmembrane – receptor signaling systems: Trk receptor tyrosine kinases (TrkA, TrkB, TrkC) and p75 NTR neurotrophin receptor. Trk receptors promote cell survival and differentiation while p75 NTR induces, in most cases, the activity of JNK-p53-Bax apoptosis pathway or suppresses intracellular survival signaling cascades. Robust Trk activation blocks p75 NTR -induced apoptosis by suppressing the JNK-p53-Bax pathway. The aim of this exploratory study was to investigate the expression levels of neurotrophin receptors, Trks and p75 NTR , and the activation of JNK pathway in human astrocytomas and in adjacent non-neoplastic brain tissue. Formalin-fixed paraffin-embedded serial sections from 33 supratentorial astrocytomas (5 diffuse fibrillary astrocytomas, WHO grade II; 6 anaplastic astrocytomas, WHO grade III; 22 glioblastomas multiforme, WHO grade IV) were immunostained following microwave pretreatment. Polyclonal antibodies against TrkA, TrkB, TrkC and monoclonal antibodies against p75 NTR and phosphorylated forms of JNK (pJNK) and c-Jun (pc-Jun) were used. The labeling index (LI), defined as the percentage of positive (labeled) cells out of the total number of tumor cells counted, was determined. Moderate to strong, granular cytoplasmic immunoreactivity for TrkA, TrkB and TrkC receptors was detected in greater than or equal to 10% of tumor cells in the majority of tumors independently of grade; on the contrary, p75 NTR receptor expression was found in a small percentage of tumor cells (~1%) in some tumors. The endothelium of tumor capillaries showed conspicuous immunoreactivity for TrkB receptor. Trk immunoreactivity seemed to be localized in some neurons and astrocytes in non-neoplastic tissue. Phosphorylated forms of JNK (pJNK) and c-Jun (pc-Jun) were significantly co-expressed in a tumor

  6. The metabotropic glutamate receptors: structure, activation mechanism and pharmacology.

    Science.gov (United States)

    Pin, Jean-Philippe; Acher, Francine

    2002-06-01

    The metabotropic glutamate receptors are G-protein coupled receptors (GPCR) involved in the regulation of many synapses, including most glutamatergic fast excitatory synapses. Eight subtypes have been identified that can be classified into three groups. The molecular characterization of these receptors revealed proteins much more complex than any other GPCRs. They are composed of a Venus Flytrap (VFT) module where glutamate binds, connected to a heptahelical domain responsible for G-protein coupling. Recent data including the structure of the VFT module determined with and without glutamate, indicate that these receptors function as dimers. Moreover a number of intracellular proteins can regulate their targeting and transduction mechanism. Such structural features of mGlu receptors offer multiple possibilities for synthetic compounds to modulate their activity. In addition to agonists and competitive antagonists acting at the glutamate binding site, a number of non-competitive antagonists with inverse agonist activity, and positive allosteric modulators have been discovered. These later compounds share specific properties that make them good candidates for therapeutic applications. First, their non-amino acid structure makes them pass more easily the blood brain barrier. Second, they are much more selective than any other compound identified so far, being the first subtype selective molecules. Third, for the negative modulators, their non competitive mechanism of action makes them relatively unaffected by high concentrations of glutamate that may be present in disease states (e.g. stroke, epilepsy, neuropathic pain, etc.). Fourth, like the benzodiazepines acting at the GABA(A) receptors, the positive modulators offer a new way to increase the activity of these receptors in vivo, with a low risk of inducing their desensitization. The present review article focuses on the specific structural features of these receptors and highlights the various possibilities these

  7. Phenolic Compounds and Antioxidant Activity of Phalaenopsis Orchid Hybrids

    Directory of Open Access Journals (Sweden)

    Truong Ngoc Minh

    2016-09-01

    Full Text Available Phalaenopsis spp. is the most commercially and economically important orchid, but their plant parts are often left unused, which has caused environmental problems. To date, reports on phytochemical analyses were most available on endangered and medicinal orchids. The present study was conducted to determine the total phenolics, total flavonoids, and antioxidant activity of ethanol extracts prepared from leaves and roots of six commercial hybrid Phalaenopsis spp. Leaf extracts of “Chian Xen Queen” contained the highest total phenolics with a value of 11.52 ± 0.43 mg gallic acid equivalent per g dry weight and the highest total flavonoids (4.98 ± 0.27 mg rutin equivalent per g dry weight. The antioxidant activity of root extracts evaluated by DPPH (2,2-diphenyl-1-picrylhydrazyl free radical scavenging assay and β-carotene bleaching method was higher than those of the leaf extracts. Eleven phenolic compounds were identified, namely, protocatechuic acid, p-hydroxybenzoic acid, vanillic acid, caffeic acid, syringic acid, vanillin, ferulic acid, sinapic acid, p-coumaric acid, benzoic acid, and ellagic acid. Ferulic, p-coumaric and sinapic acids were concentrated largely in the roots. The results suggested that the root extracts from hybrid Phalaenopsis spp. could be a potential source of natural antioxidants. This study also helps to reduce the amount of this orchid waste in industrial production, as its roots can be exploited for pharmaceutical purposes.

  8. Active Low Intrusion Hybrid Monitor for Wireless Sensor Networks.

    Science.gov (United States)

    Navia, Marlon; Campelo, Jose C; Bonastre, Alberto; Ors, Rafael; Capella, Juan V; Serrano, Juan J

    2015-09-18

    Several systems have been proposed to monitor wireless sensor networks (WSN). These systems may be active (causing a high degree of intrusion) or passive (low observability inside the nodes). This paper presents the implementation of an active hybrid (hardware and software) monitor with low intrusion. It is based on the addition to the sensor node of a monitor node (hardware part) which, through a standard interface, is able to receive the monitoring information sent by a piece of software executed in the sensor node. The intrusion on time, code, and energy caused in the sensor nodes by the monitor is evaluated as a function of data size and the interface used. Then different interfaces, commonly available in sensor nodes, are evaluated: serial transmission (USART), serial peripheral interface (SPI), and parallel. The proposed hybrid monitor provides highly detailed information, barely disturbed by the measurement tool (interference), about the behavior of the WSN that may be used to evaluate many properties such as performance, dependability, security, etc. Monitor nodes are self-powered and may be removed after the monitoring campaign to be reused in other campaigns and/or WSNs. No other hardware-independent monitoring platforms with such low interference have been found in the literature.

  9. Voltage harmonics mitigation through hybrid active power filer

    International Nuclear Information System (INIS)

    Sahito, A.A.; Tunio, S.M.; Khizer, A.N.

    2016-01-01

    Fast dynamic response, high efficiency, low cost and small size of power electronic converters have exponentially increased their use in modern power system which resulted in harmonically distorted voltage and currents. Voltage harmonics mainly caused by current harmonics are more dangerous as performance and expected operating life of other power system equipment are affected by harmonically distorted supply voltage. Electronic filter circuits are used to improve system power quality by mitigating adverse effects of harmonics. Hybrid filters having advantages of both passive and active filters are preferred to resolve the problem of harmonics efficiently and avoiding any chance of resonance. In this paper, a three phase three wire network is considered to supply an adjustable speed drive represented by a resistive load connected across a three phase bridge rectifier. Simulation of the considered system shows THD (Total Harmonic Distortion) of 18.91 and 7.61 percentage in supply current and voltage respectively. A HAPF (Hybrid Active Power Filter) is proposed to reduce these THD values below 5 percentage as recommended by IEEE Standard-519. P-Q theorem is used to calculate required parameters for proposed filter, which is implemented through hysteresis control. Simulation results confirm the effectiveness of the designed filter as THD for both current and voltage have reduced below allowable limit of 5 percentage. (author)

  10. Voltage Harmonics Mitigation through Hybrid Active Power Filter

    Directory of Open Access Journals (Sweden)

    Anwer Ali Sahito

    2016-01-01

    Full Text Available Fast dynamic response, high efficiency, low cost and small size of power electronic converters have exponentially increased their use in modern power system which resulted in harmonically distorted voltage and currents. Voltage harmonics mainly caused by current harmonics are more dangerous as performance and expected operating life of other power system equipment are affected by harmonically distorted supply voltage. Electronic filter circuits are used to improve system power quality by mitigating adverse effects of harmonics. Hybrid filters having advantages of both passive and active filters are preferred to resolve the problem of harmonics efficiently and avoiding any chance of resonance. In this paper, a three phase three wire network is considered to supply an adjustable speed drive represented by a resistive load connected across a three phase bridge rectifier. Simulation of the considered system shows THD (Total Harmonic Distortion of 18.91 and 7.61% in supply current and voltage respectively. A HAPF (Hybrid Active Power Filter is proposed to reduce these THD values below 5% as recommended by IEEE Standard-519. P-Q theorem is used to calculate required parameters for proposed filter, which is implemented through hysteresis control. Simulation results confirm the effectiveness of the designed filter as THD for both current and voltage have reduced below allowable limit of 5%.

  11. Active metal oxides and polymer hybrids as biomaterials

    Science.gov (United States)

    Jarrell, John D.

    show that silver doping improved the photoactivity of oxide coatings, but hindered activity of a specific hybrid. Doped titanium oxide and polymer hybrid coatings have potential for improving soft tissue integration of medical implants and wound healing by modulating cell proliferation, attachment, inflammation and providing controlled delivery of bioactive and antimicrobial compounds and photon induced electro-chemical activity.

  12. MWCNT/CdS hybrid nanocomposite for enhanced photocatalytic activity

    International Nuclear Information System (INIS)

    Chaudhary, Deepti; Khare, Neeraj; Vankar, V. D.

    2016-01-01

    Multi-walled carbon nanotubes (MWCNT)/CdS hybrid nanocomposite were synthesized by one step hydrothermal method. MWCNTs were used as a substrate for the growth of CdS nanoparticles. MWCNT/CdS nanocomposite and pure CdS were characterized by XRD, TEM, UV-vis and photoluminescence spectroscopy. HRTEM study confirms the intimate contact of CdS with MWCNT. The photocatalytic activity of nanocomposite was studied for the degradation of methylene blue dye under UV irradiation. The enhanced photocatalytic activity of MWCNT/CdS nanocomposite as compared to pure CdS has been attributed to reduced recombination of photogenerated charge carriers due to interfacial electron transfer from CdS to MWCNT.

  13. Multi-objective Design Method for Hybrid Active Power Filter

    Science.gov (United States)

    Yu, Jingrong; Deng, Limin; Liu, Maoyun; Qiu, Zhifeng

    2017-10-01

    In this paper, a multi-objective optimal design for transformerless hybrid active power filter (HAPF) is proposed. The interactions between the active and passive circuits is analyzed, and by taking the interactions into consideration, a three-dimensional objective problem comprising of performance, efficiency and cost of HAPF system is formulated. To deal with the multiple constraints and the strong coupling characteristics of the optimization model, a novel constraint processing mechanism based on distance measurement and adaptive penalty function is presented. In order to improve the diversity of optimal solution and the local searching ability of the particle swarm optimization (PSO) algorithm, a chaotic mutation operator based on multistage neighborhood is proposed. The simulation results show that the optimums near the ordinate origin of the three-dimension space make better tradeoff among the performance, efficiency and cost of HAPF, and the experimental results of transformerless HAPF verify the effectiveness of the method for multi-objective optimization and design.

  14. Neurotrophin receptors expression and JNK pathway activation in human astrocytomas

    Directory of Open Access Journals (Sweden)

    Maraziotis Theodore

    2007-10-01

    Full Text Available Abstract Background Neurotrophins are growth factors that regulate cell growth, differentiation and apoptosis in the nervous system. Their diverse actions are mediated through two different transmembrane – receptor signaling systems: Trk receptor tyrosine kinases (TrkA, TrkB, TrkC and p75NTR neurotrophin receptor. Trk receptors promote cell survival and differentiation while p75NTR induces, in most cases, the activity of JNK-p53-Bax apoptosis pathway or suppresses intracellular survival signaling cascades. Robust Trk activation blocks p75NTR -induced apoptosis by suppressing the JNK-p53-Bax pathway. The aim of this exploratory study was to investigate the expression levels of neurotrophin receptors, Trks and p75NTR, and the activation of JNK pathway in human astrocytomas and in adjacent non-neoplastic brain tissue. Methods Formalin-fixed paraffin-embedded serial sections from 33 supratentorial astrocytomas (5 diffuse fibrillary astrocytomas, WHO grade II; 6 anaplastic astrocytomas, WHO grade III; 22 glioblastomas multiforme, WHO grade IV were immunostained following microwave pretreatment. Polyclonal antibodies against TrkA, TrkB, TrkC and monoclonal antibodies against p75NTR and phosphorylated forms of JNK (pJNK and c-Jun (pc-Jun were used. The labeling index (LI, defined as the percentage of positive (labeled cells out of the total number of tumor cells counted, was determined. Results Moderate to strong, granular cytoplasmic immunoreactivity for TrkA, TrkB and TrkC receptors was detected in greater than or equal to 10% of tumor cells in the majority of tumors independently of grade; on the contrary, p75NTR receptor expression was found in a small percentage of tumor cells (~1% in some tumors. The endothelium of tumor capillaries showed conspicuous immunoreactivity for TrkB receptor. Trk immunoreactivity seemed to be localized in some neurons and astrocytes in non-neoplastic tissue. Phosphorylated forms of JNK (pJNK and c-Jun (pc-Jun were

  15. Activation-induced proteolysis of cytoplasmic domain of zeta in T cell receptors and Fc receptors.

    Science.gov (United States)

    Taupin, J L; Anderson, P

    1994-12-01

    The CD3-T cell receptor (TCR) complex on T cells and the Fc gamma receptor type III (Fc gamma RIII)-zeta-gamma complex on natural killer cells are functionally analogous activation receptors that associate with a family of disulfide-linked dimers composed of the related subunits zeta and gamma. Immunochemical analysis of receptor complexes separated on two-dimensional diagonal gels allowed the identification of a previously uncharacterized zeta-p14 heterodimer. zeta-p14 is a component of both CD3-TCR and Fc gamma RIII-zeta-gamma. Peptide mapping analysis shows that p14 is structurally related to zeta, suggesting that it is either: (i) derived from zeta proteolytically or (ii) the product of an alternatively spliced mRNA. The observation that COS cells transformed with a cDNA encoding zeta express zeta-p14 supports the former possibility. The expression of CD3-TCR complexes including zeta-p14 increases following activation with phorbol 12-myristate 13-acetate or concanavalin A, suggesting that proteolysis of zeta may contribute to receptor modulation or desensitization.

  16. Peroxisome proliferator-activated receptor delta activation leads to increased transintestinal cholesterol efflux

    NARCIS (Netherlands)

    Vrins, Carlos L. J.; van der Velde, Astrid E.; van den Oever, Karin; Levels, Johannes H. M.; Huet, Stephane; Elferink, Ronald P. J. Oude; Kuipers, Folkert; Groen, Albert K.

    2009-01-01

    Peroxisome proliferator-activated receptor delta (PPAR delta) is involved in regulation of energy homeostasis. Activation of PPAR delta markedly increases fecal neutral sterol secretion, the last step in reverse cholesterol transport. This phenomenon can neither be explained by increased

  17. Peroxisome proliferator-activated receptor delta activation leads to increased transintestinal cholesterol efflux

    NARCIS (Netherlands)

    Vrins, Carlos L. J.; van der Velde, Astrid E.; van den Oever, Karin; Levels, Johannes H. M.; Huet, Stephane; Oude Elferink, Ronald P. J.; Kuipers, Folkert; Groen, Albert K.

    2009-01-01

    Peroxisome proliferator-activated receptor delta (PPARdelta) is involved in regulation of energy homeostasis. Activation of PPARdelta markedly increases fecal neutral sterol secretion, the last step in reverse cholesterol transport. This phenomenon can neither be explained by increased hepatobiliary

  18. Regulation of Liver Energy Balance by the Nuclear Receptors Farnesoid X Receptor and Peroxisome Proliferator Activated Receptor α.

    Science.gov (United States)

    Kim, Kang Ho; Moore, David D

    2017-01-01

    The liver undergoes major changes in substrate utilization and metabolic output over the daily feeding and fasting cycle. These changes occur acutely in response to hormones such as insulin and glucagon, with rapid changes in signaling pathways mediated by protein phosphorylation and other post-translational modifications. They are also reflected in chronic alterations in gene expression in response to nutrient-sensitive transcription factors. Among these, the nuclear receptors farnesoid X receptor (FXR) and peroxisome proliferator activated receptor α (PPARα) provide an intriguing, coordinated response to maintain energy balance in the liver. FXR is activated in the fed state by bile acids returning to the liver, while PPARα is activated in the fasted state in response to the free fatty acids produced by adipocyte lipolysis or possibly other signals. Key Messages: Previous studies indicate that FXR and PPARα have opposing effects on each other's primary targets in key metabolic pathways including gluconeogenesis. Our more recent work shows that these 2 nuclear receptors coordinately regulate autophagy: FXR suppresses this pathway of nutrient and energy recovery, while PPARα activates it. Another recent study indicates that FXR activates the complement and coagulation pathway, while earlier studies identify this as a negative target of PPARα. Since secretion is a very energy- and nutrient-intensive process for hepatocytes, it is possible that FXR licenses it in the nutrient-rich fed state, while PPARα represses it to spare resources in the fasted state. Energy balance is a potential connection linking FXR and PPARα regulation of autophagy and secretion, 2 seemingly unrelated aspects of hepatocyte function. FXR and PPARα act coordinately to promote energy balance and homeostasis in the liver by regulating autophagy and potentially protein secretion. It is quite likely that their impact extends to additional pathways relevant to hepatic energy balance, and

  19. Human pregnane X receptor is activated by dibenzazepine carbamate-based inhibitors of constitutive androstane receptor.

    Science.gov (United States)

    Jeske, Judith; Windshügel, Björn; Thasler, Wolfgang E; Schwab, Matthias; Burk, Oliver

    2017-06-01

    Unintentional activation of xenosensing nuclear receptors pregnane X receptor (PXR) and/or constitutive androstane receptor (CAR) by clinical drug use is known to produce severe side effects in patients, which may be overcome by co-administering antagonists. However, especially antagonizing CAR is hampered by the lack of specific inhibitors, which do not activate PXR. Recently, compounds based on a dibenzazepine carbamate scaffold were identified as potent CAR inhibitors. However, their potential to activate PXR was not thoroughly investigated, even if the lead compound was named "CAR inhibitor not PXR activator 1" (CINPA1). Thus, we performed a comprehensive analysis of the interaction of CINPA1 and four analogs with PXR. Cellular assays were used to investigate intra- and intermolecular interactions and transactivation activity of PXR as a function of the compounds. Modulation of PXR target gene expression was analyzed in primary human hepatocytes. Ligand binding to PXR was investigated by molecular docking and limited proteolytic digestion. We show here that CINPA1 induced the assembly of the PXR ligand-binding domain, released co-repressors from and recruited co-activators to the receptor. CINPA1 and its analogs induced the PXR-dependent activation of a CYP3A4 reporter gene and CINPA1 induced the expression of endogenous cytochrome P450 genes in primary hepatocytes, while not consistently inhibiting CAR-mediated induction. Molecular docking revealed favorable binding of CINPA1 and analogs to the PXR ligand-binding pocket, which was confirmed in vitro. Altogether, our data provide consistent evidence that compounds with a dibenzazepine carbamate scaffold, such as CINPA1 and its four analogs, bind to and activate PXR.

  20. Characterization of a novel serotonin receptor coupled to adenylate cyclase in the hybrid neuroblastoma cell line NCB. 20

    Energy Technology Data Exchange (ETDEWEB)

    Conner, D.A.

    1988-01-01

    Pharmacological characterization of the serotonin activation of adenylate cyclase in membrane preparation using over 40 serotonergic and non-serotonergic compounds demonstrated that the receptor mediating the response was distinct from previously described mammalian serotonin receptors. Agonist activity was only observed with tryptamine and ergoline derivatives. Potent antagonism was observed with several ergoline derivatives and with compounds such as mianserin and methiothepine. A comparison of the rank order of potency of a variety of compounds for the NCB.20 cell receptor with well characterized mammalian and non-mammalian serotonin receptors showed a pharmacological similarity, but not identity, with the mammalian 5-HT{sub 1C} receptor, which modulates phosphatidylinositol metabolism, and with serotonin receptors in the parasitic trematodes Fasciola hepatica and Schistosoma mansoni, which are coupled to adenylate cyclase. Equilibrium binding analysis utilizing ({sup 3}H)serotonin, ({sup 3}H)lysergic acid diethylamide or ({sup 3}H)dihydroergotamine demonstrated that there are no abundant high affinity serotonergic sites, which implies that the serotonin activation of adenylate cyclase is mediated by receptors present in low abundance. Incubation of intact NCB.20 cells with serotinin resulted in a time and concentration dependent desensitization of the serotonin receptor.

  1. Characterization of a novel serotonin receptor coupled to adenylate cyclase in the hybrid neuroblastoma cell line NCB.20

    International Nuclear Information System (INIS)

    Conner, D.A.

    1988-01-01

    Pharmacological characterization of the serotonin activation of adenylate cyclase in membrane preparation using over 40 serotonergic and non-serotonergic compounds demonstrated that the receptor mediating the response was distinct from previously described mammalian serotonin receptors. Agonist activity was only observed with tryptamine and ergoline derivatives. Potent antagonism was observed with several ergoline derivatives and with compounds such as mianserin and methiothepine. A comparison of the rank order of potency of a variety of compounds for the NCB.20 cell receptor with well characterized mammalian and non-mammalian serotonin receptors showed a pharmacological similarity, but not identity, with the mammalian 5-HT 1C receptor, which modulates phosphatidylinositol metabolism, and with serotonin receptors in the parasitic trematodes Fasciola hepatica and Schistosoma mansoni, which are coupled to adenylate cyclase. Equilibrium binding analysis utilizing [ 3 H]serotonin, [ 3 H]lysergic acid diethylamide or [ 3 H]dihydroergotamine demonstrated that there are no abundant high affinity serotonergic sites, which implies that the serotonin activation of adenylate cyclase is mediated by receptors present in low abundance. Incubation of intact NCB.20 cells with serotinin resulted in a time and concentration dependent desensitization of the serotonin receptor

  2. Microsomal receptor for steroid hormones: functional implications for nuclear activity.

    Science.gov (United States)

    Muldoon, T G; Watson, G H; Evans, A C; Steinsapir, J

    1988-01-01

    Target tissues for steroid hormones are responsive by virtue of and to the extent of their content of functional intracellular receptors. Recent years have seen a shift in considerations of the cellular dynamics and distribution of these receptors, with current views favoring predominant intranuclear localization in the intact cell. This paper summarizes our analyses of the microsomal estrogen and androgen binding capability of rat uterine and ventral prostate tissue, respectively; these studies have revealed a set of high affinity sites that may act as a conduit for estrogen traversing the cell en route to the nucleus. These sites have many properties in common with cytosolic receptors, with the salient difference of a failure to activate to a more avid DNA-binding form under conditions which permit such activation of cytosolic receptors. The microsomal estrogen-binding proteins also have appreciable affinity for progesterone, another distinction from other known cellular estrogen receptor species. Various experimental approaches were employed to demonstrate that the microsomal receptors were not simply cytosol contaminants; the most convincing evidence is the recent successful separation of the cytosolic and microsomal forms by differential ammonium sulfate precipitation. Discrete subfractionation of subcellular components on successive sucrose gradients, with simultaneous assessments of binding capability and marker enzyme concentrations, indicates that the major portion of the binding is localized within the vesicles of the endoplasmic reticulum free of significant plasma membrane contamination. The microsomal receptors are readily solubilized by extraction with high- or low-salt-containing buffers or with steroid. The residual microsomes following such extraction have the characteristics of saturable acceptor sites for cytosolic estrogen-receptor complexes. The extent to which these sites will accept the cytosolic complexes is equal to the concentration of

  3. Modulating Estrogen Receptor-related ReceptorActivity Inhibits Cell Proliferation*

    Science.gov (United States)

    Bianco, Stéphanie; Lanvin, Olivia; Tribollet, Violaine; Macari, Claire; North, Sophie; Vanacker, Jean-Marc

    2009-01-01

    High expression of the estrogen receptor-related receptor (ERR)-α in human tumors is correlated to a poor prognosis, suggesting an involvement of the receptor in cell proliferation. In this study, we show that a synthetic compound (XCT790) that modulates the activity of ERRα reduces the proliferation of various cell lines and blocks the G1/S transition of the cell cycle in an ERRα-dependent manner. XCT790 induces, in a p53-independent manner, the expression of the cell cycle inhibitor p21waf/cip1 at the protein, mRNA, and promoter level, leading to an accumulation of hypophosphorylated Rb. Finally, XCT790 reduces cell tumorigenicity in Nude mice. PMID:19546226

  4. Hyaluronan Hybrid Cooperative Complexes as a Novel Frontier for Cellular Bioprocesses Re-Activation.

    Directory of Open Access Journals (Sweden)

    Antonietta Stellavato

    Full Text Available Hyaluronic Acid (HA-based dermal formulations have rapidly gained a large consensus in aesthetic medicine and dermatology. HA, highly expressed in the Extracellular Matrix (ECM, acts as an activator of biological cascades, stimulating cell migration and proliferation, and operating as a regulator of the skin immune surveillance, through specific interactions with its receptors. HA may be used in topical formulations, as dermal inducer, for wound healing. Moreover, intradermal HA formulations (injectable HA provide an attractive tool to counteract skin aging (e.g., facial wrinkles, dryness, and loss of elasticity and restore normal dermal functions, through simple and minimally invasive procedures. Biological activity of a commercially available hyaluronic acid, Profhilo®, based on NAHYCO™ technology, was compared to H-HA or L-HA alone. The formation of hybrid cooperative complexes was confirmed by the sudden drop in η0 values in the rheological measurements. Besides, hybrid cooperative complexes proved stable to hyaluronidase (BTH digestion. Using in vitro assays, based on keratinocytes, fibroblasts cells and on the Phenion® Full Thickness Skin Model 3D, hybrid cooperative complexes were compared to H-HA, widely used in biorevitalization procedures, and to L-HA, recently proposed as the most active fraction modulating the inflammatory response. Quantitative real-time PCR analyses were accomplished for the transcript quantification of collagens and elastin. Finally immunofluorescence staining permitted to evaluate the complete biosynthesis of all the molecules investigated. An increase in the expression levels of type I and type III collagen in fibroblasts and type IV and VII collagen in keratinocytes were found with the hybrid cooperative complexes, compared to untreated cells (CTR and to the H-HA and L-HA treatments. The increase in elastin expression found in both cellular model and in the Phenion® Full Thickness Skin Model 3D also at

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-11-15

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

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

    International Nuclear Information System (INIS)

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

    2013-01-01

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

  7. Intramolecular Crosstalk between Catalytic Activities of Receptor Kinases

    KAUST Repository

    Kwezi, Lusisizwe

    2018-01-22

    Signal modulation is important for the growth and development of plants and this process is mediated by a number of factors including physiological growth regulators and their associated signal transduction pathways. Protein kinases play a central role in signaling, including those involving pathogen response mechanisms. We previously demonstrated an active guanylate cyclase (GC) catalytic center in the brassinosteroid insensitive receptor (AtBRI1) within an active intracellular kinase domain resulting in dual enzymatic activity. Here we propose a novel type of receptor architecture that is characterized by a functional GC catalytic center nested in the cytosolic kinase domain enabling intramolecular crosstalk. This may be through a cGMP-AtBRI1 complex forming that may induce a negative feedback mechanism leading to desensitisation of the receptor, regulated through the cGMP production pathway. We further argue that the comparatively low but highly localized cGMP generated by the GC in response to a ligand is sufficient to modulate the kinase activity. This type of receptor therefore provides a molecular switch that directly and/or indirectly affects ligand dependent phosphorylation of downstream signaling cascades and suggests that subsequent signal transduction and modulation works in conjunction with the kinase in downstream signaling.

  8. Intramolecular Crosstalk between Catalytic Activities of Receptor Kinases

    KAUST Repository

    Kwezi, Lusisizwe; Wheeler, Janet I; Marondedze, Claudius; Gehring, Christoph A; Irving, Helen R

    2018-01-01

    Signal modulation is important for the growth and development of plants and this process is mediated by a number of factors including physiological growth regulators and their associated signal transduction pathways. Protein kinases play a central role in signaling, including those involving pathogen response mechanisms. We previously demonstrated an active guanylate cyclase (GC) catalytic center in the brassinosteroid insensitive receptor (AtBRI1) within an active intracellular kinase domain resulting in dual enzymatic activity. Here we propose a novel type of receptor architecture that is characterized by a functional GC catalytic center nested in the cytosolic kinase domain enabling intramolecular crosstalk. This may be through a cGMP-AtBRI1 complex forming that may induce a negative feedback mechanism leading to desensitisation of the receptor, regulated through the cGMP production pathway. We further argue that the comparatively low but highly localized cGMP generated by the GC in response to a ligand is sufficient to modulate the kinase activity. This type of receptor therefore provides a molecular switch that directly and/or indirectly affects ligand dependent phosphorylation of downstream signaling cascades and suggests that subsequent signal transduction and modulation works in conjunction with the kinase in downstream signaling.

  9. Structure-activity relationships of strychnine analogues at glycine receptors

    DEFF Research Database (Denmark)

    Mohsen, A.M.Y.; Heller, Eberhard; Holzgrabe, Ulrike

    2014-01-01

    Nine strychnine derivatives including neostrychnine, strychnidine, isostrychnine, 21,22-dihydro-21-hydroxy-22-oxo-strychnine, and several hydrogenated analogs were synthesized, and their antagonistic activities at human α1 and α1β glycine receptors were evaluated. Isostrychnine has shown the best...... pharmacological profile exhibiting an IC50 value of 1.6 μM at α1 glycine receptors and 3.7-fold preference towards the α1 subtype. SAR Analysis indicates that the lactam moiety and the C(21)[DOUBLE BOND]C(22) bond in strychnine are essential structural features for its high antagonistic potency at glycine...

  10. Diabetes and obesity treatment based on dual incretin receptor activation

    DEFF Research Database (Denmark)

    Skow, M A; Bergmann, N C; Knop, F K

    2016-01-01

    , whereas GIP seems to affect lipid metabolism. The introduction of selective GLP-1 receptor (GLP-1R) agonists for the treatment of type 2 diabetes and obesity has increased the scientific and clinical interest in incretins. Combining the body weight-lowering and glucose-lowering effects of GLP-1...... with a more potent improvement of β cell function through additional GIP action could potentially offer a more effective treatment of diabetes and obesity, with fewer adverse effects than selective GLP-1R agonists; therefore, new drugs designed to co-activate both the GIP receptor (GIPR) and the GLP-1R...

  11. Influence of phasic and tonic dopamine release on receptor activation

    DEFF Research Database (Denmark)

    Dreyer, Jakob Kristoffer Kisbye; Herrik, Kjartan F; Berg, Rune W

    2010-01-01

    Tonic and phasic dopamine release is implicated in learning, motivation, and motor functions. However, the relationship between spike patterns in dopaminergic neurons, the extracellular concentration of dopamine, and activation of dopamine receptors remains unresolved. In the present study, we...... develop a computational model of dopamine signaling that give insight into the relationship between the dynamics of release and occupancy of D(1) and D(2) receptors. The model is derived from first principles using experimental data. It has no free parameters and offers unbiased estimation...

  12. Liver X receptor and peroxisome proliferator-activated receptor as integrators of lipid homeostasis and immunity.

    Science.gov (United States)

    Kidani, Yoko; Bensinger, Steven J

    2012-09-01

    Lipid metabolism has emerged as an important modulator of innate and adaptive immune cell fate and function. The lipid-activated transcription factors peroxisome proliferator-activated receptor (PPAR) α, β/δ, γ and liver X receptor (LXR) are members of the nuclear receptor superfamily that have a well-defined role in regulating lipid homeostasis and metabolic diseases. Accumulated evidence over the last decade indicates that PPAR and LXR signaling also influence multiple facets of inflammation and immunity, thereby providing important crosstalk between metabolism and immune system. Herein, we provide a brief introduction to LXR and PPAR biology and review recent discoveries highlighting the importance of PPAR and LXR signaling in the modulation of normal and pathologic states of immunity. We also examine advances in our mechanistic understanding of how nuclear receptors impact immune system function and homeostasis. Finally, we discuss whether LXRs and PPARs could be pharmacologically manipulated to provide novel therapeutic approaches for modulation of the immune system under pathologic inflammation or in the context of allergic and autoimmune disease. © 2012 John Wiley & Sons A/S.

  13. Allele-specific expression at the androgen receptor alpha gene in a hybrid unisexual fish, the Amazon molly (Poecilia formosa.

    Directory of Open Access Journals (Sweden)

    Fangjun Zhu

    Full Text Available The all-female Amazon molly (Poecilia formosa is the result of a hybridization of the Atlantic molly (P. mexicana and the sailfin molly (P. latipinna approximately 120,000 years ago. As a gynogenetic species, P. formosa needs to copulate with heterospecific males including males from one of its bisexual ancestral species. However, the sperm only triggers embryogenesis of the diploid eggs. The genetic information of the sperm donor typically will not contribute to the next generation of P. formosa. Hence, P. formosa possesses generally one allele from each of its ancestral species at any genetic locus. This raises the question whether both ancestral alleles are equally expressed in P. formosa. Allele-specific expression (ASE has been previously assessed in various organisms, e.g., human and fish, and ASE was found to be important in the context of phenotypic variability and disease. In this study, we utilized Real-Time PCR techniques to estimate ASE of the androgen receptor alpha (arα gene in several distinct tissues of Amazon mollies. We found an allelic bias favoring the maternal ancestor (P. mexicana allele in ovarian tissue. This allelic bias was not observed in the gill or the brain tissue. Sequencing of the promoter regions of both alleles revealed an association between an Indel in a known CpG island and differential expression. Future studies may reveal whether our observed cis-regulatory divergence is caused by an ovary-specific trans-regulatory element, preferentially activating the allele of the maternal ancestor.

  14. Biodegradation of pharmaceuticals in hospital wastewater by a hybrid biofilm and activated sludge system (Hybas)

    DEFF Research Database (Denmark)

    Escola Casas, Monica; Chhetri, Ravi Kumar; Ooi, Gordon Tze Hoong

    2015-01-01

    TM is a hybrid process, based on the integrated fixed-film activated sludge technology, where plastic carriers for biofilm growth are suspended within activated sludge. To investigate the potential of a hybrid system for the removal of pharmaceuticals in hospital wastewater a pilot plant consisting of a series...

  15. Transcriptional activation by the thyroid hormone receptor through ligand-dependent receptor recruitment and chromatin remodelling.

    Science.gov (United States)

    Grøntved, Lars; Waterfall, Joshua J; Kim, Dong Wook; Baek, Songjoon; Sung, Myong-Hee; Zhao, Li; Park, Jeong Won; Nielsen, Ronni; Walker, Robert L; Zhu, Yuelin J; Meltzer, Paul S; Hager, Gordon L; Cheng, Sheue-yann

    2015-04-28

    A bimodal switch model is widely used to describe transcriptional regulation by the thyroid hormone receptor (TR). In this model, the unliganded TR forms stable, chromatin-bound complexes with transcriptional co-repressors to repress transcription. Binding of hormone dissociates co-repressors and facilitates recruitment of co-activators to activate transcription. Here we show that in addition to hormone-independent TR occupancy, ChIP-seq against endogenous TR in mouse liver tissue demonstrates considerable hormone-induced TR recruitment to chromatin associated with chromatin remodelling and activated gene transcription. Genome-wide footprinting analysis using DNase-seq provides little evidence for TR footprints both in the absence and presence of hormone, suggesting that unliganded TR engagement with repressive complexes on chromatin is, similar to activating receptor complexes, a highly dynamic process. This dynamic and ligand-dependent interaction with chromatin is likely shared by all steroid hormone receptors regardless of their capacity to repress transcription in the absence of ligand.

  16. Reduced beta-adrenergic receptor activation decreases G-protein expression and beta-adrenergic receptor kinase activity in porcine heart.

    OpenAIRE

    Ping, P; Gelzer-Bell, R; Roth, D A; Kiel, D; Insel, P A; Hammond, H K

    1995-01-01

    To determine whether beta-adrenergic receptor agonist activation influences guanosine 5'-triphosphate-binding protein (G-protein) expression and beta-adrenergic receptor kinase activity in the heart, we examined the effects of chronic beta 1-adrenergic receptor antagonist treatment (bisoprolol, 0.2 mg/kg per d i.v., 35 d) on components of the myocardial beta-adrenergic receptor-G-protein-adenylyl cyclase pathway in porcine myocardium. Three novel alterations in cardiac adrenergic signaling as...

  17. Activation of peroxisome proliferator-activated receptors (PPARs) by their ligands and protein kinase A activators

    Science.gov (United States)

    Lazennec, Gwendal; Canaple, Laurence; Saugy, Damien; Wahli, Walter

    2000-01-01

    The nuclear peroxisome proliferator-activated receptors (PPARs) α, β and γ activate the transcription of multiple genes involved in lipid metabolism. Several natural and synthetic ligands have been identified for each PPAR isotype but little is known about the phosphorylation state of these receptors. We show here that activators of protein kinase A (PKA) can enhance mouse PPAR activity in the absence and the presence of exogenous ligands in transient transfection experiments. The activation function 1 (AF-1) of PPARs was dispensable for transcriptional enhancement, whereas the activation function 2 (AF-2) was required for this effect. We also show that several domains of PPAR can be phosphorylated by PKA in vitro. Moreover, gel experiments suggest that PKA stabilizes binding of the liganded PPAR to DNA. PKA inhibitors decreased not only the kinase dependent induction of PPARs but also their ligand-dependent induction, suggesting that the ligands may also mobilize the PKA pathway to lead to maximal transcriptional induction by PPARs. Moreover, comparing PPARα KO with PPARα wild-type mice, we show that the expression of the ACO gene can be regulated by PKA-activated PPARα in liver. These data demonstrate that the PKA pathway is an important modulator of PPAR activity and we propose a model associating this pathway in the control of fatty acid β-oxidation under conditions of fasting, stress and exercise. PMID:11117527

  18. 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...

  19. Peroxisome Proliferator-Activated Receptor Alpha Target Genes

    Directory of Open Access Journals (Sweden)

    Maryam Rakhshandehroo

    2010-01-01

    Full Text Available The peroxisome proliferator-activated receptor alpha (PPARα is a ligand-activated transcription factor involved in the regulation of a variety of processes, ranging from inflammation and immunity to nutrient metabolism and energy homeostasis. PPARα serves as a molecular target for hypolipidemic fibrates drugs which bind the receptor with high affinity. Furthermore, PPARα binds and is activated by numerous fatty acids and fatty acid-derived compounds. PPARα governs biological processes by altering the expression of a large number of target genes. Accordingly, the specific role of PPARα is directly related to the biological function of its target genes. Here, we present an overview of the involvement of PPARα in lipid metabolism and other pathways through a detailed analysis of the different known or putative PPARα target genes. The emphasis is on gene regulation by PPARα in liver although many of the results likely apply to other organs and tissues as well.

  20. Glycine Receptor α2 Subunit Activation Promotes Cortical Interneuron Migration

    Directory of Open Access Journals (Sweden)

    Ariel Avila

    2013-08-01

    Full Text Available Glycine receptors (GlyRs are detected in the developing CNS before synaptogenesis, but their function remains elusive. This study demonstrates that functional GlyRs are expressed by embryonic cortical interneurons in vivo. Furthermore, genetic disruption of these receptors leads to interneuron migration defects. We discovered that extrasynaptic activation of GlyRs containing the α2 subunit in cortical interneurons by endogenous glycine activates voltage-gated calcium channels and promotes calcium influx, which further modulates actomyosin contractility to fine-tune nuclear translocation during migration. Taken together, our data highlight the molecular events triggered by GlyR α2 activation that control cortical tangential migration during embryogenesis.

  1. Environmental phthalate monoesters activate pregnane X receptor-mediated transcription

    International Nuclear Information System (INIS)

    Hurst, Christopher H.; Waxman, David J.

    2004-01-01

    Phthalate esters, widely used as plasticizers in the manufacture of products made of polyvinyl chloride, induce reproductive and developmental toxicities in rodents. The mechanism that underlies these effects of phthalate exposure, including the potential role of members of the nuclear receptor superfamily, is not known. The present study investigates the effects of phthalates on the pregnane X receptor (PXR), which mediates the induction of enzymes involved in steroid metabolism and xenobiotic detoxification. The ability of phthalate monoesters to activate PXR-mediated transcription was assayed in a HepG2 cell reporter assay following transfection with mouse PXR (mPXR), human PXR (hPXR), or the hPXR allelic variants V140M, D163G, and A370T. Mono-2-ethylhexyl phthalate (MEHP) increased the transcriptional activity of both mPXR and hPXR (5- and 15-fold, respectively) with EC 50 values of 7-8 μM. mPXR and hPXR were also activated by monobenzyl phthalate (MBzP, up to 5- to 6-fold) but were unresponsive to monomethyl phthalate and mono-n-butyl phthalate (M(n)BP) at the highest concentrations tested (300 μM). hPXR-V140M and hPXR-A370T exhibited patterns of phthalate responses similar to the wild-type receptor. By contrast, hPXR-D163G was unresponsive to all phthalate monoesters tested. Further studies revealed that hPXR-D163G did respond to rifampicin, but required approximately 40-fold higher concentrations than wild-type receptor, suggesting that the ligand-binding domain D163G variant has impaired ligand-binding activity. The responsiveness of PXR to activation by phthalate monoesters demonstrated here suggests that these ubiquitous environmental chemicals may, in part, exhibit their endocrine disruptor activities by altering PXR-regulated steroid hormone metabolism with potential adverse health effects in exposed individuals

  2. Wastewater treatment in a hybrid activated sludge baffled reactor

    Energy Technology Data Exchange (ETDEWEB)

    Tizghadam, Mostafa [Laboratoire des Sciences de l' Eau et de l' Environnement, Universite de Limoges, ENSIL, Parc ESTER, 16 Rue Atlantis, F-87068 Limoges Cedex (France); Dagot, Christophe [Laboratoire des Sciences de l' Eau et de l' Environnement, Universite de Limoges, ENSIL, Parc ESTER, 16 Rue Atlantis, F-87068 Limoges Cedex (France)], E-mail: dagot@ensil.unilim.fr; Baudu, Michel [Laboratoire des Sciences de l' Eau et de l' Environnement, Universite de Limoges, ENSIL, Parc ESTER, 16 Rue Atlantis, F-87068 Limoges Cedex (France)

    2008-06-15

    A novel hybrid activated sludge baffled reactor (HASBR), which contained both suspended and attached-growth biomass perfect mixing cells in series, was developed by installing standing and hanging baffles and introducing plastic brushes into a conventional activated sludge (CAS) reactor. It was used for the treatment of domestic wastewater. The effects on the operational performance of developing the suspended and attached-growth biomass and reactor configuration were investigated. The change of the flow regime from complete-mix to plug-flow, and the addition of plastic brushes as a support for biofilm, resulted in considerable improvements in the COD, nitrogen removal efficiency of domestic wastewater and sludge settling properties. In steady state, approximately 98 {+-} 2% of the total COD and 98 {+-} 2% of the ammonia of the influent were removed in the HASBR, when the influent wastewater concentration was 593 {+-} 11 mg COD/L and 43 {+-} 5 mg N/L, respectively, at a HRT of 10 h. These results were 93 {+-} 3 and 6 {+-} 3% for the CAS reactor, respectively. Approximately 90 {+-} 7% of the total COD was removed in the HASBR, when the influent wastewater concentration was 654 {+-} 16 mg COD/L at a 3 h HRT, and in the organic loading rate (OLR) of 5.36 kg COD m{sup -3} day{sup -1}. The result for the CAS reactor was 60 {+-} 3%. Existing CAS plants can be upgraded by changing the reactor configuration and introducing biofilm support media into the aeration tank.

  3. The Growth Hormone Receptor: Mechanism of Receptor Activation, Cell Signaling, and Physiological Aspects

    Directory of Open Access Journals (Sweden)

    Farhad Dehkhoda

    2018-02-01

    Full Text Available The growth hormone receptor (GHR, although most well known for regulating growth, has many other important biological functions including regulating metabolism and controlling physiological processes related to the hepatobiliary, cardiovascular, renal, gastrointestinal, and reproductive systems. In addition, growth hormone signaling is an important regulator of aging and plays a significant role in cancer development. Growth hormone activates the Janus kinase (JAK–signal transducer and activator of transcription (STAT signaling pathway, and recent studies have provided a new understanding of the mechanism of JAK2 activation by growth hormone binding to its receptor. JAK2 activation is required for growth hormone-mediated activation of STAT1, STAT3, and STAT5, and the negative regulation of JAK–STAT signaling comprises an important step in the control of this signaling pathway. The GHR also activates the Src family kinase signaling pathway independent of JAK2. This review covers the molecular mechanisms of GHR activation and signal transduction as well as the physiological consequences of growth hormone signaling.

  4. Prevention of demoralization in prolonged bicultural conflict and interaction: the role of cultural receptors II - genesis of hybridization.

    Science.gov (United States)

    de Figueiredo, John M

    2013-08-01

    The objective of this article is to show that bicultural hybridization for the prevention of demoralization is anchored on the discovery of certain thematic areas (cultural receptors) in which social roles or cultural mandates are missing, unclear, ambiguous or congruent. The specific setting is the history of Goa, a former Portuguese territory on the western coast of India. Both published and unpublished sources of information were studied. Education, occupation and income, the three dimensions of social class, were less dominant than other aspects of the Hindu caste system, such as birth into a group viewed as a caste, observance of marriage circles, regulations of kinship and inheritance, and identification with a location. These other aspects were preserved as much as possible. The result was the conversion of the caste system into a system more akin to social class. Other examples of cultural receptors were found. A key step in the adaptation to acculturative stress is the discovery of cultural receptors in both cultures and the development of meaningful interconnections among those receptors. Psychotherapy attempts the restoration of morale. To be effective, therapists should consider the hierarchical organization of symbols and sentiments in the patient's culture.

  5. Neurohumoral activation in heart failure: the role of adrenergic receptors

    Directory of Open Access Journals (Sweden)

    Patricia C. Brum

    2006-09-01

    Full Text Available Heart failure (HF is a common endpoint for many forms of cardiovascular disease and a significant cause of morbidity and mortality. The development of end-stage HF often involves an initial insult to the myocardium that reduces cardiac output and leads to a compensatory increase in sympathetic nervous system activity. Acutely, the sympathetic hyperactivity through the activation of beta-adrenergic receptors increases heart rate and cardiac contractility, which compensate for decreased cardiac output. However, chronic exposure of the heart to elevated levels of catecholamines released from sympathetic nerve terminals and the adrenal gland may lead to further pathologic changes in the heart, resulting in continued elevation of sympathetic tone and a progressive deterioration in cardiac function. On a molecular level, altered beta-adrenergic receptor signaling plays a pivotal role in the genesis and progression of HF. beta-adrenergic receptor number and function are decreased, and downstream mechanisms are altered. In this review we will present an overview of the normal beta-adrenergic receptor pathway in the heart and the consequences of sustained adrenergic activation in HF. The myopathic potential of individual components of the adrenergic signaling will be discussed through the results of research performed in genetic modified animals. Finally, we will discuss the potential clinical impact of beta-adrenergic receptor gene polymorphisms for better understanding the progression of HF.A insuficiência cardíaca (IC é a via final comum da maioria das doenças cardiovasculares e uma das maiores causas de morbi-mortalidade. O desenvolvimento do estágio final da IC freqüentemente envolve um insulto inicial do miocárdio, reduzindo o débito cardíaco e levando ao aumento compensatório da atividade do sistema nervoso simpático (SNS. Existem evidências de que apesar da exposição aguda ser benéfica, exposições crônicas a elevadas concentra

  6. 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

  7. Functional relevance of G-protein-coupled-receptor-associated proteins, exemplified by receptor-activity-modifying proteins (RAMPs).

    Science.gov (United States)

    Fischer, J A; Muff, R; Born, W

    2002-08-01

    The calcitonin (CT) receptor (CTR) and the CTR-like receptor (CRLR) are close relatives within the type II family of G-protein-coupled receptors, demonstrating sequence identity of 50%. Unlike the interaction between CT and CTR, receptors for the related hormones and neuropeptides amylin, CT-gene-related peptide (CGRP) and adrenomedullin (AM) require one of three accessory receptor-activity-modifying proteins (RAMPs) for ligand recognition. An amylin/CGRP receptor is revealed when CTR is co-expressed with RAMP1. When complexed with RAMP3, CTR interacts with amylin alone. CRLR, initially classed as an orphan receptor, is a CGRP receptor when co-expressed with RAMP1. The same receptor is specific for AM in the presence of RAMP2. Together with human RAMP3, CRLR defines an AM receptor, and with mouse RAMP3 it is a low-affinity CGRP/AM receptor. CTR-RAMP1, antagonized preferentially by salmon CT-(8-32) and not by CGRP-(8-37), and CRLR-RAMP1, antagonized by CGRP-(8-37), are two CGRP receptor isotypes. Thus amylin and CGRP interact specifically with heterodimeric complexes between CTR and RAMP1 or RAMP3, and CGRP and AM interact with complexes between CRLR and RAMP1, RAMP2 or RAMP3.

  8. Relative biocompatibility of micro-hybrid and nano-hybrid light-activated composite resins.

    Science.gov (United States)

    Olabisi Arigbede, Abiodun; Folasade Adeyemi, Bukola; Femi-Akinlosotu, Omowumi

    2017-01-01

    Background. In vitro studies have revealed a direct association between resin content and cytotoxicity of composite resins; however, implantation studies in this regard are sparse. This study investigates the relationship between filler content of composite resins and biocompatibility. Methods. This research employed twelve 180‒200-gr male Wistar rats, 1 nano-hybrid (Prime-Dent Inc.) and 1 micro-hybrid (Medental Inc.) composite resins containing 74% and 80‒90% filler content, respectively. The samples were assessed on the 2nd, 14th and 90th day of implantation. Four rats were allocated to each day in this experimental study. A section of 1.5mm long cured nano-hybrid and micro-hybrid materials were implanted into the right and left upper and lower limbs of the rats, respectively. Eight samples were generated on each day of observation. Inflammation was graded according to the criteria suggested by Orstavik and Major. Pearson's chi-squared test was employed to determine the relationship between the tissue responses of the two materials. Statistical significance was set at P resin had a score of 3.0 for cellular inflammation. On the 14th day, the micro-hybrid resin also exhibited a lower average grade for cellular inflammation. On the 90th day, the micro-hybrid resin had a higher grade of inflammation (0.9) compared to 0.3 recorded for nano-hybrid. The composite resins with higher filler content elicited a significantly lower grade of inflammation irrespective of the duration (χ=20.000, df=8, P=0.010) while the composite resins with lower filler content elicited a significantly lower inflammatory response on the 90th day (χ=4.000, df=1, P=0.046). Conclusion. The composite resins with higher filler content generally elicited significantly lower grades of inflammation, and the composite resins with lower filler content exhibited significantly lower inflammatory response on the 90th day of implantation.

  9. Activation of Penile Proadipogenic Peroxisome Proliferator-Activated Receptor with an Estrogen: Interaction with Estrogen Receptor Alpha during Postnatal Development

    Directory of Open Access Journals (Sweden)

    Mahmoud M. Mansour

    2008-01-01

    Full Text Available Exposure to the estrogen receptor alpha (ER ligand diethylstilbesterol (DES between neonatal days 2 to 12 induces penile adipogenesis and adult infertility in rats. The objective of this study was to investigate the in vivo interaction between DES-activated ER and the proadipogenic transcription factor peroxisome proliferator-activated receptor gamma (PPAR. Transcripts for PPARs , , and and 1a splice variant were detected in Sprague-Dawley normal rat penis with PPAR predominating. In addition, PPAR1b and PPAR2 were newly induced by DES. The PPAR transcripts were significantly upregulated with DES and reduced by antiestrogen ICI 182, 780. At the cellular level, PPAR protein was detected in urethral transitional epithelium and stromal, endothelial, neuronal, and smooth muscular cells. Treatment with DES activated ER and induced adipocyte differentiation in corpus cavernosum penis. Those adipocytes exhibited strong nuclear PPAR expression. These results suggest a biological overlap between PPAR and ER and highlight a mechanism for endocrine disruption.

  10. Endogenous activation of adenosine A(1) receptors accelerates ischemic suppression of spontaneous electrocortical activity

    DEFF Research Database (Denmark)

    Ilie, Andrei; Ciocan, Dragos; Zagrean, Ana-Maria

    2006-01-01

    Cerebral ischemia induces a rapid suppression of spontaneous brain rhythms prior to major alterations in ionic homeostasis. It was found in vitro during ischemia that the rapidly formed adenosine, resulting from the intracellular breakdown of ATP, may inhibit synaptic transmission via the A(1......) receptor subtype. The link between endogenous A(1) receptor activation during ischemia and the suppression of spontaneous electrocortical activity has not yet been established in the intact brain. The aim of this study was to investigate in vivo the effects of A(1) receptor antagonism by 8-cyclopentyl-1...

  11. Expression of μ, κ, and δ opioid receptor messenger RNA in the human CNS: a 33P in situ hybridization study

    International Nuclear Information System (INIS)

    Peckys, D.; Landwehrmeyer, G.B.

    1999-01-01

    The existence of at least three opioid receptor types, referred to as μ, κ, and δ, is well established. Complementary DNAs corresponding to the pharmacologically defined μ, κ, and δ opioid receptors have been isolated in various species including man. The expression patterns of opioid receptor transcripts in human brain has not been established with a cellular resolution, in part because of the low apparent abundance of opioid receptor messenger RNAs in human brain. To visualize opioid receptor messenger RNAs we developed a sensitive in situ hybridization histochemistry method using 33 P-labelled RNA probes. In the present study we report the regional and cellular expression of μ, κ, and δ opioid receptor messenger RNAs in selected areas of the human brain. Hybridization of the different opioid receptor probes resulted in distinct labelling patterns. For the μ and κ opioid receptor probes, the most intense regional signals were observed in striatum, thalamus, hypothalamus, cerebral cortex, cerebellum and certain brainstem areas as well as the spinal cord. The most intense signals for the δ opioid receptor probe were found in cerebral cortex. Expression of opioid receptor transcripts was restricted to subpopulations of neurons within most regions studied demonstrating differences in the cellular expression patterns of μ, κ, and δ opioid receptor messenger RNAs in numerous brain regions. The messenger RNA distribution patterns for each opioid receptor corresponded in general to the distribution of opioid receptor binding sites as visualized by receptor autoradiography. However, some mismatches, for instance between μ opioid receptor receptor binding and μ opioid receptor messenger RNA expression in the anterior striatum, were observed. A comparison of the distribution patterns of opioid receptor messenger RNAs in the human brain and that reported for the rat suggests a homologous expression pattern in many regions. However, in the human brain, κ

  12. GRK2 Constitutively Governs Peripheral Delta Opioid Receptor Activity

    Directory of Open Access Journals (Sweden)

    Allison Doyle Brackley

    2016-09-01

    Full Text Available Opioids remain the standard for analgesic care; however, adverse effects of systemic treatments contraindicate long-term administration. While most clinical opioids target mu opioid receptors (MOR, those that target the delta class (DOR also demonstrate analgesic efficacy. Furthermore, peripherally restrictive opioids represent an attractive direction for analgesia. However, opioid receptors including DOR are analgesically incompetent in the absence of inflammation. Here, we report that G protein-coupled receptor kinase 2 (GRK2 naively associates with plasma membrane DOR in peripheral sensory neurons to inhibit analgesic agonist efficacy. This interaction prevents optimal Gβ subunit association with the receptor, thereby reducing DOR activity. Importantly, bradykinin stimulates GRK2 movement away from DOR and onto Raf kinase inhibitory protein (RKIP. protein kinase C (PKC-dependent RKIP phosphorylation induces GRK2 sequestration, restoring DOR functionality in sensory neurons. Together, these results expand the known function of GRK2, identifying a non-internalizing role to maintain peripheral DOR in an analgesically incompetent state.

  13. Identification of an Activating Chicken Ig-like Receptor Recognizing Avian Influenza Viruses

    NARCIS (Netherlands)

    Jansen, Christine A; van Haarlem, Daphne A; Sperling, Beatrice; van Kooten, Peter J; de Vries, Erik; Viertlboeck, Birgit C; Vervelde, Lonneke; Göbel, Thomas W

    2016-01-01

    Chicken Ig-like receptors (CHIRs) represent a multigene family encoded by the leukocyte receptor complex that encodes a variety of receptors that are subdivided into activating CHIR-A, inhibitory CHIR-B, and bifunctional CHIR-AB. Apart from CHIR-AB, which functions as an Fc receptor, CHIR ligands

  14. Wastewater treatment in a hybrid activated sludge baffled reactor

    International Nuclear Information System (INIS)

    Tizghadam, Mostafa; Dagot, Christophe; Baudu, Michel

    2008-01-01

    A novel hybrid activated sludge baffled reactor (HASBR), which contained both suspended and attached-growth biomass perfect mixing cells in series, was developed by installing standing and hanging baffles and introducing plastic brushes into a conventional activated sludge (CAS) reactor. It was used for the treatment of domestic wastewater. The effects on the operational performance of developing the suspended and attached-growth biomass and reactor configuration were investigated. The change of the flow regime from complete-mix to plug-flow, and the addition of plastic brushes as a support for biofilm, resulted in considerable improvements in the COD, nitrogen removal efficiency of domestic wastewater and sludge settling properties. In steady state, approximately 98 ± 2% of the total COD and 98 ± 2% of the ammonia of the influent were removed in the HASBR, when the influent wastewater concentration was 593 ± 11 mg COD/L and 43 ± 5 mg N/L, respectively, at a HRT of 10 h. These results were 93 ± 3 and 6 ± 3% for the CAS reactor, respectively. Approximately 90 ± 7% of the total COD was removed in the HASBR, when the influent wastewater concentration was 654 ± 16 mg COD/L at a 3 h HRT, and in the organic loading rate (OLR) of 5.36 kg COD m -3 day -1 . The result for the CAS reactor was 60 ± 3%. Existing CAS plants can be upgraded by changing the reactor configuration and introducing biofilm support media into the aeration tank

  15. Synthesis and anthelmintic activity of some hybrid Benzimidazolyl ...

    African Journals Online (AJOL)

    Erah

    parasites a major economic and food security issue. In this context ... a new hybrid chemical profile of chalcone and benzimidazole .... standard anthelmintic drugs (fenbendazole ... laboratory according to the classical Claisen-. Schmidt using.

  16. In vitro binding and receptor-mediated activity of terlipressin at vasopressin receptors V1 and V2.

    Science.gov (United States)

    Jamil, Khurram; Pappas, Stephen Chris; Devarakonda, Krishna R

    2018-01-01

    Terlipressin, a synthetic, systemic vasoconstrictor with selective activity at vasopressin-1 (V 1 ) receptors, is a pro-drug for the endogenous/natural porcine hormone [Lys 8 ]-vasopressin (LVP). We investigated binding and receptor-mediated cellular activities of terlipressin, LVP, and endogenous human hormone [Arg 8 ]-vasopressin (AVP) at V 1 and vasopressin-2 (V 2 ) receptors. Cell membrane homogenates of Chinese hamster ovary cells expressing human V 1 and V 2 receptors were used in competitive binding assays to measure receptor-binding activity. These cells were used in functional assays to measure receptor-mediated cellular activity of terlipressin, LVP, and AVP. Binding was measured by [ 3 H]AVP counts, and the activity was measured by fluorometric detection of intracellular calcium mobilization (V 1 ) and cyclic adenosine monophosphate (V 2 ). Binding potency at V 1 and V 2 was AVP>LVP>terlipressin. LVP and terlipressin had approximately sixfold higher affinity for V 1 than for V 2 . Cellular activity potency was also AVP>LVP>terlipressin. Terlipressin was a partial agonist at V 1 and a full agonist at V 2 ; LVP was a full agonist at both V 1 and V 2 . The in vivo response to terlipressin is likely due to the partial V 1 agonist activity of terlipressin and full V 1 agonist activity of its metabolite, LVP. These results provide supportive evidence for previous findings and further establish terlipressin pharmacology for vasopressin receptors.

  17. Endogenous acute phase serum amyloid A lacks pro-inflammatory activity, contrasting the two recombinant variants that activate human neutrophils through different receptors

    Directory of Open Access Journals (Sweden)

    Karin eChristenson

    2013-04-01

    Full Text Available Most notable among the acute phase proteins is serum amyloid A (SAA, levels of which can increase 1000-fold during infections, aseptic inflammation, and/or trauma. Chronically elevated SAA levels are associated with a wide variety of pathological conditions, including obesity and rheumatic diseases. Using a recombinant hybrid of the two human SAA isoforms (SAA1 and 2 that does not exist in vivo, numerous in vitro studies have given rise to the notion that acute phase SAA is a pro-inflammatory molecule with cytokine-like properties. It is however unclear whether endogenous acute phase SAA per se mediates pro-inflammatory effects. We tested this in samples from patients with inflammatory arthritis and in a transgenic mouse model that expresses human SAA1. Endogenous human SAA did not drive production of pro-inflammatory IL-8/KC in either of these settings. Human neutrophils derived from arthritis patients displayed no signs of activation, despite being exposed to severely elevated SAA levels in circulation, and SAA-rich sera also failed to activate cells in vitro. In contrast, two recombinant SAA variants (the hybrid SAA and SAA1 both activated human neutrophils, inducing L-selectin shedding, production of reactive oxygen species, and production of IL-8. The hybrid SAA was approximately 100-fold more potent than recombinant SAA1. Recombinant hybrid SAA and SAA1 activated neutrophils through different receptors, with recombinant SAA1 being a ligand for formyl peptide receptor 2 (FPR2. We conclude that even though recombinant SAAs can be valuable tools for studying neutrophil activation, they do not reflect the nature of the endogenous protein.

  18. Acute activation, desensitization and smoldering activation of human acetylcholine receptors.

    Directory of Open Access Journals (Sweden)

    Barbara G Campling

    Full Text Available The behavioral effects of nicotine and other nicotinic agonists are mediated by AChRs in the brain. The relative contribution of acute activation versus chronic desensitization of AChRs is unknown. Sustained "smoldering activation" occurs over a range of agonist concentrations at which activated and desensitized AChRs are present in equilibrium. We used a fluorescent dye sensitive to changes in membrane potential to examine the effects of acute activation and chronic desensitization by nicotinic AChR agonists on cell lines expressing human α4β2, α3β4 and α7 AChRs. We examined the effects of acute and prolonged application of nicotine and the partial agonists varenicline, cytisine and sazetidine-A on these AChRs. The range of concentrations over which nicotine causes smoldering activation of α4β2 AChRs was centered at 0.13 µM, a level found in smokers. However, nicotine produced smoldering activation of α3β4 and α7 AChRs at concentrations well above levels found in smokers. The α4β2 expressing cell line contains a mixture of two stoichiometries, namely (α4β22β2 and (α4β22α4. The (α4β22β2 stoichiometry is more sensitive to activation by nicotine. Sazetidine-A activates and desensitizes only this stoichiometry. Varenicline, cytisine and sazetidine-A were partial agonists on this mixture of α4β2 AChRs, but full agonists on α3β4 and α7 AChRs. It has been reported that cytisine and varenicline are most efficacious on the (α4β22α4 stoichiometry. In this study, we distinguish the dual effects of activation and desensitization of AChRs by these nicotinic agonists and define the range of concentrations over which smoldering activation can be sustained.

  19. Cyclin D3 interacts with vitamin D receptor and regulates its transcription activity

    International Nuclear Information System (INIS)

    Jian Yongzhi; Yan Jun; Wang Hanzhou; Chen Chen; Sun Maoyun; Jiang Jianhai; Lu Jieqiong; Yang Yanzhong; Gu Jianxin

    2005-01-01

    D-type cyclins are essential for the progression through the G1 phase of the cell cycle. Besides serving as cell cycle regulators, D-type cyclins were recently reported to have transcription regulation functions. Here, we report that cyclin D3 is a new interacting partner of vitamin D receptor (VDR), a member of the superfamily of nuclear receptors for steroid hormones, thyroid hormone, and the fat-soluble vitamins A and D. The interaction was confirmed with methods of yeast two-hybrid system, in vitro binding analysis and in vivo co-immunoprecipitation. Cyclin D3 interacted with VDR in a ligand-independent manner, but treatment of the ligand, 1,25-dihydroxyvitamin D3, strengthened the interaction. Confocal microscopy analysis showed that ligand-activated VDR led to an accumulation of cyclin D3 in the nuclear region. Cyclin D3 up-regulated transcriptional activity of VDR and this effect was counteracted by overexpression of CDK4 and CDK6. These findings provide us a new clue to understand the transcription regulation functions of D-type cyclins

  20. Conditional expression of constitutively active estrogen receptor {alpha} in chondrocytes impairs longitudinal bone growth in mice

    Energy Technology Data Exchange (ETDEWEB)

    Ikeda, Kazuhiro [Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama (Japan); Tsukui, Tohru [Experimental Animal Laboratory, Research Center for Genomic Medicine, Saitama Medical University, Saitama (Japan); Imazawa, Yukiko; Horie-Inoue, Kuniko [Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama (Japan); Inoue, Satoshi, E-mail: INOUE-GER@h.u-tokyo.ac.jp [Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama (Japan); Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo (Japan); Department of Anti-Aging Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo (Japan)

    2012-09-07

    Highlights: Black-Right-Pointing-Pointer Conditional transgenic mice expressing constitutively active estrogen receptor {alpha} (caER{alpha}) in chondrocytes were developed. Black-Right-Pointing-Pointer Expression of caER{alpha} in chondrocytes impaired longitudinal bone growth in mice. Black-Right-Pointing-Pointer caER{alpha} affects chondrocyte proliferation and differentiation. Black-Right-Pointing-Pointer This mouse model is useful for understanding the physiological role of ER{alpha}in vivo. -- Abstract: Estrogen plays important roles in the regulation of chondrocyte proliferation and differentiation, which are essential steps for longitudinal bone growth; however, the mechanisms of estrogen action on chondrocytes have not been fully elucidated. In the present study, we generated conditional transgenic mice, designated as caER{alpha}{sup ColII}, expressing constitutively active mutant estrogen receptor (ER) {alpha} in chondrocytes, using the chondrocyte-specific type II collagen promoter-driven Cre transgenic mice. caER{alpha}{sup ColII} mice showed retardation in longitudinal growth, with short bone lengths. BrdU labeling showed reduced proliferation of hypertrophic chondrocytes in the proliferating layer of the growth plate of tibia in caER{alpha}{sup ColII} mice. In situ hybridization analysis of type X collagen revealed that the maturation of hypertrophic chondrocytes was impaired in caER{alpha}{sup ColII} mice. These results suggest that ER{alpha} is a critical regulator of chondrocyte proliferation and maturation during skeletal development, mediating longitudinal bone growth in vivo.

  1. Conditional expression of constitutively active estrogen receptor α in chondrocytes impairs longitudinal bone growth in mice

    International Nuclear Information System (INIS)

    Ikeda, Kazuhiro; Tsukui, Tohru; Imazawa, Yukiko; Horie-Inoue, Kuniko; Inoue, Satoshi

    2012-01-01

    Highlights: ► Conditional transgenic mice expressing constitutively active estrogen receptor α (caERα) in chondrocytes were developed. ► Expression of caERα in chondrocytes impaired longitudinal bone growth in mice. ► caERα affects chondrocyte proliferation and differentiation. ► This mouse model is useful for understanding the physiological role of ERαin vivo. -- Abstract: Estrogen plays important roles in the regulation of chondrocyte proliferation and differentiation, which are essential steps for longitudinal bone growth; however, the mechanisms of estrogen action on chondrocytes have not been fully elucidated. In the present study, we generated conditional transgenic mice, designated as caERα ColII , expressing constitutively active mutant estrogen receptor (ER) α in chondrocytes, using the chondrocyte-specific type II collagen promoter-driven Cre transgenic mice. caERα ColII mice showed retardation in longitudinal growth, with short bone lengths. BrdU labeling showed reduced proliferation of hypertrophic chondrocytes in the proliferating layer of the growth plate of tibia in caERα ColII mice. In situ hybridization analysis of type X collagen revealed that the maturation of hypertrophic chondrocytes was impaired in caERα ColII mice. These results suggest that ERα is a critical regulator of chondrocyte proliferation and maturation during skeletal development, mediating longitudinal bone growth in vivo.

  2. The prostaglandin EP1 receptor potentiates kainate receptor activation via a protein kinase C pathway and exacerbates status epilepticus

    Science.gov (United States)

    Rojas, Asheebo; Gueorguieva, Paoula; Lelutiu, Nadia; Quan, Yi; Shaw, Renee; Dingledine, Raymond

    2014-01-01

    Prostaglandin E2 (PGE2) regulates membrane excitability, synaptic transmission, plasticity, and neuronal survival. The consequences of PGE2 release following seizures has been the subject of much study. Here we demonstrate that the prostaglandin E2 receptor 1 (EP1, or Ptger1) modulates native kainate receptors, a family of ionotropic glutamate receptors widely expressed throughout the central nervous system. Global ablation of the EP1 gene in mice (EP1-KO) had no effect on seizure threshold after kainate injection but reduced the likelihood to enter status epilepticus. EP1-KO mice that did experience typical status epilepticus had reduced hippocampal neurodegeneration and a blunted inflammatory response. Further studies with native prostanoid and kainate receptors in cultured cortical neurons, as well as with recombinant prostanoid and kainate receptors expressed in Xenopus oocytes, demonstrated that EP1 receptor activation potentiates heteromeric but not homomeric kainate receptors via a second messenger cascade involving phospholipase C, calcium and protein kinase C. Three critical GluK5 C-terminal serines underlie the potentiation of the GluK2/GluK5 receptor by EP1 activation. Taken together, these results indicate that EP1 receptor activation during seizures, through a protein kinase C pathway, increases the probability of kainic acid induced status epilepticus, and independently promotes hippocampal neurodegeneration and a broad inflammatory response. PMID:24952362

  3. Deflation-activated receptors, not classical inflation-activated receptors, mediate the Hering-Breuer deflation reflex.

    Science.gov (United States)

    Yu, Jerry

    2016-11-01

    Many airway sensory units respond to both lung inflation and deflation. Whether those responses to opposite stimuli come from one sensor (one-sensor theory) or more than one sensor (multiple-sensor theory) is debatable. One-sensor theory is commonly presumed in the literature. This article proposes a multiple-sensor theory in which a sensory unit contains different sensors for sensing different forces. Two major types of mechanical sensors operate in the lung: inflation- and deflation-activated receptors (DARs). Inflation-activated sensors can be further divided into slowly adapting receptors (SARs) and rapidly adapting receptors (RARs). Many SAR and RAR units also respond to lung deflation because they contain DARs. Pure DARs, which respond to lung deflation only, are rare in large animals but are easily identified in small animals. Lung deflation-induced reflex effects previously attributed to RARs should be assigned to DARs (including pure DARs and DARs associated with SARs and RARs) if the multiple-sensor theory is accepted. Thus, based on the information, it is proposed that activation of DARs can attenuate lung deflation, shorten expiratory time, increase respiratory rate, evoke inspiration, and cause airway secretion and dyspnea.

  4. One-step electrochemical synthesis of a graphene–ZnO hybrid for improved photocatalytic activity

    International Nuclear Information System (INIS)

    Wei, Ang; Xiong, Li; Sun, Li; Liu, Yanjun; Li, Weiwei; Lai, Wenyong; Liu, Xiangmei; Wang, Lianhui; Huang, Wei; Dong, Xiaochen

    2013-01-01

    Graphical abstract: - Highlights: • Graphene–ZnO hybrid was synthesized by one-step electrochemical deposition. • Graphene–ZnO hybrid presents a special structure and wide UV–vis absorption spectra. • Graphene–ZnO hybrid exhibits an exceptionally higher photocatalytic activity for the degradation of dye methylene blue. - Abstract: A graphene–ZnO (G-ZnO) hybrid was synthesized by one-step electrochemical deposition. During the formation of ZnO nanostructure by cathodic electrochemical deposition, the graphene oxide was electrochemically reduced to graphene simultaneously. Scanning electron microscope images, X-ray photoelectron spectroscopy, X-ray diffraction, Raman spectra, and UV–vis absorption spectra indicate the resulting G-ZnO hybrid presents a special structure and wide UV–vis absorption spectra. More importantly, it exhibits an exceptionally higher photocatalytic activity for the degradation of dye methylene blue than that of pure ZnO nanostructure under both ultraviolet and sunlight irradiation

  5. Synthesis of Polythiophene–Fullerene Hybrid Additives as Potential Compatibilizers of BHJ Active Layers

    Directory of Open Access Journals (Sweden)

    Sofia Kakogianni

    2016-12-01

    Full Text Available Perfluorophenyl functionalities have been introduced as side chain substituents onto regioregular poly(3-hexyl thiophene (rr-P3HT, under various percentages. These functional groups were then converted to azides which were used to create polymeric hybrid materials with fullerene species, either C60 or C70. The P3HT–fullerene hybrids thus formed were thereafter evaluated as potential compatibilizers of BHJ active layers comprising P3HT and fullerene based acceptors. Therefore, a systematic investigation of the optical and morphological properties of the purified polymer–fullerene hybrid materials was performed, via different complementary techniques. Additionally, P3HT:PC70BM blends containing various percentages of the herein synthesized hybrid material comprising rr-P3HT and C70 were investigated via Transmission Electron Microscopy (TEM in an effort to understand the effect of the hybrids as additives on the morphology and nanophase separation of this typically used active layer blend for OPVs.

  6. Agent-based power sharing scheme for active hybrid power sources

    Science.gov (United States)

    Jiang, Zhenhua

    The active hybridization technique provides an effective approach to combining the best properties of a heterogeneous set of power sources to achieve higher energy density, power density and fuel efficiency. Active hybrid power sources can be used to power hybrid electric vehicles with selected combinations of internal combustion engines, fuel cells, batteries, and/or supercapacitors. They can be deployed in all-electric ships to build a distributed electric power system. They can also be used in a bulk power system to construct an autonomous distributed energy system. An important aspect in designing an active hybrid power source is to find a suitable control strategy that can manage the active power sharing and take advantage of the inherent scalability and robustness benefits of the hybrid system. This paper presents an agent-based power sharing scheme for active hybrid power sources. To demonstrate the effectiveness of the proposed agent-based power sharing scheme, simulation studies are performed for a hybrid power source that can be used in a solar car as the main propulsion power module. Simulation results clearly indicate that the agent-based control framework is effective to coordinate the various energy sources and manage the power/voltage profiles.

  7. Implications of compound heterozygous insulin receptor mutations in congenital muscle fibre type disproportion myopathy for the receptor kinase activation

    DEFF Research Database (Denmark)

    Klein, H H; Müller, R; Vestergaard, H

    1999-01-01

    We studied insulin receptor kinase activation in two brothers with congenital muscle fibre type disproportion myopathy and compound heterozygous mutations of the insulin receptor gene, their parents, and their unaffected brother. In the father who has a heterozygote Arg1174-->Gln mutation, in sit...

  8. Urokinase-type plasminogen activator receptor (uPAR), tissue factor (TF) and epidermal growth factor receptor (EGFR)

    DEFF Research Database (Denmark)

    Christensen, Anders; Kiss, Katalin; Lelkaitis, Giedrius

    2017-01-01

    Background: Tumor-specific biomarkers are a prerequisite for the development of targeted imaging and therapy in oral squamous cell carcinoma (OSCC). urokinase-type Plasminogen Activator Receptor (uPAR), Tissue Factor (TF) and Epidermal Growth Factor Receptor (EGFR) are three biomarkers that exhib...... with a reduced survival. uPAR seems to be a prognostic biomarker in oral cancer....

  9. Methamphetamine Increases Locomotion and Dopamine Transporter Activity in Dopamine D5 Receptor-Deficient Mice

    OpenAIRE

    Hayashizaki, Seiji; Hirai, Shinobu; Ito, Yumi; Honda, Yoshiko; Arime, Yosefu; Sora, Ichiro; Okado, Haruo; Kodama, Tohru; Takada, Masahiko

    2013-01-01

    Dopamine regulates the psychomotor stimulant activities of amphetamine-like substances in the brain. The effects of dopamine are mediated through five known dopamine receptor subtypes in mammals. The functional relevance of D5 dopamine receptors in the central nervous system is not well understood. To determine the functional relevance of D5 dopamine receptors, we created D5 dopamine receptor-deficient mice and then used these mice to assess the roles of D5 dopamine receptors in the behaviora...

  10. Behavioral meaningful opioidergic stimulation activates kappa receptor gene expression

    International Nuclear Information System (INIS)

    Teodorov, E.; Ferrari, M.F.R.; Fior-Chadi, D.R.; Camarini, R.; Felício, L.F.

    2012-01-01

    The periaqueductal gray (PAG) has been reported to be a location for opioid regulation of pain and a potential site for behavioral selection in females. Opioid-mediated behavioral and physiological responses differ according to the activity of opioid receptor subtypes. The present study investigated the effects of the peripheral injection of the kappa-opioid receptor agonist U69593 into the dorsal subcutaneous region of animals on maternal behavior and on Oprk1 gene activity in the PAG of female rats. Female Wistar rats weighing 200-250 g at the beginning of the study were randomly divided into 2 groups for maternal behavior and gene expression experiments. On day 5, pups were removed at 7:00 am and placed in another home cage that was distant from their mother. Thirty minutes after removing the pups, the dams were treated with U69593 (0.15 mg/kg, sc) or 0.9% saline (up to 1 mL/kg) and after 30 min were evaluated in the maternal behavior test. Latencies in seconds for pup retrieval, grouping, crouching, and full maternal behavior were scored. The results showed that U69593 administration inhibited maternal behavior (P < 0.05) because a lower percentage of U69593 group dams showed retrieval of first pup, retrieving all pups, grouping, crouching and displaying full maternal behavior compared to the saline group. Opioid gene expression was evaluated using real-time reverse-transcription polymerase chain reaction (RT-PCR). A single injection of U69593 increased Oprk1 PAG expression in both virgin (P < 0.05) and lactating female rats (P < 0.01), with no significant effect on Oprm1 or Oprd1 gene activity. Thus, the expression of kappa-opioid receptors in the PAG may be modulated by single opioid receptor stimulation and behavioral meaningful opioidergic transmission in the adult female might occur simultaneously to specific changes in gene expression of kappa-opioid receptor subtype. This is yet another alert for the complex role of the opioid system in female

  11. Behavioral meaningful opioidergic stimulation activates kappa receptor gene expression

    Energy Technology Data Exchange (ETDEWEB)

    Teodorov, E. [Centro de Matemática, Computação e Cognição, Universidade Federal do ABC, São Paulo, SP (Brazil); Ferrari, M.F.R. [Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, SP (Brazil); Fior-Chadi, D.R. [Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, São Paulo, SP (Brazil); Camarini, R. [Departamento de Farmacologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP (Brazil); Felício, L.F. [Departamento de Patologia, Faculdade de Medicina Veterinária e Zootecnia, Universidade de São Paulo, São Paulo, SP (Brazil)

    2012-06-01

    The periaqueductal gray (PAG) has been reported to be a location for opioid regulation of pain and a potential site for behavioral selection in females. Opioid-mediated behavioral and physiological responses differ according to the activity of opioid receptor subtypes. The present study investigated the effects of the peripheral injection of the kappa-opioid receptor agonist U69593 into the dorsal subcutaneous region of animals on maternal behavior and on Oprk1 gene activity in the PAG of female rats. Female Wistar rats weighing 200-250 g at the beginning of the study were randomly divided into 2 groups for maternal behavior and gene expression experiments. On day 5, pups were removed at 7:00 am and placed in another home cage that was distant from their mother. Thirty minutes after removing the pups, the dams were treated with U69593 (0.15 mg/kg, sc) or 0.9% saline (up to 1 mL/kg) and after 30 min were evaluated in the maternal behavior test. Latencies in seconds for pup retrieval, grouping, crouching, and full maternal behavior were scored. The results showed that U69593 administration inhibited maternal behavior (P < 0.05) because a lower percentage of U69593 group dams showed retrieval of first pup, retrieving all pups, grouping, crouching and displaying full maternal behavior compared to the saline group. Opioid gene expression was evaluated using real-time reverse-transcription polymerase chain reaction (RT-PCR). A single injection of U69593 increased Oprk1 PAG expression in both virgin (P < 0.05) and lactating female rats (P < 0.01), with no significant effect on Oprm1 or Oprd1 gene activity. Thus, the expression of kappa-opioid receptors in the PAG may be modulated by single opioid receptor stimulation and behavioral meaningful opioidergic transmission in the adult female might occur simultaneously to specific changes in gene expression of kappa-opioid receptor subtype. This is yet another alert for the complex role of the opioid system in female

  12. Behavioral meaningful opioidergic stimulation activates kappa receptor gene expression

    Directory of Open Access Journals (Sweden)

    E. Teodorov

    2012-10-01

    Full Text Available The periaqueductal gray (PAG has been reported to be a location for opioid regulation of pain and a potential site for behavioral selection in females. Opioid-mediated behavioral and physiological responses differ according to the activity of opioid receptor subtypes. The present study investigated the effects of the peripheral injection of the kappa-opioid receptor agonist U69593 into the dorsal subcutaneous region of animals on maternal behavior and on Oprk1 gene activity in the PAG of female rats. Female Wistar rats weighing 200-250 g at the beginning of the study were randomly divided into 2 groups for maternal behavior and gene expression experiments. On day 5, pups were removed at 7:00 am and placed in another home cage that was distant from their mother. Thirty minutes after removing the pups, the dams were treated with U69593 (0.15 mg/kg, sc or 0.9% saline (up to 1 mL/kg and after 30 min were evaluated in the maternal behavior test. Latencies in seconds for pup retrieval, grouping, crouching, and full maternal behavior were scored. The results showed that U69593 administration inhibited maternal behavior (P < 0.05 because a lower percentage of kappa group dams showed retrieval of first pup, retrieving all pups, grouping, crouching and displaying full maternal behavior compared to the saline group. Opioid gene expression was evaluated using real-time reverse-transcription polymerase chain reaction (RT-PCR. A single injection of U69593 increased Oprk1 PAG expression in both virgin (P < 0.05 and lactating female rats (P < 0.01, with no significant effect on Oprm1 or Oprd1 gene activity. Thus, the expression of kappa-opioid receptors in the PAG may be modulated by single opioid receptor stimulation and behavioral meaningful opioidergic transmission in the adult female might occur simultaneously to specific changes in gene expression of kappa-opioid receptor subtype. This is yet another alert for the complex role of the opioid system in

  13. Stimulation of cannabinoid receptor 2 (CB2 suppresses microglial activation

    Directory of Open Access Journals (Sweden)

    Fernandez Francisco

    2005-12-01

    Full Text Available Abstract Background Activated microglial cells have been implicated in a number of neurodegenerative disorders, including Alzheimer's disease (AD, multiple sclerosis (MS, and HIV dementia. It is well known that inflammatory mediators such as nitric oxide (NO, cytokines, and chemokines play an important role in microglial cell-associated neuron cell damage. Our previous studies have shown that CD40 signaling is involved in pathological activation of microglial cells. Many data reveal that cannabinoids mediate suppression of inflammation in vitro and in vivo through stimulation of cannabinoid receptor 2 (CB2. Methods In this study, we investigated the effects of a cannabinoid agonist on CD40 expression and function by cultured microglial cells activated by IFN-γ using RT-PCR, Western immunoblotting, flow cytometry, and anti-CB2 small interfering RNA (siRNA analyses. Furthermore, we examined if the stimulation of CB2 could modulate the capacity of microglial cells to phagocytise Aβ1–42 peptide using a phagocytosis assay. Results We found that the selective stimulation of cannabinoid receptor CB2 by JWH-015 suppressed IFN-γ-induced CD40 expression. In addition, this CB2 agonist markedly inhibited IFN-γ-induced phosphorylation of JAK/STAT1. Further, this stimulation was also able to suppress microglial TNF-α and nitric oxide production induced either by IFN-γ or Aβ peptide challenge in the presence of CD40 ligation. Finally, we showed that CB2 activation by JWH-015 markedly attenuated CD40-mediated inhibition of microglial phagocytosis of Aβ1–42 peptide. Taken together, these results provide mechanistic insight into beneficial effects provided by cannabinoid receptor CB2 modulation in neurodegenerative diseases, particularly AD.

  14. UV ACTIVATION OF RECEPTOR TYROSINE KINASE-ACTIVITY

    NARCIS (Netherlands)

    COFFER, PJ; BURGERING, BMT; PEPPELENBOSCH, MP; BOS, JL; KRUIJER, W

    1995-01-01

    The exposure of mammalian cells to ultraviolet radiation (UV) may lead to DNA damage resulting in mutation and thus possibly cancer, while irradiation can further act as a potent tumour promoter. In addition UV induces p21ras-mediated signalling leading to activation of transcription factors such as

  15. Facilitation of neocortical presynaptic terminal development by NMDA receptor activation

    Directory of Open Access Journals (Sweden)

    Sceniak Michael P

    2012-02-01

    Full Text Available Abstract Background Neocortical circuits are established through the formation of synapses between cortical neurons, but the molecular mechanisms of synapse formation are only beginning to be understood. The mechanisms that control synaptic vesicle (SV and active zone (AZ protein assembly at developing presynaptic terminals have not yet been defined. Similarly, the role of glutamate receptor activation in control of presynaptic development remains unclear. Results Here, we use confocal imaging to demonstrate that NMDA receptor (NMDAR activation regulates accumulation of multiple SV and AZ proteins at nascent presynaptic terminals of visual cortical neurons. NMDAR-dependent regulation of presynaptic assembly occurs even at synapses that lack postsynaptic NMDARs. We also provide evidence that this control of presynaptic terminal development is independent of glia. Conclusions Based on these data, we propose a novel NMDAR-dependent mechanism for control of presynaptic terminal development in excitatory neocortical neurons. Control of presynaptic development by NMDARs could ultimately contribute to activity-dependent development of cortical receptive fields.

  16. 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.

  17. Down syndrome critical region 2 protein inhibits the transcriptional activity of peroxisome proliferator-activated receptor β in HEK293 cells

    International Nuclear Information System (INIS)

    Song, Hae Jin; Park, Joongkyu; Seo, Su Ryeon; Kim, Jongsun; Paik, Seung R.; Chung, Kwang Chul

    2008-01-01

    Down syndrome is mainly caused by a trisomy of chromosome 21. The Down syndrome critical region 2 (DSCR2) gene is located within a part of chromosome 21, the Down syndrome critical region (DSCR). To investigate the function of DSCR2, we sought to identify DSCR2-interacting proteins using yeast two-hybrid assays. A human fetal brain cDNA library was screened, and DSCR2 was found to interact with a member of the nuclear receptor superfamily, peroxisome proliferator-activated receptor β, (PPARβ). A co-immunoprecipitation assay demonstrated that DSCR2 physically interacts with PPARβ in mammalian HEK293 cells. DSCR2 also inhibited the ligand-induced transcriptional activity of PPARβ. Furthermore, PPARβ also decreased the solubility of DSCR2, which increased levels of insoluble DSCR2

  18. Receptor activity-independent recruitment of βarrestin2 reveals specific signalling modes

    Science.gov (United States)

    Terrillon, Sonia; Bouvier, Michel

    2004-01-01

    The roles of βarrestins in regulating G protein coupling and receptor endocytosis following agonist stimulation of G protein-coupled receptors are well characterised. However, their ability to act on their own as direct modulators or activators of signalling remains poorly characterised. Here, βarrestin2 intrinsic signalling properties were assessed by forcing the recruitment of this accessory protein to vasopressin V1a or V2 receptors independently of agonist-promoted activation of the receptors. Such induction of a stable interaction with βarrestin2 initiated receptor endocytosis leading to intracellular accumulation of the βarrestin/receptor complexes. Interestingly, βarrestin2 association to a single receptor protomer was sufficient to elicit receptor dimer internalisation. In addition to recapitulating βarrestin2 classical actions on receptor trafficking, the receptor activity-independent recruitment of βarrestin2 activated the extracellular signal-regulated kinases. In the latter case, recruitment to the receptor itself was not required since kinase activation could be mediated by βarrestin2 translocation to the plasma membrane in the absence of any interacting receptor. These data demonstrate that βarrestin2 can act as a ‘bonafide' signalling molecule even in the absence of activated receptor. PMID:15385966

  19. Activity Recognition Using Hybrid Generative/Discriminative Models on Home Environments Using Binary Sensors

    Directory of Open Access Journals (Sweden)

    Araceli Sanchis

    2013-04-01

    Full Text Available Activities of daily living are good indicators of elderly health status, and activity recognition in smart environments is a well-known problem that has been previously addressed by several studies. In this paper, we describe the use of two powerful machine learning schemes, ANN (Artificial Neural Network and SVM (Support Vector Machines, within the framework of HMM (Hidden Markov Model in order to tackle the task of activity recognition in a home setting. The output scores of the discriminative models, after processing, are used as observation probabilities of the hybrid approach. We evaluate our approach by comparing these hybrid models with other classical activity recognition methods using five real datasets. We show how the hybrid models achieve significantly better recognition performance, with significance level p < 0:05, proving that the hybrid approach is better suited for the addressed domain.

  20. DMPD: Receptor tyrosine kinases and the regulation of macrophage activation. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 14726496 Receptor tyrosine kinases and the regulation of macrophage activation. Cor...osine kinases and the regulation of macrophage activation. PubmedID 14726496 Title Receptor tyrosine...rell PH, Morrison AC, Lutz MA. J Leukoc Biol. 2004 May;75(5):731-7. Epub 2004 Jan 14. (.png) (.svg) (.html) (.csml) Show Receptor tyr

  1. Dopamine receptor activation increases HIV entry into primary human macrophages.

    Directory of Open Access Journals (Sweden)

    Peter J Gaskill

    Full Text Available Macrophages are the primary cell type infected with HIV in the central nervous system, and infection of these cells is a major component in the development of neuropathogenesis and HIV-associated neurocognitive disorders. Within the brains of drug abusers, macrophages are exposed to increased levels of dopamine, a neurotransmitter that mediates the addictive and reinforcing effects of drugs of abuse such as cocaine and methamphetamine. In this study we examined the effects of dopamine on HIV entry into primary human macrophages. Exposure to dopamine during infection increased the entry of R5 tropic HIV into macrophages, irrespective of the concentration of the viral inoculum. The entry pathway affected was CCR5 dependent, as antagonizing CCR5 with the small molecule inhibitor TAK779 completely blocked entry. The effect was dose-dependent and had a steep threshold, only occurring above 108 M dopamine. The dopamine-mediated increase in entry required dopamine receptor activation, as it was abrogated by the pan-dopamine receptor antagonist flupenthixol, and could be mediated through both subtypes of dopamine receptors. These findings indicate that the effects of dopamine on macrophages may have a significant impact on HIV pathogenesis. They also suggest that drug-induced increases in CNS dopamine may be a common mechanism by which drugs of abuse with distinct modes of action exacerbate neuroinflammation and contribute to HIV-associated neurocognitive disorders in infected drug abusers.

  2. Synaptic activity regulates AMPA receptor trafficking through different recycling pathways

    Science.gov (United States)

    Zheng, Ning; Jeyifous, Okunola; Munro, Charlotte; Montgomery, Johanna M; Green, William N

    2015-01-01

    Changes in glutamatergic synaptic strength in brain are dependent on AMPA-type glutamate receptor (AMPAR) recycling, which is assumed to occur through a single local pathway. In this study, we present evidence that AMPAR recycling occurs through different pathways regulated by synaptic activity. Without synaptic stimulation, most AMPARs recycled in dynamin-independent endosomes containing the GTPase, Arf6. Few AMPARs recycled in dynamin-dependent endosomes labeled by transferrin receptors (TfRs). AMPAR recycling was blocked by alterations in the GTPase, TC10, which co-localized with Arf6 endosomes. TC10 mutants that reduced AMPAR recycling had no effect on increased AMPAR levels with long-term potentiation (LTP) and little effect on decreased AMPAR levels with long-term depression. However, internalized AMPAR levels in TfR-containing recycling endosomes increased after LTP, indicating increased AMPAR recycling through the dynamin-dependent pathway with synaptic plasticity. LTP-induced AMPAR endocytosis is inconsistent with local recycling as a source of increased surface receptors, suggesting AMPARs are trafficked from other sites. DOI: http://dx.doi.org/10.7554/eLife.06878.001 PMID:25970033

  3. Dopamine Receptor Activation Increases HIV Entry into Primary Human Macrophages

    Science.gov (United States)

    Gaskill, Peter J.; Yano, Hideaki H.; Kalpana, Ganjam V.; Javitch, Jonathan A.; Berman, Joan W.

    2014-01-01

    Macrophages are the primary cell type infected with HIV in the central nervous system, and infection of these cells is a major component in the development of neuropathogenesis and HIV-associated neurocognitive disorders. Within the brains of drug abusers, macrophages are exposed to increased levels of dopamine, a neurotransmitter that mediates the addictive and reinforcing effects of drugs of abuse such as cocaine and methamphetamine. In this study we examined the effects of dopamine on HIV entry into primary human macrophages. Exposure to dopamine during infection increased the entry of R5 tropic HIV into macrophages, irrespective of the concentration of the viral inoculum. The entry pathway affected was CCR5 dependent, as antagonizing CCR5 with the small molecule inhibitor TAK779 completely blocked entry. The effect was dose-dependent and had a steep threshold, only occurring above 108 M dopamine. The dopamine-mediated increase in entry required dopamine receptor activation, as it was abrogated by the pan-dopamine receptor antagonist flupenthixol, and could be mediated through both subtypes of dopamine receptors. These findings indicate that the effects of dopamine on macrophages may have a significant impact on HIV pathogenesis. They also suggest that drug-induced increases in CNS dopamine may be a common mechanism by which drugs of abuse with distinct modes of action exacerbate neuroinflammation and contribute to HIV-associated neurocognitive disorders in infected drug abusers. PMID:25268786

  4. Antibacterial activity of berberine-NorA pump inhibitor hybrids with a methylene ether linking group.

    Science.gov (United States)

    Samosorn, Siritron; Tanwirat, Bongkot; Muhamad, Nussara; Casadei, Gabriele; Tomkiewicz, Danuta; Lewis, Kim; Suksamrarn, Apichart; Prammananan, Therdsak; Gornall, Karina C; Beck, Jennifer L; Bremner, John B

    2009-06-01

    Conjugation of the NorA substrate berberine and the NorA inhibitor 5-nitro-2-phenyl-1H-indole via a methylene ether linking group gave the 13-substituted berberine-NorA inhibitor hybrid, 3. A series of simpler arylmethyl ether hybrid structures were also synthesized. The hybrid 3 showed excellent antibacterial activity (MIC Staphylococcus aureus, 1.7 microM), which was over 382-fold more active than the parent antibacterial berberine, against this bacterium. This compound was also shown to block the NorA efflux pump in S. aureus.

  5. Quinoline-Based Hybrid Compounds with Antimalarial Activity

    Directory of Open Access Journals (Sweden)

    Xhamla Nqoro

    2017-12-01

    Full Text Available The application of quinoline-based compounds for the treatment of malaria infections is hampered by drug resistance. Drug resistance has led to the combination of quinolines with other classes of antimalarials resulting in enhanced therapeutic outcomes. However, the combination of antimalarials is limited by drug-drug interactions. In order to overcome the aforementioned factors, several researchers have reported hybrid compounds prepared by reacting quinoline-based compounds with other compounds via selected functionalities. This review will focus on the currently reported quinoline-based hybrid compounds and their preclinical studies.

  6. Increased abundance of insulin/insulin-like growth factor-I hybrid receptors in skeletal muscle of obese subjects is correlated with in vivo insulin sensitivity.

    Science.gov (United States)

    Federici, M; Porzio, O; Lauro, D; Borboni, P; Giovannone, B; Zucaro, L; Hribal, M L; Sesti, G

    1998-08-01

    We reported that in noninsulin-dependent diabetes melitus (NIDDM) patients expression of insulin/insulin-like growth factor I (IGF-I) hybrid receptors is increased in insulin target tissues. Whether this is a defect associated with NIDDM or represents a generalized abnormality associated with insulin resistant states is still unsettled. To address this, we applied a microwell-based immunoassay to measure abundance of insulin receptors, type 1 IGF receptors, and hybrid receptors in muscle of eight normal and eight obese subjects. Maximal insulin binding to insulin receptors was lower in obese than in control subjects (B/T = 1.8 +/- 0.20 and 2.6 +/- 0.30; P < 0.03, respectively) and was negatively correlated with insulinemia (r = -0.60; P < 0.01). Maximal IGF-I binding to type 1 IGF receptors was higher in obese than in controls (B/T = 1.9 +/- 0.20 and 0.86 +/- 0.10; P < 0.0001, respectively) and was negatively correlated with plasma IGF-I levels (r = -0.69; P < 0.003). Hybrid receptor abundance was higher in obese than in normal subjects (B/T = 1.21 +/- 0.14 and 0.44 +/- 0.06; P < 0.0003, respectively) and was negatively correlated with insulin binding (r = -0.60; P < 0.01) and positively correlated with IGF-I binding (r = 0.92; P < 0.0001). Increased abundance of hybrids was correlated with insulinemia (r = 0.70; P < 0.002) and body mass index (r = 0.71; P < 0.0019), whereas it was negatively correlated with in vivo insulin sensitivity measured by ITT (r = -0.67; P < 0.016). These results indicate that downregulation of insulin receptors or upregulation of type 1 IGF receptors because of changes in plasma insulin and IGF-I levels may result in modifications in hybrid receptor abundance.

  7. Targeting protease activated receptor-1 with P1pal-12 limits bleomycin-induced pulmonary fibrosis

    NARCIS (Netherlands)

    Lin, Cong; Duitman, Janwillem; Daalhuisen, Joost; ten Brink, Marieke; von der Thüsen, Jan; van der Poll, Tom; Borensztajn, Keren; Spek, C. Arnold

    2014-01-01

    Idiopathic pulmonary fibrosis is the most devastating fibrotic diffuse parenchymal lung disease which remains refractory to pharmacological therapies. Therefore, novel treatments are urgently required. Protease-activated receptor (PAR)-1 is a G-protein-coupled receptor that mediates critical

  8. Functionally Selective AT(1) Receptor Activation Reduces Ischemia Reperfusion Injury

    DEFF Research Database (Denmark)

    Hostrup, Anders; Christensen, Gitte Lund; Bentzen, Bo Hjort

    2012-01-01

    of the physiological functions of AngII. The AT(1)R mediates its effects through both G protein-dependent and independent signaling, which can be separated by functionally selective agonists. In the present study we investigate the effect of AngII and the ß-arrestin biased agonist [SII]AngII on ischemia......]AngII had a protective effect. Together these results demonstrate a cardioprotective effect of simultaneous blockade of G protein signaling and activation of G protein independent signaling through AT(1 )receptors....

  9. Vitamin D receptor activation and survival in chronic kidney disease.

    Science.gov (United States)

    Kovesdy, C P; Kalantar-Zadeh, K

    2008-06-01

    Replacement of activated vitamin D has been the cornerstone of therapy for secondary hyperparathyroidism (SHPT). Recent findings from several large observational studies have suggested that the benefits of vitamin D receptor activators (VDRA) may extend beyond the traditional parathyroid hormone (PTH)-lowering effect, and could result in direct cardiovascular and metabolic benefits. The advent of several new analogs of the activated vitamin D molecule has widened our therapeutic armamentarium, but has also made therapeutic decisions more complicated. Treatment of SHPT has become even more complex with the arrival of the first calcium-sensing receptor (CSR) agonist (cinacalcet hydrochloride) and with the uncovering of novel mechanisms responsible for SHPT. We provide a brief overview of the physiology and pathophysiology of SHPT, with a focus on vitamin D metabolism, and discuss various practical aspects of VDRA therapy and its reported association with survival in recent observational studies. A detailed discussion of the available agents is aimed at providing the practicing physician with a clear understanding of the advantages or disadvantages of the individual medications. A number of open questions are also analyzed, including the present and future roles of CSR agonists and 25(OH) vitamin D replacement.

  10. Design, synthesis and antibacterial activity of a novel hybrid ...

    African Journals Online (AJOL)

    Antimicrobial peptides produced by many tissues and cell types of invertebrates, insects and humans as part of their innate immune system, have received increasing attention as potential candidates due to their administration as pharmaceutical agents. In the present study, a novel hybrid antimicrobial peptide LFM23 ...

  11. 4-Aminoquinoline-pyrimidine hybrids: synthesis, antimalarial activity, heme binding and docking studies.

    Science.gov (United States)

    Kumar, Deepak; Khan, Shabana I; Tekwani, Babu L; Ponnan, Prija; Rawat, Diwan S

    2015-01-07

    A series of novel 4-aminoquinoline-pyrimidine hybrids has been synthesized and evaluated for their antimalarial activity. Several compounds showed promising in vitro antimalarial activity against both CQ-sensitive and CQ-resistant strains with high selectivity index. All the compounds were found to be non-toxic to the mammalian cell lines. Selected compound 7g exhibited significant suppression of parasitemia in the in vivo assay. The heme binding studies were conducted to determine the mode of action of these hybrid molecules. These compounds form a stable 1:1 complex with hematin suggesting that heme may be one of the possible targets of these hybrids. The interaction of these conjugate hybrids was also investigated by the molecular docking studies in the binding site of PfDHFR. The pharmacokinetic property analysis of best active compounds was also studied using ADMET prediction. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  12. Hybrid and plug-in hybrid electric vehicle performance testing by the US Department of Energy Advanced Vehicle Testing Activity

    Science.gov (United States)

    Karner, Donald; Francfort, James

    The Advanced Vehicle Testing Activity (AVTA), part of the U.S. Department of Energy's FreedomCAR and Vehicle Technologies Program, has conducted testing of advanced technology vehicles since August 1995 in support of the AVTA goal to provide benchmark data for technology modeling, and vehicle development programs. The AVTA has tested full size electric vehicles, urban electric vehicles, neighborhood electric vehicles, and hydrogen internal combustion engine powered vehicles. Currently, the AVTA is conducting baseline performance, battery benchmark and fleet tests of hybrid electric vehicles (HEV) and plug-in hybrid electric vehicles (PHEV). Testing has included all HEVs produced by major automotive manufacturers and spans over 2.5 million test miles. Testing is currently incorporating PHEVs from four different vehicle converters. The results of all testing are posted on the AVTA web page maintained by the Idaho National Laboratory.

  13. Hybrid approach to structure modeling of the histamine H3 receptor: Multi-level assessment as a tool for model verification.

    Directory of Open Access Journals (Sweden)

    Jakub Jończyk

    Full Text Available The crucial role of G-protein coupled receptors and the significant achievements associated with a better understanding of the spatial structure of known receptors in this family encouraged us to undertake a study on the histamine H3 receptor, whose crystal structure is still unresolved. The latest literature data and availability of different software enabled us to build homology models of higher accuracy than previously published ones. The new models are expected to be closer to crystal structures; and therefore, they are much more helpful in the design of potential ligands. In this article, we describe the generation of homology models with the use of diverse tools and a hybrid assessment. Our study incorporates a hybrid assessment connecting knowledge-based scoring algorithms with a two-step ligand-based docking procedure. Knowledge-based scoring employs probability theory for global energy minimum determination based on information about native amino acid conformation from a dataset of experimentally determined protein structures. For a two-step docking procedure two programs were applied: GOLD was used in the first step and Glide in the second. Hybrid approaches offer advantages by combining various theoretical methods in one modeling algorithm. The biggest advantage of hybrid methods is their intrinsic ability to self-update and self-refine when additional structural data are acquired. Moreover, the diversity of computational methods and structural data used in hybrid approaches for structure prediction limit inaccuracies resulting from theoretical approximations or fuzziness of experimental data. The results of docking to the new H3 receptor model allowed us to analyze ligand-receptor interactions for reference compounds.

  14. Involvement of Activating NK Cell Receptors and Their Modulation in Pathogen Immunity

    Directory of Open Access Journals (Sweden)

    Francesco Marras

    2011-01-01

    Full Text Available Natural Killer (NK cells are endowed with cell-structure-sensing receptors providing inhibitory protection from self-destruction (inhibitory NK receptors, iNKRs, including killer inhibitory receptors and other molecules and rapid triggering potential leading to functional cell activation by Toll-like receptors (TLRs, cytokine receptors, and activating NK cell receptors including natural cytotoxicity receptors (NCRs, i.e., NKp46, NKp46, and NKp44. NCR and NKG2D recognize ligands on infected cells which may be endogenous or may directly bind to some structures derived from invading pathogens. In this paper, we address the known direct or indirect interactions between activating receptors and pathogens and their expression during chronic HIV and HCV infections.

  15. An improved ivermectin-activated chloride channel receptor for inhibiting electrical activity in defined neuronal populations

    DEFF Research Database (Denmark)

    Lynagh, Timothy Peter; Lynch, Joseph W

    2010-01-01

    The ability to silence the electrical activity of defined neuronal populations in vivo is dramatically advancing our understanding of brain function. This technology may eventually be useful clinically for treating a variety of neuropathological disorders caused by excessive neuronal activity...... conductance, homomeric expression, and human origin may render the F207A/A288G alpha1 glycine receptor an improved silencing receptor for neuroscientific and clinical purposes. As all known highly ivermectin-sensitive GluClRs contain an endogenous glycine residue at the corresponding location, this residue...

  16. Peroxisome Proliferators-Activated Receptor (PPAR Modulators and Metabolic Disorders

    Directory of Open Access Journals (Sweden)

    Min-Chul Cho

    2008-01-01

    Full Text Available Overweight and obesity lead to an increased risk for metabolic disorders such as impaired glucose regulation/insulin resistance, dyslipidemia, and hypertension. Several molecular drug targets with potential to prevent or treat metabolic disorders have been revealed. Interestingly, the activation of peroxisome proliferator-activated receptor (PPAR, which belongs to the nuclear receptor superfamily, has many beneficial clinical effects. PPAR directly modulates gene expression by binding to a specific ligand. All PPAR subtypes (α,γ, and σ are involved in glucose metabolism, lipid metabolism, and energy balance. PPAR agonists play an important role in therapeutic aspects of metabolic disorders. However, undesired effects of the existing PPAR agonists have been reported. A great deal of recent research has focused on the discovery of new PPAR modulators with more beneficial effects and more safety without producing undesired side effects. Herein, we briefly review the roles of PPAR in metabolic disorders, the effects of PPAR modulators in metabolic disorders, and the technologies with which to discover new PPAR modulators.

  17. 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.

  18. Cyclic AMP-receptor protein activates aerobactin receptor IutA expression in Vibrio vulnificus.

    Science.gov (United States)

    Kim, Choon-Mee; Kim, Seong-Jung; Shin, Sung-Heui

    2012-04-01

    The ferrophilic bacterium Vibrio vulnificus can utilize the siderophore aerobactin of Escherichia coli for iron acquisition via its specific receptor IutA. This siderophore piracy by V. vulnificus may contribute to its survival and proliferation, especially in mixed bacterial environments. In this study, we examined the effects of glucose, cyclic AMP (cAMP), and cAMP-receptor protein (Crp) on iutA expression in V. vulnificus. Glucose dose-dependently repressed iutA expression. A mutation in cya encoding adenylate cyclase required for cAMP synthesis severely repressed iutA expression, and this change was recovered by in trans complementing cya or the addition of exogenous cAMP. Furthermore, a mutation in crp encoding Crp severely repressed iutA expression, and this change was recovered by complementing crp. Accordingly, glucose deprivation under iron-limited conditions is an environmental signal for iutA expression, and Crp functions as an activator that regulates iutA expression in response to glucose availability.

  19. Cyprodinil as an activator of aryl hydrocarbon receptor

    International Nuclear Information System (INIS)

    Fang, Chien-Chung; Chen, Fei-Yun; Chen, Chang-Rong; Liu, Chien-Chiang; Wong, Liang-Chi; Liu, Yi-Wen; Su, Jyan-Gwo Joseph

    2013-01-01

    Highlights: ► Cyprodinil activated the aryl hydrocarbon receptor (AHR). ► Cyprodinil induced nuclear translocation of the AHR, and the expression of CYP1A1. ► Cyprodinil enhanced dexamethasone-induced gene expression. ► Cyprodinil phosphorylated ERK, indicating its deregulation of ERK activity. -- Abstract: Cyprodinil is a pyrimidinamine fungicide, used worldwide by agriculture. It is used to protect fruit plants and vegetables from a wide range of pathogens. Benzo[a]pyrene (BaP) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are toxic environmental pollutants and are prototypes of aryl hydrocarbon receptor (AHR) ligands. Although the structure of cyprodinil distinctly differs from those of BaP and TCDD, our results show that cyprodinil induced nuclear translocation of the AHR, and induced the transcriptional activity of aryl hydrocarbon response element (AHRE). Cyprodinil induced the expression of cytochrome P450 (CYP) 1A1, a well-known AHR-targeted gene, in ovarian granulosa cells, HO23, and hepatoma cells, Hepa-1c1c7. Its induction did not appear in AHR signal-deficient cells, and was blocked by the AHR antagonist, CH-223191. Cyprodinil decreased AHR expression in HO23 cells, resulting in CYP1A1 expression decreasing after it peaked at 9 h of treatment in HO23 cells. Dexamethasone is a synthetic agonist of glucocorticoids. Cyprodinil enhanced dexamethasone-induced gene expression, and conversely, its induction of CYP1A1 expression was decreased by dexamethasone in HO23 cells, indicating its induction of crosstalk between the AHR and glucocorticoid receptor and its role as a potential endocrine disrupter. In addition to BaP, TCDD, and an AHR agonist, β-NF, cyprodinil also phosphorylated extracellular signal-regulated kinase (ERK) in HO23 and Hepa-1c1c7 cells, indicating its deregulation of ERK activity. In summary, our results demonstrate that cyprodinil, similar to BaP, acts as an AHR activator, a potential endocrine disrupter, and an ERK disrupter

  20. Activity, Abundance, and Localization of Quorum Sensing Receptors in Vibrio harveyi.

    Science.gov (United States)

    Lorenz, Nicola; Shin, Jae Yen; Jung, Kirsten

    2017-01-01

    Quorum sensing (QS) is a process enabling a bacterial population to communicate via small molecules called autoinducers (AIs). This intercellular communication process allows single cells to synchronize their behavior within a population. The marine bacterium Vibrio harveyi ATCC BAA-1116 channels the information of three AI signals into one QS cascade. Three receptors perceive these AIs, the hybrid histidine kinases LuxN, Lux(P)Q and CqsS, to transduce the information to the histidine phosphotransfer (HPt) protein LuxU via phosphorelay, and finally to the response regulator LuxO. Hence, the level of phosphorylated LuxO depends on the AI concentrations. The phosphorylated LuxO (P-LuxO) controls the expression of small regulatory RNAs (sRNAs), which together with the RNA chaperon Hfq, destabilize the transcript of the master regulator luxR . LuxR is responsible for the induction and repression of several genes (e.g., for bioluminescence, exoprotease and siderophore production). In vivo studies with various mutants have demonstrated that the ratio between kinase and phosphatase activities of the individual QS receptors and therefore the P-LuxO/LuxO ratio is crucial not only for the output strength but also for the degree of noise. This study was undertaken to better understand the inherent design principles of this complex signaling cascade, which allows sensing and integration of different signals, but also the differentiated output in individual cells. Therefore, we quantitatively analyzed not only the enzymatic activities, but also the abundance and localization of the three QS receptors. We found that LuxN presents the highest capacity to phosphorylate LuxU, while the phosphatase activity was comparable to LuxQ and CqsS in vitro . In whole cells the copy number of LuxN was higher than that of LuxQ and CqsS, and further increased in the late exponential growth phase. Microscopy experiments indicate that LuxN and LuxQ form independent clusters. Altogether, these

  1. Designing CNC Knit for Hybrid Membrane And Bending Active Structures

    DEFF Research Database (Denmark)

    Tamke, Martin; Holden Deleuran, Anders; Gengnagel, Christoph

    2015-01-01

    specific properties and detailing. CNC knitting with high tenacity yarn enables this practice and offers an alternative to current woven membranes. The design and fabrication of an 8m high fabric tower through an interdisciplinary team of architects, structural and textile engineers, allowed to investigate...... means to design, specify, make and test CNC knit as material for hybrid structures in architectural scale. This paper shares the developed process, identifies challenges, potentials and future work...

  2. Regulation of platelet activating factor receptor coupled phosphoinositide-specific phospholipase C activity

    International Nuclear Information System (INIS)

    Morrison, W.J.

    1988-01-01

    The major objectives of this study were two-fold. The first was to establish whether binding of platelet activating factor (PAF) to its receptor was integral to the stimulation of polyphosphoinositide-specific phospholipase C (PLC) in rabbit platelets. The second was to determine regulatory features of this receptor-coupled mechanism. [ 3 H]PAF binding demonstrated two binding sites, a high affinity site with a inhibitory constant (Ki) of 2.65 nM and a low affinity site with a Ki of 0.80 μM. PAF receptor coupled activation of phosphoinositide-specific PLC was studied in platelets which were made refractory, by short term pretreatments, to either PAF or thrombin. Saponin-permeabilized rabbit platelets continue to regulate the mechanism(s) coupling PAF receptors to PLC stimulation. However, TRPγS and GDPβS, which affect guanine nucleotide regulatory protein functions, were unable to modulate the PLC activity to any appreciable extent as compared to PAF. The possible involvement of protein kinase C (PKC) activation in regulating PAF-stimulated PLC activity was studied in rabbit platelets pretreated with staurosporine followed by pretreatments with PAF or phorbol 12-myristate 13-acetate (PMA)

  3. Hybrid Chaos Synchronization of Four-Scroll Systems via Active Control

    Science.gov (United States)

    Karthikeyan, Rajagopal; Sundarapandian, Vaidyanathan

    2014-03-01

    This paper investigates the hybrid chaos synchronization of identical Wang four-scroll systems (Wang, 2009), identical Liu-Chen four-scroll systems (Liu and Chen, 2004) and non-identical Wang and Liu-Chen four-scroll systems. Active control method is the method adopted to achieve the hybrid chaos synchronization of the four-scroll chaotic systems addressed in this paper and our synchronization results are established using Lyapunov stability theory. Since the Lyapunov exponents are not required for these calculations, the active control method is effective and convenient to hybrid synchronize identical and different Wang and Liu-Chen four-scroll chaotic systems. Numerical simulations are also shown to illustrate and validate the hybrid synchronization results derived in this paper.

  4. Synthesis of organic/inorganic hybrid gel with acid activated clay after γ-ray radiation.

    Science.gov (United States)

    Kim, Donghyun; Lee, Hoik; Sohn, Daewon

    2014-08-01

    A hybrid gel was prepared from acid activated clay (AA clay) and acrylic acid by gamma ray irradiation. Irradiated inorganic particles which have peroxide groups act as initiator because it generates oxide radicals by increasing temperature. Inorganic nanoparticles which are rigid part in hybrid gel also contribute to increase the mechanical property as a crosslinker. We prepared two hybrid gels to compare the effect of acid activated treatment of clay; one is synthesized with raw clay particles and another is synthesized with AA clay particles. The composition and structure of AA clay particles and raw clay particles were confirmed by X-ray diffraction (XRD), X-ray fluorescence instrument and surface area analyzer. And chemical and physical property of hybrid gel with different ratios of acrylic acid and clay particle was tested by Raman spectroscope and universal testing machine (UTM). The synthesized hydrogel with 76% gel contents can elongated approximately 1000% of its original size.

  5. An insight into the biological activities of heterocyclic-fatty acid hybrid molecules.

    Science.gov (United States)

    Venepally, Vijayendar; Reddy Jala, Ram Chandra

    2017-12-01

    Heterocyclic compounds are the interesting core structures for the development of new bioactive compounds. Fatty acids are derived from renewable raw materials and exhibit various biological activities. Several researchers are amalgamating these two bioactive components to yield bioactive hybrid molecules with some desirable features. Heterocyclic-fatty acid hybrid derivatives are a new class of heterocyclic compounds with a broad range of biological activities and significance in the field of medicinal chemistry. Over the last few years, many research articles emphasized the significance of heterocyclic-fatty acid hybrid derivatives. The present review article focuses the developments in designing and biological evaluation of heterocyclic-fatty acid hybrid molecules. Copyright © 2017. Published by Elsevier Masson SAS.

  6. The role of GH receptor tyrosine phosphorylation in Stat5 activation

    DEFF Research Database (Denmark)

    Hansen, J A; Hansen, L H; Wang, X

    1997-01-01

    Stimulation of GH receptors leads to rapid activation of Jak2 kinase and subsequent tyrosine phosphorylation of the GH receptor. Three specific tyrosines located in the C-terminal domain of the GH receptor have been identified as being involved in GH-stimulated transcription of the Spi 2.1 promoter....... Mutated GH receptors lacking all but one of these three tyrosines are able to mediate a transcriptional response when transiently transfected into CHO cells together with a Spi 2.1 promoter/luciferase construct. Similarly, these GH receptors were found to be able to mediate activation of Stat5 DNA......-binding activity, whereas the GH receptor mutant lacking all intracellular tyrosines was not. Synthetic tyrosine phosphorylated peptides corresponding to the GH receptor sequence around the three tyrosines inhibited Stat5 DNA-binding activity while their non-phosphorylated counterparts were ineffective. Tyrosine...

  7. Promoting Student Autonomy and Competence Using a Hybrid Model for Teaching Physical Activity

    Directory of Open Access Journals (Sweden)

    Christine Bachman

    2015-01-01

    Full Text Available For approximately twenty-years, Web-enhanced learning environments have been popular in higher education. Much research has examined how best practices can integrate technology, pedagogical theories, and resources to enhance learning. Numerous studies of hybrid teaching have revealed mostly positive effects. Yet, very little research has examined how to teach a successful physical activity course using a hybrid format. Review of the literature: We reviewed the research regarding the design and implementation of a Web-enhanced physical activity course in a college population using pedagogical principles of learning and the10 self-determination theory. Method: Data were collected from students at the beginning and end of the course. The hybrid course consisted of completing weekly online activities, and selecting and participating in a face-to-face physical activity based on student’s choice. Conclusion: The authors propose this template as a model to assist faculty in designing and implementing a blended physical activity course.

  8. Polyaniline hybridized surface defective ZnO nanorods with long-term stable photoelectrochemical activity

    International Nuclear Information System (INIS)

    Bera, Susanta; Khan, Hasmat; Biswas, Indranil; Jana, Sunirmal

    2016-01-01

    Highlights: • Polyaniline (PANI) hybridized ZnO nanorods was synthesized by solution method. • Surface defects were found in the nanorods. • The hybrid material exhibited an enhancement in visible light absorption. • A long-term stable photoelectrochemical activity of the material was found. • Advancement in the properties would be PANI hybridization and surface defects. - Abstract: We report surfactant/template free precursor solution based synthesis of polyaniline (PANI) hybridized surface defective ZnO nanorods by a two-step process. Initially, ZnO nanorods have been prepared at 95 °C, followed by hybridization (coating) of PANI onto the ZnO via in situ polymerization of aniline monomer, forming ZnO-PANI nanohybrid (ZP). The structural properties of ZP have been analyzed by X-ray diffraction (XRD) and transmission electron microscopic (TEM) studies. The presence of surface defects especially the oxygen vacancies in ZnO has been characterized by photoluminescence emission, high resolution TEM, X-ray photoelectron spectroscopy (XPS) and micro-Raman spectral measurements. The chemical interaction of PANI with ZnO has been examined by Fourier transform infrared (FTIR) and XPS analyses. A significant enhancement in visible absorption of ZP sample is found as evidenced from UV–vis diffused reflectance spectral study. BET nitrogen adsorption-desorption isotherm shows an improved textural property (pore size, pore volume) of ZP. Moreover, a long-term stable photoelectrochemical activity (PEC) of ZP is found compare to pristine ZnO. The synergic effect of PANI hybridization and the presence of surface defects in ZnO NRs can enhance the PEC by prolonging the recombination rate of photogenerated charge carriers. The effect can also provide large number of active sites to make electrolyte diffusion and mass transportation easier in the nanohybrid. This simple synthesis strategy can be adopted for PANI hybridization with different metal oxide semiconductors

  9. Polyaniline hybridized surface defective ZnO nanorods with long-term stable photoelectrochemical activity

    Energy Technology Data Exchange (ETDEWEB)

    Bera, Susanta; Khan, Hasmat [Sol-Gel Division, CSIR-Central Glass and Ceramic Research Institute (CSIR-CGCRI), 196 Raja S.C. Mullick Road, P.O. Jadavpur University, Kolkata 700 032, West Bengal (India); Biswas, Indranil [Materials Characterization and Instrumentation Division, CSIR-Central Glass and Ceramic Research Institute (CSIR-CGCRI), 196 Raja S.C. Mullick Road, P.O. Jadavpur University, Kolkata 700 032, West Bengal (India); Jana, Sunirmal, E-mail: sjana@cgcri.res.in [Sol-Gel Division, CSIR-Central Glass and Ceramic Research Institute (CSIR-CGCRI), 196 Raja S.C. Mullick Road, P.O. Jadavpur University, Kolkata 700 032, West Bengal (India)

    2016-10-15

    Highlights: • Polyaniline (PANI) hybridized ZnO nanorods was synthesized by solution method. • Surface defects were found in the nanorods. • The hybrid material exhibited an enhancement in visible light absorption. • A long-term stable photoelectrochemical activity of the material was found. • Advancement in the properties would be PANI hybridization and surface defects. - Abstract: We report surfactant/template free precursor solution based synthesis of polyaniline (PANI) hybridized surface defective ZnO nanorods by a two-step process. Initially, ZnO nanorods have been prepared at 95 °C, followed by hybridization (coating) of PANI onto the ZnO via in situ polymerization of aniline monomer, forming ZnO-PANI nanohybrid (ZP). The structural properties of ZP have been analyzed by X-ray diffraction (XRD) and transmission electron microscopic (TEM) studies. The presence of surface defects especially the oxygen vacancies in ZnO has been characterized by photoluminescence emission, high resolution TEM, X-ray photoelectron spectroscopy (XPS) and micro-Raman spectral measurements. The chemical interaction of PANI with ZnO has been examined by Fourier transform infrared (FTIR) and XPS analyses. A significant enhancement in visible absorption of ZP sample is found as evidenced from UV–vis diffused reflectance spectral study. BET nitrogen adsorption-desorption isotherm shows an improved textural property (pore size, pore volume) of ZP. Moreover, a long-term stable photoelectrochemical activity (PEC) of ZP is found compare to pristine ZnO. The synergic effect of PANI hybridization and the presence of surface defects in ZnO NRs can enhance the PEC by prolonging the recombination rate of photogenerated charge carriers. The effect can also provide large number of active sites to make electrolyte diffusion and mass transportation easier in the nanohybrid. This simple synthesis strategy can be adopted for PANI hybridization with different metal oxide semiconductors

  10. Antibody-induced dimerization activates the epidermal growth factor receptor tyrosine kinase

    NARCIS (Netherlands)

    Spaargaren, M.; Defize, L. H.; Boonstra, J.; de Laat, S. W.

    1991-01-01

    The relationship between epidermal growth factor receptor (EGF-R) protein tyrosine kinase activation and ligand-induced receptor dimerization was investigated using several bivalent anti-EGF-R antibodies directed against various receptor epitopes. In A431 membrane preparations and permeabilized

  11. Molecular pharmacological phenotyping of EBI2. An orphan seven-transmembrane receptor with constitutive activity

    DEFF Research Database (Denmark)

    Rosenkilde, Mette M; Benned-Jensen, Tau; Holst, Peter J

    2006-01-01

    Epstein-Barr virus (EBV)-induced receptor 2 (EBI2) is an orphan seven-transmembrane (7TM) receptor originally identified as the most up-regulated gene (>200-fold) in EBV-infected cells. Here we show that EBI2 signals with constitutive activity through Galpha(i) as determined by a receptor...

  12. Insulin-Insulin-like Growth Factors Hybrids as Molecular Probes of Hormone:Receptor Binding Specificity

    Czech Academy of Sciences Publication Activity Database

    Křížková, Květoslava; Chrudinová, Martina; Povalová, Anna; Selicharová, Irena; Collinsová, Michaela; Vaněk, Václav; Brzozowski, A. M.; Jiráček, Jiří; Žáková, Lenka

    2016-01-01

    Roč. 55, č. 21 (2016), s. 2903-2913 ISSN 0006-2960 R&D Projects: GA ČR GA15-19018S Institutional support: RVO:61388963 Keywords : alanine scanning mutagenesis * high-affinity binding * type 1 IGF receptor Subject RIV: CE - Biochemistry Impact factor: 2.938, year: 2016 http://pubs.acs.org/doi/pdf/10.1021/acs.biochem.6b00140

  13. Preparation of zeolite-A/chitosan hybrid composites and their bioactivities and antimicrobial activities

    International Nuclear Information System (INIS)

    Yu, Liang; Gong, Jie; Zeng, Changfeng; Zhang, Lixiong

    2013-01-01

    Zeolite-A/chitosan hybrid composites with zeolite contents of 20–55 wt.% were prepared by in situ transformation of silica/chitosan mixtures in a sodium aluminate alkaline solution through impregnation–gelation–hydrothermal synthesis. The products were characterized by X-ray diffraction, diffuse reflectance infrared Fourier transform spectroscopy, scanning electron microscopy, thermogravimetric analysis, and mercury penetration porosimetry. Their in vitro bioactivities were examined using as-synthesized and Ca 2+ -exchanged hybrid composites in simulated body fluid (SBF) for hydroxyapatite (HAP) growth. Their antimicrobial activities for Escherichia coli (E. coli) in trypticase soy broth (TSB) were evaluated using Ag + -exchanged hybrid composites. The zeolite-A/chitosan hybrid composites could be prepared as various shapes, including cylinders, plates and thin films. They possessed macropores with pore sizes ranging from 100 to 300 μm and showed compressive mechanical strength as high as 3.2 MPa when the zeolite content was 35 wt.%. Fast growth on the Ca 2+ -exchanged hybrid composites was observed with the highest weight gain of 51.4% in 30 days. The 35 wt.% Ag + -exchanged hybrid composite showed the highest antimicrobial activity, which could reduce the 9 × 10 6 CFU mL −1 E. coli concentration to zero within 4 h of incubation time with the Ag + -exchanged hybrid composite amount of 0.4 g L −1 . The bioactivity and antimicrobial activity could be combined by ion-exchanging the composites first with Ca 2+ and then with Ag + . These zeolite-A/chitosan hybrid composites have potential applications on tissue engineering and antimicrobial food packaging. - Graphical abstract: Zeolite A/chitosan hybrid composites were prepared by in situ transformation of precursors in the chitosan matrix, which possess macroporous structures and exhibit superior bioactivity and antimicrobial activity and potential biomedical application. Highlights: • Zeolite A

  14. Preparation of zeolite-A/chitosan hybrid composites and their bioactivities and antimicrobial activities

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Liang; Gong, Jie [State Key Laboratory of Materials-Oriented Chemical Engineering, College of Chemistry and Chemical Engineering, Nanjing University of Technology, Nanjing 210009 (China); Zeng, Changfeng [College of Mechanic and Power Engineering, Nanjing University of Technology, Nanjing 210009 (China); Zhang, Lixiong, E-mail: lixiongzhang@yahoo.com [State Key Laboratory of Materials-Oriented Chemical Engineering, College of Chemistry and Chemical Engineering, Nanjing University of Technology, Nanjing 210009 (China)

    2013-10-15

    Zeolite-A/chitosan hybrid composites with zeolite contents of 20–55 wt.% were prepared by in situ transformation of silica/chitosan mixtures in a sodium aluminate alkaline solution through impregnation–gelation–hydrothermal synthesis. The products were characterized by X-ray diffraction, diffuse reflectance infrared Fourier transform spectroscopy, scanning electron microscopy, thermogravimetric analysis, and mercury penetration porosimetry. Their in vitro bioactivities were examined using as-synthesized and Ca{sup 2+}-exchanged hybrid composites in simulated body fluid (SBF) for hydroxyapatite (HAP) growth. Their antimicrobial activities for Escherichia coli (E. coli) in trypticase soy broth (TSB) were evaluated using Ag{sup +}-exchanged hybrid composites. The zeolite-A/chitosan hybrid composites could be prepared as various shapes, including cylinders, plates and thin films. They possessed macropores with pore sizes ranging from 100 to 300 μm and showed compressive mechanical strength as high as 3.2 MPa when the zeolite content was 35 wt.%. Fast growth on the Ca{sup 2+}-exchanged hybrid composites was observed with the highest weight gain of 51.4% in 30 days. The 35 wt.% Ag{sup +}-exchanged hybrid composite showed the highest antimicrobial activity, which could reduce the 9 × 10{sup 6} CFU mL{sup −1}E. coli concentration to zero within 4 h of incubation time with the Ag{sup +}-exchanged hybrid composite amount of 0.4 g L{sup −1}. The bioactivity and antimicrobial activity could be combined by ion-exchanging the composites first with Ca{sup 2+} and then with Ag{sup +}. These zeolite-A/chitosan hybrid composites have potential applications on tissue engineering and antimicrobial food packaging. - Graphical abstract: Zeolite A/chitosan hybrid composites were prepared by in situ transformation of precursors in the chitosan matrix, which possess macroporous structures and exhibit superior bioactivity and antimicrobial activity and potential biomedical

  15. Peroxisome Proliferator-Activated Receptor-γ in Thyroid Autoimmunity

    Directory of Open Access Journals (Sweden)

    Silvia Martina Ferrari

    2015-01-01

    Full Text Available Peroxisome proliferator-activated receptor- (PPAR- γ expression has been shown in thyroid tissue from patients with thyroiditis or Graves’ disease and furthermore in the orbital tissue of patients with Graves’ ophthalmopathy (GO, such as in extraocular muscle cells. An increasing body of evidence shows the importance of the (C-X-C motif receptor 3 (CXCR3 and cognate chemokines (C-X-C motif ligand (CXCL9, CXCL10, and CXCL11, in the T helper 1 immune response and in inflammatory diseases such as thyroid autoimmune disorders. PPAR-γ agonists show a strong inhibitory effect on the expression and release of CXCR3 chemokines, in vitro, in various kinds of cells, such as thyrocytes, and in orbital fibroblasts, preadipocytes, and myoblasts from patients with GO. Recently, it has been demonstrated that rosiglitazone is involved in a higher risk of heart failure, stroke, and all-cause mortality in old patients. On the contrary, pioglitazone has not shown these effects until now; this favors pioglitazone for a possible use in patients with thyroid autoimmunity. However, further studies are ongoing to explore the use of new PPAR-γ agonists in the treatment of thyroid autoimmune disorders.

  16. Topical Rosiglitazone Treatment Improves Ulcerative Colitis by Restoring Peroxisome Proliferator-Activated Receptor-gamma Activity

    DEFF Research Database (Denmark)

    Pedersen, G.; Brynskov, Jørn

    2010-01-01

    OBJECTIVES: Impaired epithelial expression of peroxisome proliferator-activated receptor-gamma (PPAR gamma) has been described in animal colitis models and briefly in patients with ulcerative colitis, but the functional significance in humans is not well defined. We examined PPAR gamma expression...

  17. Activation of Protease-Activated Receptor 2 Induces VEGF Independently of HIF-1

    DEFF Research Database (Denmark)

    Rasmussen, J.G.; Riis, Simone Elkjær; Frøbert, O.

    2012-01-01

    Human adipose stem cells (hASCs) can promote angiogenesis through secretion of proangiogenic factors such as vascular endothelial growth factor (VEGF). In other cell types, it has been shown that induction of VEGF is mediated by both protease activated receptor 2 (PAR2) and hypoxia inducible fact...

  18. Substance P receptor desensitization requires receptor activation but not phospholipase C

    International Nuclear Information System (INIS)

    Sugiya, Hiroshi; Putney, J.W. Jr.

    1988-01-01

    Previous studies have shown that exposure of parotid acinar cells to substance P at 37 degree C results in activation of phospholipase C, formation of [ 3 H]inositol 1,4,5-trisphosphate (IP 3 ), and persistent desensitization of the substance P response. In cells treated with antimycin in medium containing glucose, ATP was decreased to ∼20% of control values, IP 3 formation was completely inhibited, but desensitization was unaffected. When cells were treated with antimycin in the absence of glucose, cellular ATP was decreased to ∼5% of control values, and both IP 3 formation and desensitization were blocked. A series of substance P-related peptides increased the formation of [ 3 H]IP 3 and induced desensitization of the substance P response with a similar rank order of potencies. The substance P antagonist, [D-Pro 2 , D-Try 7,9 ]-substance P, inhibited substance P-induced IP 3 formation and desensitization but did not induce desensitization. These results suggest that the desensitization of substance P-induced IP 3 formation requires agonist activation of a P-type substance P receptor, and that one or more cellular ATP-dependent processes are required for this reaction. However, activation of phospholipase C and the generation of inositol phosphates does not seem to be a prerequisite for desensitization

  19. DNA/RNA hybrid substrates modulate the catalytic activity of purified AID.

    Science.gov (United States)

    Abdouni, Hala S; King, Justin J; Ghorbani, Atefeh; Fifield, Heather; Berghuis, Lesley; Larijani, Mani

    2018-01-01

    Activation-induced cytidine deaminase (AID) converts cytidine to uridine at Immunoglobulin (Ig) loci, initiating somatic hypermutation and class switching of antibodies. In vitro, AID acts on single stranded DNA (ssDNA), but neither double-stranded DNA (dsDNA) oligonucleotides nor RNA, and it is believed that transcription is the in vivo generator of ssDNA targeted by AID. It is also known that the Ig loci, particularly the switch (S) regions targeted by AID are rich in transcription-generated DNA/RNA hybrids. Here, we examined the binding and catalytic behavior of purified AID on DNA/RNA hybrid substrates bearing either random sequences or GC-rich sequences simulating Ig S regions. If substrates were made up of a random sequence, AID preferred substrates composed entirely of DNA over DNA/RNA hybrids. In contrast, if substrates were composed of S region sequences, AID preferred to mutate DNA/RNA hybrids over substrates composed entirely of DNA. Accordingly, AID exhibited a significantly higher affinity for binding DNA/RNA hybrid substrates composed specifically of S region sequences, than any other substrates composed of DNA. Thus, in the absence of any other cellular processes or factors, AID itself favors binding and mutating DNA/RNA hybrids composed of S region sequences. AID:DNA/RNA complex formation and supporting mutational analyses suggest that recognition of DNA/RNA hybrids is an inherent structural property of AID. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Hybridization of two major termite invaders as a consequence of human activity.

    Science.gov (United States)

    Chouvenc, Thomas; Helmick, Ericka E; Su, Nan-Yao

    2015-01-01

    While hybridization of an invasive species with a native species is a common occurrence, hybridization between two invasive species is rare. Formosan subterranean termites (Coptotermes formosanus) and Asian subterranean termites (C. gestroi) are both ecologically successful and are the two most economically important termite pests in the world. Both species have spread throughout many areas of the world due to human activity; however, their distributions overlap in only three narrow areas because of distinct ecological requirements. In south Florida, where C. formosanus and C. gestroi are both invasive, the dispersal flight seasons of both species overlapped for the first time on record in 2013 and 2014. Pairings of heterospecific individuals were readily observed in the field and C. gestroi males preferentially engaged in mating behavior with C. formosanus females rather than females from their own species. In the laboratory, heterospecific and conspecific pairings had an equal colony establishment rate, but heterospecific incipient colonies had twice the growth rate of conspecific incipient colonies, suggesting a potential case of hybrid vigor. As all pre-zygotic barriers were lifted between the two species in the field, the apparent absence of post-zygotic barriers in the laboratory raises the possibility for introgressive hybridization in south Florida. While laboratory observations remain to be confirmed in the field, and the alate hybrid fertility is currently unknown, our results raise a tangible concern about the hybridization of two major destructive pest species. Such hybridization would likely be associated with a new economic impact.

  1. Hybridization of two major termite invaders as a consequence of human activity.

    Directory of Open Access Journals (Sweden)

    Thomas Chouvenc

    Full Text Available While hybridization of an invasive species with a native species is a common occurrence, hybridization between two invasive species is rare. Formosan subterranean termites (Coptotermes formosanus and Asian subterranean termites (C. gestroi are both ecologically successful and are the two most economically important termite pests in the world. Both species have spread throughout many areas of the world due to human activity; however, their distributions overlap in only three narrow areas because of distinct ecological requirements. In south Florida, where C. formosanus and C. gestroi are both invasive, the dispersal flight seasons of both species overlapped for the first time on record in 2013 and 2014. Pairings of heterospecific individuals were readily observed in the field and C. gestroi males preferentially engaged in mating behavior with C. formosanus females rather than females from their own species. In the laboratory, heterospecific and conspecific pairings had an equal colony establishment rate, but heterospecific incipient colonies had twice the growth rate of conspecific incipient colonies, suggesting a potential case of hybrid vigor. As all pre-zygotic barriers were lifted between the two species in the field, the apparent absence of post-zygotic barriers in the laboratory raises the possibility for introgressive hybridization in south Florida. While laboratory observations remain to be confirmed in the field, and the alate hybrid fertility is currently unknown, our results raise a tangible concern about the hybridization of two major destructive pest species. Such hybridization would likely be associated with a new economic impact.

  2. Exercise reduces adipose tissue via cannabinoid receptor type 1 which is regulated by peroxisome proliferator-activated receptor-delta

    DEFF Research Database (Denmark)

    Yan, Zhen Cheng; Liu, Dao Yan; Zhang, Li Li

    2007-01-01

    Obesity is one major cardiovascular risk factor. We tested effects of endurance exercise on cannabinoid receptor type 1 (CB1) and peroxisome proliferator-activated receptor-delta (PPAR-delta)-dependent pathways in adipose tissue. Male Wistar rats were randomly assigned to standard laboratory chow...... or a high-fat diet without and with regular endurance exercise. Exercise in rats on high-fat diet significantly reduced visceral fat mass, blood pressure, and adipocyte size (each p...

  3. In situ hybridization on the change of m1 receptor mRNA in different brain areas of aged rats and the effect of Yin tonic Zhimu studied

    International Nuclear Information System (INIS)

    Hu Yaer; Xia Zongqin; Yi Ningyu

    1996-01-01

    The change of gene expression of m1 receptors in different brain areas of aged rats and the effects of water extract of the Yin tonic Zhimu and its active principle ZMS was studied. In situ hybridization using 35 S-labelled m1 and m2 probes and analysis of the autoradiographs using a computerized image-analyzer was selected. The grain density of m1 mRNA in striatum was significantly lowered in old rats as compared with young rats (decreased by 12.26 +- 3.60, P<0.01). Long-term oral administration of ZMS, the active principle of Yin tonic Zhimu but not the water extraction of Zhimu, elevated the m1 mRNA in striatum of aged rats (increased by 15.71 +- 3.27, P<0.01). Neither significant change of the grain density of m1 mRNA in old rats nor significant effect of Zhimu or ZMS was observed in cerebral cortex and hippocampus. The m1 mRNA level in striatum is decreased in aged rats and ZMS is able to elevate it

  4. Preparation of zeolite-A/chitosan hybrid composites and their bioactivities and antimicrobial activities.

    Science.gov (United States)

    Yu, Liang; Gong, Jie; Zeng, Changfeng; Zhang, Lixiong

    2013-10-01

    Zeolite-A/chitosan hybrid composites with zeolite contents of 20-55 wt.% were prepared by in situ transformation of silica/chitosan mixtures in a sodium aluminate alkaline solution through impregnation-gelation-hydrothermal synthesis. The products were characterized by X-ray diffraction, diffuse reflectance infrared Fourier transform spectroscopy, scanning electron microscopy, thermogravimetric analysis, and mercury penetration porosimetry. Their in vitro bioactivities were examined using as-synthesized and Ca(2+)-exchanged hybrid composites in simulated body fluid (SBF) for hydroxyapatite (HAP) growth. Their antimicrobial activities for Escherichia coli (E. coli) in trypticase soy broth (TSB) were evaluated using Ag(+)-exchanged hybrid composites. The zeolite-A/chitosan hybrid composites could be prepared as various shapes, including cylinders, plates and thin films. They possessed macropores with pore sizes ranging from 100 to 300 μm and showed compressive mechanical strength as high as 3.2 MPa when the zeolite content was 35 wt.%. Fast growth on the Ca(2+)-exchanged hybrid composites was observed with the highest weight gain of 51.4% in 30 days. The 35 wt.% Ag(+)-exchanged hybrid composite showed the highest antimicrobial activity, which could reduce the 9×10(6) CFU mL(-1)E. coli concentration to zero within 4h of incubation time with the Ag(+)-exchanged hybrid composite amount of 0.4 g L(-1). The bioactivity and antimicrobial activity could be combined by ion-exchanging the composites first with Ca(2+) and then with Ag(+). These zeolite-A/chitosan hybrid composites have potential applications on tissue engineering and antimicrobial food packaging. Copyright © 2013 Elsevier B.V. All rights reserved.

  5. Receptor activity modifying proteins (RAMPs) interact with the VPAC1 receptor: evidence for differential RAMP modulation of multiple signalling pathways

    International Nuclear Information System (INIS)

    Christopoulos, G.; Morfis, M.; Sexton, P.M.; Christopoulos, A.; Laburthe, M.; Couvineau, A.

    2001-01-01

    Full text: Receptor activity modifying proteins (RAMP) constitute a family of three accessory proteins that affect the expression and/or phenotype of the calcitonin receptor (CTR) or CTR-like receptor (CRLR). In this study we screened a range of class II G protein-coupled receptors (PTH1, PTH2, GHRH, VPAC1, VPAC2 receptors) for possible RAMP interactions by measurement of receptor-induced translocation of c-myc tagged RAMP1 or HA tagged RAMP3. Of these, only the VPAC1 receptor caused significant translocation of c-myc-RAMP1 or HA-RAMP3 to the cell surface. Co-transfection of VPAC1 and RAMPs did not alter 125 I-VIP binding and specificity. VPAC1 receptor function was subsequently analyzed through parallel determinations of cAMP accumulation and phosphoinositide (PI) hydrolysis in the presence and absence of each of the three RAMPs. In contrast to CTR-RAMP interaction, where there was an increase in cAMP Pharmacologisand a decrease in PI hydrolysis, VPAC1-RAMP interaction was characterized by a specific increase in agonist-mediated PI hydrolysis when co-transfected with RAMP2. This change was due to an enhancement of Emax with no change in EC 50 value for VIP. No significant change in cAMP accumulation was observed. This is the first demonstration of an interaction of RAMPs with a G protein-coupled receptor outside the CTR family and may suggest a more generalized role for RAMPs in modulating G protein-coupled receptor signaling. Copyright (2001) Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists

  6. Activated graphene as a cathode material for Li-ion hybrid supercapacitors.

    Science.gov (United States)

    Stoller, Meryl D; Murali, Shanthi; Quarles, Neil; Zhu, Yanwu; Potts, Jeffrey R; Zhu, Xianjun; Ha, Hyung-Wook; Ruoff, Rodney S

    2012-03-14

    Chemically activated graphene ('activated microwave expanded graphite oxide', a-MEGO) was used as a cathode material for Li-ion hybrid supercapacitors. The performance of a-MEGO was first verified with Li-ion electrolyte in a symmetrical supercapacitor cell. Hybrid supercapacitors were then constructed with a-MEGO as the cathode and with either graphite or Li(4)Ti(5)O(12) (LTO) for the anode materials. The results show that the activated graphene material works well in a symmetrical cell with the Li-ion electrolyte with specific capacitances as high as 182 F g(-1). In a full a-MEGO/graphite hybrid cell, specific capacitances as high as 266 F g(-1) for the active materials at operating potentials of 4 V yielded gravimetric energy densities for a packaged cell of 53.2 W h kg(-1).

  7. Calcium is the switch in the moonlighting dual function of the ligand-activated receptor kinase phytosulfokine receptor 1

    KAUST Repository

    Muleya, Victor

    2014-09-23

    Background: A number of receptor kinases contain guanylate cyclase (GC) catalytic centres encapsulated in the cytosolic kinase domain. A prototypical example is the phytosulfokine receptor 1 (PSKR1) that is involved in regulating growth responses in plants. PSKR1 contains both kinase and GC activities however the underlying mechanisms regulating the dual functions have remained elusive. Findings: Here, we confirm the dual activity of the cytoplasmic domain of the PSKR1 receptor. We show that mutations within the guanylate cyclase centre modulate the GC activity while not affecting the kinase catalytic activity. Using physiologically relevant Ca2+ levels, we demonstrate that its GC activity is enhanced over two-fold by Ca2+ in a concentration-dependent manner. Conversely, increasing Ca2+ levels inhibits kinase activity up to 500-fold at 100 nM Ca2+. Conclusions: Changes in calcium at physiological levels can regulate the kinase and GC activities of PSKR1. We therefore propose a functional model of how calcium acts as a bimodal switch between kinase and GC activity in PSKR1 that could be relevant to other members of this novel class of ligand-activated receptor kinases.

  8. The adipogenic acetyltransferase Tip60 targets activation function 1 of peroxisome proliferator-activated receptor gamma

    DEFF Research Database (Denmark)

    van Beekum, Olivier; Brenkman, Arjan B; Grøntved, Lars

    2008-01-01

    The transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) plays a key role in the regulation of lipid and glucose metabolism in adipocytes, by regulating their differentiation, maintenance, and function. The transcriptional activity of PPARgamma is dictated by the set...... in cells, and through use of chimeric proteins, we established that coactivation by Tip60 critically depends on the N-terminal activation function 1 of PPARgamma, a domain involved in isotype-specific gene expression and adipogenesis. Chromatin immunoprecipitation experiments showed that the endogenous Tip...... of proteins with which this nuclear receptor interacts under specific conditions. Here we identify the HIV-1 Tat-interacting protein 60 (Tip60) as a novel positive regulator of PPARgamma transcriptional activity. Using tandem mass spectrometry, we found that PPARgamma and the acetyltransferase Tip60 interact...

  9. Digital Simulation of a Hybrid Active Filter - An Active Filter in Series with a Shunt Passive Filter

    OpenAIRE

    Sitaram, Mahesh I; Padiyar, KR; Ramanarayanan, V

    1998-01-01

    Active filters have long been in use for the filtering of power system load harmonics. In this paper, the digital simulation results of a hybrid active power filter system for a rectifier load are presented. The active filter is used for filtering higher order harmonics as the dominant harmonics are filtered by the passive filter. This reduces the rating of the active filter significantly. The DC capacitor voltage of the active filter is controlled using a PI controller.

  10. A hybrid active filter for damping of harmonic resonance in industrial power systems

    OpenAIRE

    Fujita, Hideaki; Yamasaki, Takahiro; Akagi, Hirofumi

    1998-01-01

    This paper proposes a hybrid active filter for damping of harmonic resonance in industrial power systems. The hybrid filter consists of a small-rated active filter and a 5th tuned passive filter. The active filter is characterized by detecting the 5th harmonic current flowing into the passive filter. It is controlled in such a way as to behave as a negative or positive resistor by adjusting a feedback gain from a negative to positive value, and vice versa. The negative resistor presented by t...

  11. Plasticizers May Activate Human Hepatic Peroxisome Proliferator-Activated Receptor α Less Than That of a Mouse but May Activate Constitutive Androstane Receptor in Liver

    Science.gov (United States)

    Ito, Yuki; Nakamura, Toshiki; Yanagiba, Yukie; Ramdhan, Doni Hikmat; Yamagishi, Nozomi; Naito, Hisao; Kamijima, Michihiro; Gonzalez, Frank J.; Nakajima, Tamie

    2012-01-01

    Dibutylphthalate (DBP), di(2-ethylhexyl)phthalate (DEHP), and di(2-ethylhexyl)adipate (DEHA) are used as plasticizers. Their metabolites activate peroxisome proliferator-activated receptor (PPAR) α, which may be related to their toxicities. However, species differences in the receptor functions between rodents and human make it difficult to precisely extrapolate their toxicity from animal studies to human. In this paper, we compared the species differences in the activation of mouse and human hepatic PPARα by these plasticizers using wild-type (mPPARα) and humanized PPARα (hPPARα) mice. At 12 weeks old, each genotyped male mouse was classified into three groups, and fed daily for 2 weeks per os with corn oil (vehicle control), 2.5 or 5.0 mmol/kg DBP (696, 1392 mg/kg), DEHP (977, 1953 mg/kg), and DEHA (926, 1853 mg/kg), respectively. Generally, hepatic PPARα of mPPARα mice was more strongly activated than that of hPPARα mice when several target genes involving β-oxidation of fatty acids were evaluated. Interestingly, all plasticizers also activated hepatic constitutive androstane receptor (CAR) more in hPPARα mice than in mPPARα mice. Taken together, these plasticizers activated mouse and human hepatic PPARα as well as CAR. The activation of PPARα was stronger in mPPARα mice than in hPPARα mice, while the opposite was true of CAR. PMID:22792086

  12. Plasticizers May Activate Human Hepatic Peroxisome Proliferator-Activated Receptor α Less Than That of a Mouse but May Activate Constitutive Androstane Receptor in Liver

    Directory of Open Access Journals (Sweden)

    Yuki Ito

    2012-01-01

    Full Text Available Dibutylphthalate (DBP, di(2-ethylhexylphthalate (DEHP, and di(2-ethylhexyladipate (DEHA are used as plasticizers. Their metabolites activate peroxisome proliferator-activated receptor (PPAR α, which may be related to their toxicities. However, species differences in the receptor functions between rodents and human make it difficult to precisely extrapolate their toxicity from animal studies to human. In this paper, we compared the species differences in the activation of mouse and human hepatic PPARα by these plasticizers using wild-type (mPPARα and humanized PPARα (hPPARα mice. At 12 weeks old, each genotyped male mouse was classified into three groups, and fed daily for 2 weeks per os with corn oil (vehicle control, 2.5 or 5.0 mmol/kg DBP (696, 1392 mg/kg, DEHP (977, 1953 mg/kg, and DEHA (926, 1853 mg/kg, respectively. Generally, hepatic PPARα of mPPARα mice was more strongly activated than that of hPPARα mice when several target genes involving β-oxidation of fatty acids were evaluated. Interestingly, all plasticizers also activated hepatic constitutive androstane receptor (CAR more in hPPARα mice than in mPPARα mice. Taken together, these plasticizers activated mouse and human hepatic PPARα as well as CAR. The activation of PPARα was stronger in mPPARα mice than in hPPARα mice, while the opposite was true of CAR.

  13. Mu-opioid receptor knockout mice show diminished food-anticipatory activity

    NARCIS (Netherlands)

    Kas, Martien J H; van den Bos, Ruud; Baars, Annemarie M; Lubbers, Marianne; Lesscher, Heidi M B; Hillebrand, Jacquelien J G; Schuller, Alwin G; Pintar, John E; Spruijt, Berry M

    We have previously suggested that during or prior to activation of anticipatory behaviour to a coming reward, mu-opioid receptors are activated. To test this hypothesis schedule induced food-anticipatory activity in mu-opioid receptor knockout mice was measured using running wheels. We hypothesized

  14. Targeting the urokinase plasminogen activator receptor inhibits ovarian cancer metastasis.

    Science.gov (United States)

    Kenny, Hilary A; Leonhardt, Payton; Ladanyi, Andras; Yamada, S Diane; Montag, Anthony; Im, Hae Kyung; Jagadeeswaran, Sujatha; Shaw, David E; Mazar, Andrew P; Lengyel, Ernst

    2011-02-01

    To understand the functional and preclinical efficacy of targeting the urokinase plasminogen activator receptor (u-PAR) in ovarian cancer. Expression of u-PAR was studied in 162 epithelial ovarian cancers, including 77 pairs of corresponding primary and metastatic tumors. The effect of an antibody against u-PAR (ATN-658) on proliferation, adhesion, invasion, apoptosis, and migration was assessed in 3 (SKOV3ip1, HeyA8, and CaOV3) ovarian cancer cell lines. The impact of the u-PAR antibody on tumor weight, number, and survival was examined in corresponding ovarian cancer xenograft models and the mechanism by which ATN-658 blocks metastasis was explored. Only 8% of all ovarian tumors were negative for u-PAR expression. Treatment of SKOV3ip1, HeyA8, and CaOV3 ovarian cancer cell lines with the u-PAR antibody inhibited cell invasion, migration, and adhesion. In vivo, anti-u-PAR treatment reduced the number of tumors and tumor weight in CaOV3 and SKOV3ip1 xenografts and reduced tumor weight and increased survival in HeyA8 xenografts. Immunostaining of CaOV3 xenograft tumors and ovarian cancer cell lines showed an increase in active-caspase 3 and TUNEL staining. Treatment with u-PAR antibody inhibited α(5)-integrin and u-PAR colocalization on primary human omental extracellular matrix. Anti-u-PAR treatment also decreased the expression of urokinase, u-PAR, β(3)-integrin, and fibroblast growth factor receptor-1 both in vitro and in vivo. This study shows that an antibody against u-PAR reduces metastasis, induces apoptosis, and reduces the interaction between u-PAR and α(5)-integrin. This provides a rationale for targeting the u-PAR pathway in patients with ovarian cancer and for further testing of ATN-658 in this indication. ©2010 AACR.

  15. Regulated internalization of NMDA receptors drives PKD1-mediated suppression of the activity of residual cell-surface NMDA receptors.

    Science.gov (United States)

    Fang, Xiao-Qian; Qiao, Haifa; Groveman, Bradley R; Feng, Shuang; Pflueger, Melissa; Xin, Wen-Kuan; Ali, Mohammad K; Lin, Shuang-Xiu; Xu, Jindong; Duclot, Florian; Kabbaj, Mohamed; Wang, Wei; Ding, Xin-Sheng; Santiago-Sim, Teresa; Jiang, Xing-Hong; Salter, Michael W; Yu, Xian-Min

    2015-11-19

    Constitutive and regulated internalization of cell surface proteins has been extensively investigated. The regulated internalization has been characterized as a principal mechanism for removing cell-surface receptors from the plasma membrane, and signaling to downstream targets of receptors. However, so far it is still not known whether the functional properties of remaining (non-internalized) receptor/channels may be regulated by internalization of the same class of receptor/channels. The N-methyl-D-aspartate receptor (NMDAR) is a principal subtype of glutamate-gated ion channel and plays key roles in neuronal plasticity and memory functions. NMDARs are well-known to undergo two types of regulated internalization - homologous and heterologous, which can be induced by high NMDA/glycine and DHPG, respectively. In the present work, we investigated effects of regulated NMDAR internalization on the activity of residual cell-surface NMDARs and neuronal functions. In electrophysiological experiments we discovered that the regulated internalization of NMDARs not only reduced the number of cell surface NMDARs but also caused an inhibition of the activity of remaining (non-internalized) surface NMDARs. In biochemical experiments we identified that this functional inhibition of remaining surface NMDARs was mediated by increased serine phosphorylation of surface NMDARs, resulting from the activation of protein kinase D1 (PKD1). Knockdown of PKD1 did not affect NMDAR internalization but prevented the phosphorylation and inhibition of remaining surface NMDARs and NMDAR-mediated synaptic functions. These data demonstrate a novel concept that regulated internalization of cell surface NMDARs not only reduces the number of NMDARs on the cell surface but also causes an inhibition of the activity of remaining surface NMDARs through intracellular signaling pathway(s). Furthermore, modulating the activity of remaining surface receptors may be an effective approach for treating receptor

  16. Repressive effects of resveratrol on androgen receptor transcriptional activity.

    Directory of Open Access Journals (Sweden)

    Wen-feng Shi

    2009-10-01

    Full Text Available The chemopreventive effects of resveratrol (RSV on prostate cancer have been well established; the androgen receptor (AR plays pivotal roles in prostatic tumorigenesis. However, the exact underlying molecular mechanisms about the effects of RSV on AR have not been fully elucidated. A model system is needed to determine whether and how RSV represses AR transcriptional activity.The AR cDNA was first cloned into the retroviral vector pOZ-N and then integrated into the genome of AR-negative HeLa cells to generate the AR(+ cells. The constitutively expressed AR was characterized by monitoring hormone-stimulated nuclear translocation, DNA binding, and transcriptional activation, with the AR(- cells serving as controls. AR(+ cells were treated with RSV, and both AR protein levels and AR transcriptional activity were measured simultaneously. Chromatin immunoprecipitation (ChIP assays were used to detect the effects of RSV on the recruitment of AR to its cognate element (ARE.AR in the AR (+ stable cell line functions in a manner similar to that of endogenously expressed AR. Using this model system we clearly demonstrated that RSV represses AR transcriptional activity independently of any effects on AR protein levels. However, neither the hormone-mediated nucleus translocation nor the AR/ARE interaction was affected by RSV treatment.We demonstrated unambiguously that RSV regulates AR target gene expression, at least in part, by repressing AR transcriptional activity. Repressive effects of RSV on AR activity result from mechanisms other than the affects of AR nuclear translocation or DNA binding.

  17. Activity of wild-type and hybrid Bacillus thuringiensis delta-endotoxins against Agrotis ipsilon

    NARCIS (Netherlands)

    Maagd, de R.A.; Weemen-Hendriks, M.; Molthoff, J.W.; Naimov, S.

    2003-01-01

    Twelve Cry1 and two Cry9 ?-endotoxins fromBacillus thuringiensis were tested for their activity against black cutworm (Agrotis ipsilon).A. ipsilon was not susceptible to many toxins, but three toxins had significant activity. Cry9Ca was the most toxic, followed by Cry1Aa and Cry1Fb. Hybrids between

  18. Activation of postnatal neural stem cells requires nuclear receptor TLX.

    Science.gov (United States)

    Niu, Wenze; Zou, Yuhua; Shen, Chengcheng; Zhang, Chun-Li

    2011-09-28

    Neural stem cells (NSCs) continually produce new neurons in postnatal brains. However, the majority of these cells stay in a nondividing, inactive state. The molecular mechanism that is required for these cells to enter proliferation still remains largely unknown. Here, we show that nuclear receptor TLX (NR2E1) controls the activation status of postnatal NSCs in mice. Lineage tracing indicates that TLX-expressing cells give rise to both activated and inactive postnatal NSCs. Surprisingly, loss of TLX function does not result in spontaneous glial differentiation, but rather leads to a precipitous age-dependent increase of inactive cells with marker expression and radial morphology for NSCs. These inactive cells are mispositioned throughout the granular cell layer of the dentate gyrus during development and can proliferate again after reintroduction of ectopic TLX. RNA-seq analysis of sorted NSCs revealed a TLX-dependent global expression signature, which includes the p53 signaling pathway. TLX regulates p21 expression in a p53-dependent manner, and acute removal of p53 can rescue the proliferation defect of TLX-null NSCs in culture. Together, these findings suggest that TLX acts as an essential regulator that ensures the proliferative ability of postnatal NSCs by controlling their activation through genetic interaction with p53 and other signaling pathways.

  19. The non-biphenyl-tetrazole angiotensin AT1 receptor antagonist eprosartan is a unique and robust inverse agonist of the active state of the AT1 receptor.

    Science.gov (United States)

    Takezako, Takanobu; Unal, Hamiyet; Karnik, Sadashiva S; Node, Koichi

    2018-03-23

    Conditions such as hypertension and renal allograft rejection are accompanied by chronic, agonist-independent, signalling by angiotensin II AT 1 receptors. The current treatment paradigm for these diseases entails the preferred use of inverse agonist AT 1 receptor blockers (ARBs). However, variability in the inverse agonist activities of common biphenyl-tetrazole ARBs for the active state of AT 1 receptors often leads to treatment failure. Therefore, characterization of robust inverse agonist ARBs for the active state of AT 1 receptors is necessary. To identify the robust inverse agonist for active state of AT 1 receptors and its molecular mechanism, we performed site-directed mutagenesis, competition binding assay, inositol phosphate production assay and molecular modelling for both ground-state wild-type AT 1 receptors and active-state N111G mutant AT 1 receptors. Although candesartan and telmisartan exhibited weaker inverse agonist activity for N111G- compared with WT-AT 1 receptors, only eprosartan exhibited robust inverse agonist activity for both N111G- and WT- AT 1 receptors. Specific ligand-receptor contacts for candesartan and telmisartan are altered in the active-state N111G- AT 1 receptors compared with the ground-state WT-AT 1 receptors, suggesting an explanation of their attenuated inverse agonist activity for the active state of AT 1 receptors. In contrast, interactions between eprosartan and N111G-AT 1 receptors were not significantly altered, and the inverse agonist activity of eprosartan was robust. Eprosartan may be a better therapeutic option than other ARBs. Comparative studies investigating eprosartan and other ARBs for the treatment of diseases caused by chronic, agonist-independent, AT 1 receptor activation are warranted. © 2018 The British Pharmacological Society.

  20. Triclocarban mediates induction of xenobiotic metabolism through activation of the constitutive androstane receptor and the estrogen receptor alpha.

    Directory of Open Access Journals (Sweden)

    Mei-Fei Yueh

    Full Text Available Triclocarban (3,4,4'-trichlorocarbanilide, TCC is used as a broad-based antimicrobial agent that is commonly added to personal hygiene products. Because of its extensive use in the health care industry and resistance to degradation in sewage treatment processes, TCC has become a significant waste product that is found in numerous environmental compartments where humans and wildlife can be exposed. While TCC has been linked to a range of health and environmental effects, few studies have been conducted linking exposure to TCC and induction of xenobiotic metabolism through regulation by environmental sensors such as the nuclear xenobiotic receptors (XenoRs. To identify the ability of TCC to activate xenobiotic sensors, we monitored XenoR activities in response to TCC treatment using luciferase-based reporter assays. Among the XenoRs in the reporter screening assay, TCC promotes both constitutive androstane receptor (CAR and estrogen receptor alpha (ERα activities. TCC treatment to hUGT1 mice resulted in induction of the UGT1A genes in liver. This induction was dependent upon the constitutive active/androstane receptor (CAR because no induction occurred in hUGT1Car(-/- mice. Induction of the UGT1A genes by TCC corresponded with induction of Cyp2b10, another CAR target gene. TCC was demonstrated to be a phenobarbital-like activator of CAR in receptor-based assays. While it has been suggested that TCC be classified as an endocrine disruptor, it activates ERα leading to induction of Cyp1b1 in female ovaries as well as in promoter activity. Activation of ERα by TCC in receptor-based assays also promotes induction of human CYP2B6. These observations demonstrate that TCC activates nuclear xenobiotic receptors CAR and ERα both in vivo and in vitro and might have the potential to alter normal physiological homeostasis. Activation of these xenobiotic-sensing receptors amplifies gene expression profiles that might represent a mechanistic base for

  1. Electrically and hybrid-induced muscle activations: effects of muscle size and fiber type

    Directory of Open Access Journals (Sweden)

    Kelly Stratton

    2016-07-01

    Full Text Available The effect of three electrical stimulation (ES frequencies (10, 35, and 50 Hz on two muscle groups with different proportions of fast and slow twitch fibers (abductor pollicis brevis (APB and vastus lateralis (VL was explored. We evaluated the acute muscles’ responses individually and during hybrid activations (ES superimposed by voluntary activations. Surface electromyography (sEMG and force measurements were evaluated as outcomes. Ten healthy adults (mean age: 24.4 ± 2.5 years participated after signing an informed consent form approved by the university Institutional Review Board. Protocols were developed to: 1 compare EMG activities during each frequency for each muscle when generating 25% Maximum Voluntary Contraction (MVC force, and 2 compare EMG activities during each frequency when additional voluntary activation was superimposed over ES-induced 25% MVC to reach 50% and 75% MVC. Empirical mode decomposition (EMD was utilized to separate ES artifacts from voluntary muscle activation. For both muscles, higher stimulation frequency (35 and 50Hz induced higher electrical output detected at 25% of MVC, suggesting more recruitment with higher frequencies. Hybrid activation generated proportionally less electrical activity than ES alone. ES and voluntary activations appear to generate two different modes of muscle recruitment. ES may provoke muscle strength by activating more fatiguing fast acting fibers, but voluntary activation elicits more muscle coordination. Therefore, during the hybrid activation, less electrical activity may be detected due to recruitment of more fatigue-resistant deeper muscle fibers, not reachable by surface EMG.

  2. Sulpiride and the role of dopaminergic receptor blockade in the antipsychotic activity of neuroleptics

    Energy Technology Data Exchange (ETDEWEB)

    Memo, M; Battaini, F; Spano, P F; Trabucchi, M [University of Brescia, (Italy). Dept. of Pharmacology

    1981-01-01

    It is now generally recognized that dopamine receptors excist in the CNS as different subtypes: D/sub 1/ receptors, associated with adenylyl cyclase activity, and D/sub 2/ receptor, uncoupled to a cyclic AMP generating system. In order to understand the role of D/sub 1/ and D/sub 2/ receptors in the antipsychotic action of neuroleptics, we have performed subchronic treatment with haloperidol, a drug which acts on D/sub 1/ receptors, and sulpiride, a selective antagonist to D/sub 2/ receptors. Long-term treatment with haloperidol does not induce significant supersensitivity of the D/sub 2/ receptors. In fact under these conditions /sup 3/H-(-)-sulpiride binding, which is a marker of D/sub 2/ receptor function, does not increase in rat striatum, while the long-term administration of sulpiride, itself produces supersensitivity of D/sub 2/ receptors. Moreover, sulpiride does not induce supersensitivity of the D/sub 1/ receptors, characterized by /sup 3/H-spiroperidol binding. These data suggest that both types of dopamine receptors may be involved in the clinical antipsychotic effects of neuroleptics. Unilateral leison of the nigrostriatal dopaminergic pathway produces an increase of striatal dopaminergic receptors, measured either by /sup 3/H-spiroperidol and /sup 3/H-(-)-sulpiride binding. These findings suggest that D/sub 1/ and D/sub 2/ receptors are present in postsynaptic membranes while it is still not known whether they exist in the same cellular elements.

  3. Sulpiride and the role of dopaminergic receptor blockade in the antipsychotic activity of neuroleptics

    International Nuclear Information System (INIS)

    Memo, M.; Battaini, F.; Spano, P.F.; Trabucchi, M.

    1981-01-01

    It is now generally recognized that dopamine receptors excist in the CNS as different subtypes: D 1 receptors, associated with adenylyl cyclase activity, and D 2 receptor, uncoupled to a cyclic APM generating system. In order to understand the role of D 1 and D 2 receptors in the antipsychotic action of neuroleptics, we have performed subchronic treatment with haloperidol, a drug which acts on D 1 receptors, and sulpiride, a selective antagonist to D 2 receptors. Long-term treatment with haloperidol does not induce significant supersensitivity of the D 2 receptors. In fact under these conditions 3 H-(-)-sulpiride binding, which is a marker of D 2 receptor function, does not increase in rat striatum, while the long-term administration of sulpiride, itself produces supersensitivity of D 2 receptors. Moreover, sulpiride does not induce supersensitivity of the D 1 receptors, characterized by 3 H-spiroperidol binding. These data suggest that both types of dopamine receptors may be involved in the clinical antipsychotic effects of neuroleptics. Unilateral leison of the nigrostriatal dopaminergic pathway produces an increase of striatal dopaminergic receptors, measured either by 3 H-spiroperidol and 3 H-(-)-sulpiride binding. These findings suggest that D 1 and D 2 receptors are present in postsynaptic membranes while it is still not known whether they exist in the same cellular elements. (author)

  4. Trilobolide-steroid hybrids: Synthesis, cytotoxic and antimycobacterial activity

    Czech Academy of Sciences Publication Activity Database

    Jurášek, M.; Džubák, P.; Rimpelová, S.; Sedlák, David; Konečný, P.; Frydrych, I.; Gurska, S.; Hajdúch, M.; Bogdanová, K.; Kolář, M.; Muller, Tomáš; Kmoníčková, Eva; Ruml, T.; Harmatha, Juraj; Drašar, P. B.

    2017-01-01

    Roč. 117, JAN (2017), s. 97-104 ISSN 0039-128X R&D Projects: GA MŠk(CZ) LO1304; GA MŠk LO1220; GA MŠk LM2015063 Grant - others:GA ČR(CZ) GA14-04329S Institutional support: RVO:68378050 ; RVO:68378041 ; RVO:61388963 Keywords : Trilobolide * Steroids * Click chemistry * Cytotoxicity * sar * Steroid receptor Subject RIV: EB - Genetics ; Molecular Biology; CC - Organic Chemistry (UOCHB-X) OBOR OECD: Biochemistry and molecular biology; Organic chemistry (UOCHB-X) Impact factor: 2.282, year: 2016

  5. Mechanoreceptor afferent activity compared with receptor field dimensions and pressure changes in feline urinary bladder.

    Science.gov (United States)

    Downie, J W; Armour, J A

    1992-11-01

    The relationship between vesical mechanoreceptor field dimensions and afferent nerve activity recorded in pelvic plexus nerve filaments was examined in chloralose-anesthetized cats. Orthogonal receptor field dimensions were monitored with piezoelectric ultrasonic crystals. Reflexly generated bladder contractile activity made measurements difficult, therefore data were collected from cats subjected to actual sacral rhizotomy. Afferent activity was episodic and was initiated at different pressure and receptor field dimension thresholds. Maximum afferent activity did not correlate with maximum volume or pressure. Furthermore, activity was not linearly related to intravesical pressure, receptor field dimensions, or calculated wall tension. Pressure-length hysteresis of the receptor fields occurred. The responses of identified afferent units and their associated receptor field dimensions to brief contractions elicited by the ganglion stimulant 1,1-dimethyl-4-phenylpiperazinium iodide (2.5-20 micrograms i.a.), studied under constant volume or constant pressure conditions, are compatible with bladder mechanoreceptors behaving as tension receptors. Because activity generated by bladder mechanoreceptors did not correlate in a simple fashion with intravesical pressure or receptor field dimensions, it is concluded that such receptors are influenced by the viscoelastic properties of the bladder wall. Furthermore, as a result of the heterogeneity of the bladder wall, receptor field tension appears to offer a more precise relationship with the activity of bladder wall mechanoreceptors than does intravesical pressure.

  6. Hybrid coded aperture and Compton imaging using an active mask

    International Nuclear Information System (INIS)

    Schultz, L.J.; Wallace, M.S.; Galassi, M.C.; Hoover, A.S.; Mocko, M.; Palmer, D.M.; Tornga, S.R.; Kippen, R.M.; Hynes, M.V.; Toolin, M.J.; Harris, B.; McElroy, J.E.; Wakeford, D.; Lanza, R.C.; Horn, B.K.P.; Wehe, D.K.

    2009-01-01

    The trimodal imager (TMI) images gamma-ray sources from a mobile platform using both coded aperture (CA) and Compton imaging (CI) modalities. In this paper we will discuss development and performance of image reconstruction algorithms for the TMI. In order to develop algorithms in parallel with detector hardware we are using a GEANT4 [J. Allison, K. Amako, J. Apostolakis, H. Araujo, P.A. Dubois, M. Asai, G. Barrand, R. Capra, S. Chauvie, R. Chytracek, G. Cirrone, G. Cooperman, G. Cosmo, G. Cuttone, G. Daquino, et al., IEEE Trans. Nucl. Sci. NS-53 (1) (2006) 270] based simulation package to produce realistic data sets for code development. The simulation code incorporates detailed detector modeling, contributions from natural background radiation, and validation of simulation results against measured data. Maximum likelihood algorithms for both imaging methods are discussed, as well as a hybrid imaging algorithm wherein CA and CI information is fused to generate a higher fidelity reconstruction.

  7. In Situ Hybridization Method Reveals (Pro)renin Receptor Expressing Cells in the Pituitary Gland of Rats: Correlation with Anterior Pituitary Hormones.

    Science.gov (United States)

    Takahashi, Kazuhiro; Yatabe, Megumi; Fujiwara, Ken; Hirose, Takuo; Totsune, Kazuhito; Yashiro, Takashi

    2013-02-28

    Expression of (pro)renin receptor ((P)RR), a specific receptor for renin and prorenin, was studied in rat pituitary gland. In situ hybridization showed that cells expressing (P)RR mRNA were widely distributed in the anterior lobe and intermediate lobe of the pituitary gland. Double-staining using in situ hybridization for (P)RR mRNA and immunohistochemistry for the pituitary hormones showed that (P)RR mRNA was expressed in most of the GH cells and ACTH cells in the anterior lobe. (P)RR mRNA was also expressed in a few prolactin cells and TSH cells, but not in LH cells. The present study has shown for the first time the distribution of (P)RR mRNA expressing cells in the rat pituitary gland. These findings suggest that (P)RR plays physiological roles in the pituitary gland, such as the modulation of the pituitary hormone secretion.

  8. In Situ Hybridization Method Reveals (Pro)renin Receptor Expressing Cells in the Pituitary Gland of Rats: Correlation with Anterior Pituitary Hormones

    International Nuclear Information System (INIS)

    Takahashi, Kazuhiro; Yatabe, Megumi; Fujiwara, Ken; Hirose, Takuo; Totsune, Kazuhito; Yashiro, Takashi

    2013-01-01

    Expression of (pro)renin receptor ((P)RR), a specific receptor for renin and prorenin, was studied in rat pituitary gland. In situ hybridization showed that cells expressing (P)RR mRNA were widely distributed in the anterior lobe and intermediate lobe of the pituitary gland. Double-staining using in situ hybridization for (P)RR mRNA and immunohistochemistry for the pituitary hormones showed that (P)RR mRNA was expressed in most of the GH cells and ACTH cells in the anterior lobe. (P)RR mRNA was also expressed in a few prolactin cells and TSH cells, but not in LH cells. The present study has shown for the first time the distribution of (P)RR mRNA expressing cells in the rat pituitary gland. These findings suggest that (P)RR plays physiological roles in the pituitary gland, such as the modulation of the pituitary hormone secretion

  9. Oleamide activates peroxisome proliferator-activated receptor gamma (PPARγ in vitro

    Directory of Open Access Journals (Sweden)

    Dionisi Mauro

    2012-05-01

    Full Text Available Abstract Background Oleamide (ODA is a fatty acid primary amide first identified in the cerebrospinal fluid of sleep-deprived cats, which exerts effects on vascular and neuronal tissues, with a variety of molecular targets including cannabinoid receptors and gap junctions. It has recently been reported to exert a hypolipidemic effect in hamsters. Here, we have investigated the nuclear receptor family of peroxisome proliferator-activated receptors (PPARs as potential targets for ODA action. Results Activation of PPARα, PPARβ and PPARγ was assessed using recombinant expression in Chinese hamster ovary cells with a luciferase reporter gene assay. Direct binding of ODA to the ligand binding domain of each of the three PPARs was monitored in a cell-free fluorescent ligand competition assay. A well-established assay of PPARγ activity, the differentiation of 3T3-L1 murine fibroblasts into adipocytes, was assessed using an Oil Red O uptake-based assay. ODA, at 10 and 50 μM, was able to transactivate PPARα, PPARβ and PPARγ receptors. ODA bound to the ligand binding domain of all three PPARs, although complete displacement of fluorescent ligand was only evident for PPARγ, at which an IC50 value of 38 μM was estimated. In 3T3-L1 cells, ODA, at 10 and 20 μM, induced adipogenesis. Conclusions We have, therefore, identified a novel site of action of ODA through PPAR nuclear receptors and shown how ODA should be considered as a weak PPARγ ligand in vitro.

  10. Hybrid Active Filter with Variable Conductance for Harmonic Resonance Suppression in Industrial Power Systems

    DEFF Research Database (Denmark)

    Lee, Tzung-Lin; Wang, Yen-Ching; Li, Jian-Cheng

    2015-01-01

    Unintentional series and/or parallel resonances, due to the tuned passive filter and the line inductance, may result in severe harmonic distortion in the industrial power system. This paper presents a hybrid active filter to suppress harmonic resonance and reduce harmonic distortion as well...... expensive. A reasonable trade-off between filtering performances and cost is to use the hybrid active filter. Design consideration are presented and experimental results are provided to validate effectiveness of the proposed method. Furthermore, this paper discusses filtering performances on line impedance...

  11. HybridPLAY: A New Technology to Foster Outdoors Physical Activity, Verbal Communication and Teamwork.

    Science.gov (United States)

    Díaz, Diego José; Boj, Clara; Portalés, Cristina

    2016-04-23

    This paper presents HybridPLAY, a novel technology composed of a sensor and mobile-based video games that transforms urban playgrounds into game scenarios. With this technology we aim to stimulate physical activity and playful learning by creating an entertaining environment in which users can actively participate and collaborate. HybridPLAY is different from other existing technologies that enhance playgrounds, as it is not integrated in them but can be attached to the different elements of the playgrounds, making its use more ubiquitous (i.e., not restricted to the playgrounds). HybridPLAY was born in 2007 as an artistic concept, and evolved after different phases of research and testing by almost 2000 users around the world (in workshops, artistic events, conferences, etc.). Here, we present the temporal evolution of HybridPLAY with the different versions of the sensors and the video games, and a detailed technical description of the sensors and the way interactions are produced. We also present the outcomes after the evaluation by users at different events and workshops. We believe that HybridPLAY has great potential to contribute to increased physical activity in kids, and also to improve the learning process and monitoring at school centres by letting users create the content of the apps, leading to new narratives and fostering creativity.

  12. Evaluation of methods for extraction of the volitional EMG in dynamic hybrid muscle activation

    Directory of Open Access Journals (Sweden)

    Mizrahi Joseph

    2006-11-01

    Full Text Available Abstract Background Hybrid muscle activation is a modality used for muscle force enhancement, in which muscle contraction is generated from two different excitation sources: volitional and external, by means of electrical stimulation (ES. Under hybrid activation, the overall EMG signal is the combination of the volitional and ES-induced components. In this study, we developed a computational scheme to extract the volitional EMG envelope from the overall dynamic EMG signal, to serve as an input signal for control purposes, and for evaluation of muscle forces. Methods A "synthetic" database was created from in-vivo experiments on the Tibialis Anterior of the right foot to emulate hybrid EMG signals, including the volitional and induced components. The database was used to evaluate the results obtained from six signal processing schemes, including seven different modules for filtration, rectification and ES component removal. The schemes differed from each other by their module combinations, as follows: blocking window only, comb filter only, blocking window and comb filter, blocking window and peak envelope, comb filter and peak envelope and, finally, blocking window, comb filter and peak envelope. Results and conclusion The results showed that the scheme including all the modules led to an excellent approximation of the volitional EMG envelope, as extracted from the hybrid signal, and underlined the importance of the artifact blocking window module in the process. The results of this work have direct implications on the development of hybrid muscle activation rehabilitation systems for the enhancement of weakened muscles.

  13. HybridPLAY: A New Technology to Foster Outdoors Physical Activity, Verbal Communication and Teamwork

    Directory of Open Access Journals (Sweden)

    Diego José Díaz

    2016-04-01

    Full Text Available This paper presents HybridPLAY, a novel technology composed of a sensor and mobile-based video games that transforms urban playgrounds into game scenarios. With this technology we aim to stimulate physical activity and playful learning by creating an entertaining environment in which users can actively participate and collaborate. HybridPLAY is different from other existing technologies that enhance playgrounds, as it is not integrated in them but can be attached to the different elements of the playgrounds, making its use more ubiquitous (i.e., not restricted to the playgrounds. HybridPLAY was born in 2007 as an artistic concept, and evolved after different phases of research and testing by almost 2000 users around the world (in workshops, artistic events, conferences, etc.. Here, we present the temporal evolution of HybridPLAY with the different versions of the sensors and the video games, and a detailed technical description of the sensors and the way interactions are produced. We also present the outcomes after the evaluation by users at different events and workshops. We believe that HybridPLAY has great potential to contribute to increased physical activity in kids, and also to improve the learning process and monitoring at school centres by letting users create the content of the apps, leading to new narratives and fostering creativity.

  14. HybridPLAY: A New Technology to Foster Outdoors Physical Activity, Verbal Communication and Teamwork

    Science.gov (United States)

    Díaz, Diego José; Boj, Clara; Portalés, Cristina

    2016-01-01

    This paper presents HybridPLAY, a novel technology composed of a sensor and mobile-based video games that transforms urban playgrounds into game scenarios. With this technology we aim to stimulate physical activity and playful learning by creating an entertaining environment in which users can actively participate and collaborate. HybridPLAY is different from other existing technologies that enhance playgrounds, as it is not integrated in them but can be attached to the different elements of the playgrounds, making its use more ubiquitous (i.e., not restricted to the playgrounds). HybridPLAY was born in 2007 as an artistic concept, and evolved after different phases of research and testing by almost 2000 users around the world (in workshops, artistic events, conferences, etc.). Here, we present the temporal evolution of HybridPLAY with the different versions of the sensors and the video games, and a detailed technical description of the sensors and the way interactions are produced. We also present the outcomes after the evaluation by users at different events and workshops. We believe that HybridPLAY has great potential to contribute to increased physical activity in kids, and also to improve the learning process and monitoring at school centres by letting users create the content of the apps, leading to new narratives and fostering creativity. PMID:27120601

  15. Molecular vibration-activity relationship in the agonism of adenosine receptors.

    Science.gov (United States)

    Chee, Hyun Keun; Oh, S June

    2013-12-01

    The molecular vibration-activity relationship in the receptor-ligand interaction of adenosine receptors was investigated by structure similarity, molecular vibration, and hierarchical clustering in a dataset of 46 ligands of adenosine receptors. The resulting dendrogram was compared with those of another kind of fingerprint or descriptor. The dendrogram result produced by corralled intensity of molecular vibrational frequency outperformed four other analyses in the current study of adenosine receptor agonism and antagonism. The tree that was produced by clustering analysis of molecular vibration patterns showed its potential for the functional classification of adenosine receptor ligands.

  16. Molecular Vibration-Activity Relationship in the Agonism of Adenosine Receptors

    Directory of Open Access Journals (Sweden)

    Hyun Keun Chee

    2013-12-01

    Full Text Available The molecular vibration-activity relationship in the receptor-ligand interaction of adenosine receptors was investigated by structure similarity, molecular vibration, and hierarchical clustering in a dataset of 46 ligands of adenosine receptors. The resulting dendrogram was compared with those of another kind of fingerprint or descriptor. The dendrogram result produced by corralled intensity of molecular vibrational frequency outperformed four other analyses in the current study of adenosine receptor agonism and antagonism. The tree that was produced by clustering analysis of molecular vibration patterns showed its potential for the functional classification of adenosine receptor ligands.

  17. E3 protein of bovine coronavirus is a receptor-destroying enzyme with acetylesterase activity

    International Nuclear Information System (INIS)

    Vlasak, R.; Luytjes, W.; Leider, J.; Spaan, W.; Palese, P.

    1988-01-01

    In addition to members of the Orthomyxoviridae and Paramyxoviridae, several coronaviruses have been shown to possess receptor-destroying activities. Purified bovine coronavirus (BCV) preparations have an esterase activity which inactivates O-acetylsialic acid-containing receptors on erythrocytes. Diisopropyl fluorophosphate (DFP) completely inhibits this receptor-destroying activity of BCV, suggesting that the viral enzyme is a serine esterase. Treatment of purified BCV with [ 3 H]DFP and subsequent sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the proteins revealed that the esterase/receptor-destroying activity of BCV is associated with the E3 protein was specifically phosphorylated. This finding suggests that the esterase/receptor-destroying activity of BCV is associated with the E3 protein. Furthermore, treatment of BCV with DFP dramatically reduced its infectivity in a plaque assay. It is assumed that the esterase activity of BCV is required in an early step of virus replication, possible during virus entry or uncoating

  18. E3 protein of bovine coronavirus is a receptor-destroying enzyme with acetylesterase activity

    Energy Technology Data Exchange (ETDEWEB)

    Vlasak, R.; Luytjes, W.; Leider, J.; Spaan, W.; Palese, P.

    1988-12-01

    In addition to members of the Orthomyxoviridae and Paramyxoviridae, several coronaviruses have been shown to possess receptor-destroying activities. Purified bovine coronavirus (BCV) preparations have an esterase activity which inactivates O-acetylsialic acid-containing receptors on erythrocytes. Diisopropyl fluorophosphate (DFP) completely inhibits this receptor-destroying activity of BCV, suggesting that the viral enzyme is a serine esterase. Treatment of purified BCV with (/sup 3/H)DFP and subsequent sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the proteins revealed that the esterase/receptor-destroying activity of BCV is associated with the E3 protein was specifically phosphorylated. This finding suggests that the esterase/receptor-destroying activity of BCV is associated with the E3 protein. Furthermore, treatment of BCV with DFP dramatically reduced its infectivity in a plaque assay. It is assumed that the esterase activity of BCV is required in an early step of virus replication, possible during virus entry or uncoating.

  19. Continuous cellularization of calcium phosphate hybrid scaffolds induced by plasma polymer activation

    International Nuclear Information System (INIS)

    Bergemann, Claudia; Cornelsen, Matthias; Quade, Antje; Laube, Thorsten; Schnabelrauch, Matthias; Rebl, Henrike; Weißmann, Volker; Seitz, Hermann; Nebe, Barbara

    2016-01-01

    The generation of hybrid materials based on β-tricalcium phosphate (TCP) and various biodegradable polymers like poly(L-lactide-co-D,L-lactide) (PLA) represents a common approach to overcoming the disadvantages of pure TCP devices. These disadvantages lie in TCP's mechanical properties, such as brittleness. The positive characteristic of PLA — improvement of compressive strength of calcium phosphate scaffolds – is diametrically opposed to its cell attractiveness. Therefore, the objective of this work was to optimize osteoblast migration and cellularization inside a three-dimensionally (3D) printed, PLA polymer stabilized TCP hybrid scaffold by a plasma polymer process depositing amino groups via allylamine. MG-63 osteoblastic cells inside the 10 mm hybrid scaffold were dynamically cultivated for 14 days in a 3D model system integrated in a perfusion reactor. The whole TCP/PLA hybrid scaffold was continuously colonized due to plasma polymerized allylamine activation inducing the migration potential of osteoblasts. - Highlights: • Mechanical stabilization of β-tricalcium phosphate scaffolds by PLA infiltration • Hybrid scaffolds with higher cell attraction due to plasma polymerized allylamine • 3D perfusion in vitro model for observation of cell migration inside scaffolds • Enhanced cell migration within plasma polymer coated TCP hybrid scaffolds

  20. Continuous cellularization of calcium phosphate hybrid scaffolds induced by plasma polymer activation

    Energy Technology Data Exchange (ETDEWEB)

    Bergemann, Claudia [University Medical Center Rostock, Cell Biology, Schillingallee 69, D-18057 Rostock (Germany); Cornelsen, Matthias [University of Rostock, Fluid Technology and Microfluidics, Justus-von-Liebig Weg 6, D-18059 Rostock (Germany); Quade, Antje [Leibniz-Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Str. 2, D-17489 Greifswald (Germany); Laube, Thorsten; Schnabelrauch, Matthias [INNOVENT e.V., Biomaterials Department, Pruessingstrasse 27B, D-07745 Jena (Germany); Rebl, Henrike [University Medical Center Rostock, Cell Biology, Schillingallee 69, D-18057 Rostock (Germany); Weißmann, Volker [Institute for Polymer Technologies (IPT) e.V., Alter Holzhafen 19, D-23966 Wismar (Germany); Seitz, Hermann [University of Rostock, Fluid Technology and Microfluidics, Justus-von-Liebig Weg 6, D-18059 Rostock (Germany); Nebe, Barbara, E-mail: barbara.nebe@med.uni-rostock.de [University Medical Center Rostock, Cell Biology, Schillingallee 69, D-18057 Rostock (Germany)

    2016-02-01

    The generation of hybrid materials based on β-tricalcium phosphate (TCP) and various biodegradable polymers like poly(L-lactide-co-D,L-lactide) (PLA) represents a common approach to overcoming the disadvantages of pure TCP devices. These disadvantages lie in TCP's mechanical properties, such as brittleness. The positive characteristic of PLA — improvement of compressive strength of calcium phosphate scaffolds – is diametrically opposed to its cell attractiveness. Therefore, the objective of this work was to optimize osteoblast migration and cellularization inside a three-dimensionally (3D) printed, PLA polymer stabilized TCP hybrid scaffold by a plasma polymer process depositing amino groups via allylamine. MG-63 osteoblastic cells inside the 10 mm hybrid scaffold were dynamically cultivated for 14 days in a 3D model system integrated in a perfusion reactor. The whole TCP/PLA hybrid scaffold was continuously colonized due to plasma polymerized allylamine activation inducing the migration potential of osteoblasts. - Highlights: • Mechanical stabilization of β-tricalcium phosphate scaffolds by PLA infiltration • Hybrid scaffolds with higher cell attraction due to plasma polymerized allylamine • 3D perfusion in vitro model for observation of cell migration inside scaffolds • Enhanced cell migration within plasma polymer coated TCP hybrid scaffolds.

  1. Renal cells activate the platelet receptor CLEC-2 through podoplanin

    Science.gov (United States)

    Christou, Charita M.; Pearce, Andrew C.; Watson, Aleksandra A.; Mistry, Anita R.; Pollitt, Alice Y.; Fenton-May, Angharad E.; Johnson, Louise A.; Jackson, David G.; Watson, Steve P.; O'Callaghan, Chris A.

    2009-01-01

    We have recently shown that the C-type lectin-like receptor, CLEC-2, is expressed on platelets and that it mediates powerful platelet aggregation by the snake venom toxin, rhodocytin. In addition, we have provided indirect evidence for an endogenous ligand for CLEC-2 in renal cells expressing human immunodeficiency virus type 1 (HIV-1). This putative ligand facilitates transmission of HIV through its incorporation into the viral envelope and binding to CLEC-2 on platelets. The aim of this study was to identify the ligand on these cells which binds to CLEC-2 on platelets. Recombinant CLEC-2 exhibits specific binding to 293T cells in which the HIV can be grown. Further, 293T cells activate both platelets and CLEC-2-transfected DT-40 B cells. The transmembrane protein podoplanin was identified on 293T cells and demonstrated to mediate both binding of 293T cells to CLEC-2 and 293T cell activation of CLEC-2-transfected DT-40 B cells. Podoplanin is expressed on renal cells (podocytes). Further, a direct interaction between CLEC-2 and podoplanin was confirmed using surface plasmon resonance and was shown to be independent of glycosylation of CLEC-2. The interaction has an affinity of 24.5 ± 3.7μM. The present study identifies podoplanin as a ligand for CLEC-2 on renal cells. PMID:18215137

  2. Mechanical stress activates NMDA receptors in the absence of agonists.

    Science.gov (United States)

    Maneshi, Mohammad Mehdi; Maki, Bruce; Gnanasambandam, Radhakrishnan; Belin, Sophie; Popescu, Gabriela K; Sachs, Frederick; Hua, Susan Z

    2017-01-03

    While studying the physiological response of primary rat astrocytes to fluid shear stress in a model of traumatic brain injury (TBI), we found that shear stress induced Ca 2+ entry. The influx was inhibited by MK-801, a specific pore blocker of N-Methyl-D-aspartic acid receptor (NMDAR) channels, and this occurred in the absence of agonists. Other NMDA open channel blockers ketamine and memantine showed a similar effect. The competitive glutamate antagonists AP5 and GluN2B-selective inhibitor ifenprodil reduced NMDA-activated currents, but had no effect on the mechanically induced Ca 2+ influx. Extracellular Mg 2+ at 2 mM did not significantly affect the shear induced Ca 2+ influx, but at 10 mM it produced significant inhibition. Patch clamp experiments showed mechanical activation of NMDAR and inhibition by MK-801. The mechanical sensitivity of NMDARs may play a role in the normal physiology of fluid flow in the glymphatic system and it has obvious relevance to TBI.

  3. The Electrochemical Characteristics of Hybrid Capacitor Prepared by Chemical Activation of NaOH

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Jeong Eun; Bae, Ga Yeong; Yang, Jeong Min; Lee, Jong Dae [Chungbuk National Univ., Chungju (Korea, Republic of)

    2013-06-15

    Active carbons with high specific surface area and micro pore structure were prepared from the coconut shell char using the chemical activation method of NaOH. The preparation process has been optimized through the analysis of experimental variables such as activating chemical agents to char ratio and the flow rate of gas during carbonization. The active carbons with the surface area (2,481m{sup 2}/g) and mean pore size (2.32 nm) were obtained by chemical activation with NaOH. The electrochemical performances of hybrid capacitor were investigated using LiMn{sub 2}O{sub 4}, LiCoO{sub 2} as the positive electrode and prepared active carbon as the negative electrode. The electrochemical behaviors of hybrid capacitor using organic electrolytes (LiPF{sub 6}, TEABF{sub 4}) were characterized by constant current charge/discharge, cyclic voltammetry, cycle and leakage tests. The hybrid capacitor using LiMn{sub 2}O{sub 4}/AC electrodes had better capacitance than other hybrid systems and was able to deliver a specific energy as high as 131 Wh/kg at a specific power of 1,448 W/kg.

  4. The Electrochemical Characteristics of Hybrid Capacitor Prepared by Chemical Activation of NaOH

    International Nuclear Information System (INIS)

    Choi, Jeong Eun; Bae, Ga Yeong; Yang, Jeong Min; Lee, Jong Dae

    2013-01-01

    Active carbons with high specific surface area and micro pore structure were prepared from the coconut shell char using the chemical activation method of NaOH. The preparation process has been optimized through the analysis of experimental variables such as activating chemical agents to char ratio and the flow rate of gas during carbonization. The active carbons with the surface area (2,481m 2 /g) and mean pore size (2.32 nm) were obtained by chemical activation with NaOH. The electrochemical performances of hybrid capacitor were investigated using LiMn 2 O 4 , LiCoO 2 as the positive electrode and prepared active carbon as the negative electrode. The electrochemical behaviors of hybrid capacitor using organic electrolytes (LiPF 6 , TEABF 4 ) were characterized by constant current charge/discharge, cyclic voltammetry, cycle and leakage tests. The hybrid capacitor using LiMn 2 O 4 /AC electrodes had better capacitance than other hybrid systems and was able to deliver a specific energy as high as 131 Wh/kg at a specific power of 1,448 W/kg

  5. β1-adrenergic receptors activate two distinct signaling pathways in striatal neurons

    Science.gov (United States)

    Meitzen, John; Luoma, Jessie I.; Stern, Christopher M.; Mermelstein, Paul G.

    2010-01-01

    Monoamine action in the dorsal striatum and nucleus accumbens plays essential roles in striatal physiology. Although research often focuses on dopamine and its receptors, norepinephrine and adrenergic receptors are also crucial in regulating striatal function. While noradrenergic neurotransmission has been identified in the striatum, little is known regarding the signaling pathways activated by β-adrenergic receptors in this brain region. Using cultured striatal neurons, we characterized a novel signaling pathway by which activation of β1-adrenergic receptors leads to the rapid phosphorylation of cAMP Response Element Binding Protein (CREB), a transcription-factor implicated as a molecular switch underlying long-term changes in brain function. Norepinephrine-mediated CREB phosphorylation requires β1-adrenergic receptor stimulation of a receptor tyrosine kinase, ultimately leading to the activation of a Ras/Raf/MEK/MAPK/MSK signaling pathway. Activation of β1-adrenergic receptors also induces CRE-dependent transcription and increased c-fos expression. In addition, stimulation of β1-adrenergic receptors produces cAMP production, but surprisingly, β1-adrenergic receptor activation of adenylyl cyclase was not functionally linked to rapid CREB phosphorylation. These findings demonstrate that activation of β1-adrenergic receptors on striatal neurons can stimulate two distinct signaling pathways. These adrenergic actions can produce long-term changes in gene expression, as well as rapidly modulate cellular physiology. By elucidating the mechanisms by which norepinephrine and β1-adrenergic receptor activation affects striatal physiology, we provide the means to more fully understand the role of monoamines in modulating striatal function, specifically how norepinephrine and β1-adrenergic receptors may affect striatal physiology. PMID:21143600

  6. Rapid and Simple Detection of Hot Spot Point Mutations of Epidermal Growth Factor Receptor, BRAF, and NRAS in Cancers Using the Loop-Hybrid Mobility Shift Assay

    Science.gov (United States)

    Matsukuma, Shoichi; Yoshihara, Mitsuyo; Kasai, Fumio; Kato, Akinori; Yoshida, Akira; Akaike, Makoto; Kobayashi, Osamu; Nakayama, Haruhiko; Sakuma, Yuji; Yoshida, Tsutomu; Kameda, Yoichi; Tsuchiya, Eiju; Miyagi, Yohei

    2006-01-01

    A simple and rapid method to detect the epidermal growth factor receptor hot spot mutation L858R in lung adenocarcinoma was developed based on principles similar to the universal heteroduplex generator technology. A single-stranded oligonucleotide with an internal deletion was used to generate heteroduplexes (loop-hybrids) bearing a loop in the complementary strand derived from the polymerase chain reaction product of the normal or mutant allele. By placing deletion in the oligonucleotide adjacent to the mutational site, difference in electrophoretic mobility between loop-hybrids with normal and mutated DNA was distinguishable in a native polyacrylamide gel. The method was also modified to detect in-frame deletion mutations of epidermal growth factor receptor in lung adenocarcinomas. In addition, the method was adapted to detect hot spot mutations in the B-type Raf kinase (BRAF) at V600 and in a Ras-oncogene (NRAS) at Q61, the mutations commonly found in thyroid carcinomas. Our mutation detection system, designated the loop-hybrid mobility shift assay was sensitive enough to detect mutant DNA comprising 7.5% of the total DNA. As a simple and straightforward mutation detection technique, loop-hybrid mobility shift assay may be useful for the molecular diagnosis of certain types of clinical cancers. Other applications are also discussed. PMID:16931592

  7. Structure-activity relationships of rosiglitazone for peroxisome proliferator-activated receptor gamma transrepression.

    Science.gov (United States)

    Toyota, Yosuke; Nomura, Sayaka; Makishima, Makoto; Hashimoto, Yuichi; Ishikawa, Minoru

    2017-06-15

    Anti-inflammatory effects of peroxisome proliferator-activated receptor gamma (PPRAγ) ligands are thought to be largely due to PPARγ-mediated transrepression. Thus, transrepression-selective PPARγ ligands without agonistic activity or with only partial agonistic activity should exhibit anti-inflammatory properties with reduced side effects. Here, we investigated the structure-activity relationships (SARs) of PPARγ agonist rosiglitazone, focusing on transrepression activity. Alkenic analogs showed slightly more potent transrepression with reduced efficacy of transactivating agonistic activity. Removal of the alkyl group on the nitrogen atom improved selectivity for transrepression over transactivation. Among the synthesized compounds, 3l exhibited stronger transrepressional activity (IC 50 : 14μM) and weaker agonistic efficacy (11%) than rosiglitazone or pioglitazone. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Peroxisome proliferators-activated receptor (PPAR) regulation in cardiac metabolism and disease

    NARCIS (Netherlands)

    el Azzouzi, H.

    2009-01-01

    Peroxisome proliferators-activated receptors (PPARs) are members of the nuclear receptor family of ligand activated transcription factors and consist of the three isoforms, PPAR, PPAR/ and PPAR. Considerable evidence has established the importance of PPARs in myocardial lipid homeostasis and

  9. Activation of toll-like receptors and dendritic cells by a broad range of bacterial molecules

    NARCIS (Netherlands)

    Boele, L.C.L.; Bajramovic, J.J.; Vries, A.M.M.B.C. de; Voskamp-Visser, I.A.I.; Kaman, W.E.; Kleij, D. van der

    2009-01-01

    Activation of pattern recognition receptors such as Toll-like receptors (TLRs) by pathogens leads to activation and maturation of dendritic cells (DC), which orchestrate the development of the adaptive immune response. To create an overview of the effects of a broad range of pathogenic bacteria,

  10. Plasma soluble urokinase plasminogen activator receptor in children with urinary tract infection

    DEFF Research Database (Denmark)

    Wittenhagen, Per; Andersen, Jesper Brandt; Hansen, Anita

    2011-01-01

    In this prospective study we investigated the role of plasma levels of soluble urokinase plasminogen activator receptor (suPAR) in children with urinary tract infection.......In this prospective study we investigated the role of plasma levels of soluble urokinase plasminogen activator receptor (suPAR) in children with urinary tract infection....

  11. Phosphorous digestibility and activity of intestinal phytase in hybrid tilapia, Oreochromis niloticus X O. aureus

    Science.gov (United States)

    La Vorgna, M.W.; Hafez, Y.; Hughes, S.G.; Handwerker, T.

    2003-01-01

    Experiments were conducted to determine the degree to which phytate-bound phosphorus from plant protein sources could be used by hybrid tilapia (Oreochromis niloticus X O. aureus). Utilizing an inert marker technique with chromic oxide, hybrid tilapia in our study were effective at utilizing both inorganic and phytate phosphorus as evidenced by average apparent digestibility values of 93.2% and 90.0% for total and phytate phosphorus, respectively. Analysis of the intestinal brush border membrane of the tilapia revealed enzyme activity that was capable of hydrolyzing phytic acid. The presence of phytic acid hydrolyzing enzyme activity in the intestinal brush border provides a probable mechanism by which these hybrid tilapia are able to utilize phytate phosphorus effectively. ?? 2003 by The Haworth Press, Inc. All rights reserved.

  12. Design, fabrication and performance of a hybrid photovoltaic/thermal (PV/T) active solar still

    International Nuclear Information System (INIS)

    Kumar, Shiv; Tiwari, Arvind

    2010-01-01

    Two solar stills (single slope passive and single slope photovoltaic/thermal (PV/T) active solar still) were fabricated and tested at solar energy park, IIT New Delhi (India) for composite climate. Photovoltaic operated DC water pump was used between solar still and photovoltaic (PV) integrated flat plate collector to re-circulate the water through the collectors and transfer it to the solar still. The newly designed hybrid (PV/T) active solar still is self-sustainable and can be used in remote areas, need to transport distilled water from a distance and not connected to grid, but blessed with ample solar energy. Experiments were performed for 0.05, 0.10, and 0.15 m water depth, round the year 2006-2007 for both the stills. It has been observed that maximum daily yield of 2.26 kg and 7.22 kg were obtained from passive and hybrid active solar still, respectively at 0.05 m water depth. The daily yield from hybrid active solar still is around 3.2 and 5.5 times higher than the passive solar still in summer and winter month, respectively. The study has shown that this design of the hybrid active solar still also provides higher electrical and overall thermal efficiency, which is about 20% higher than the passive solar still.

  13. Probing Dominant Negative Behavior of Glucocorticoid Receptor β through a Hybrid Structural and Biochemical Approach

    Energy Technology Data Exchange (ETDEWEB)

    Min, Jungki; Perera, Lalith; Krahn, Juno M.; Jewell, Christine M.; Moon, Andrea F.; Cidlowski, John A.; Pedersen, Lars C.

    2018-02-05

    ABSTRACT

    Glucocorticoid receptor β (GRβ) is associated with glucocorticoid resistance via dominant negative regulation of GRα. To better understand how GRβ functions as a dominant negative inhibitor of GRα at a molecular level, we determined the crystal structure of the ligand binding domain of GRβ complexed with the antagonist RU-486. The structure reveals that GRβ binds RU-486 in the same ligand binding pocket as GRα, and the unique C-terminal amino acids of GRβ are mostly disordered. Binding energy analysis suggests that these C-terminal residues of GRβ do not contribute to RU-486 binding. Intriguingly, the GRβ/RU-486 complex binds corepressor peptide with affinity similar to that of a GRα/RU-486 complex, despite the lack of helix 12. Our biophysical and biochemical analyses reveal that in the presence of RU-486, GRβ is found in a conformation that favors corepressor binding, potentially antagonizing GRα function. This study thus presents an unexpected molecular mechanism by which GRβ could repress transcription.

  14. Modulation of receptors and adenylate cyclase activity during sucrose feeding, food deprivation, and cold exposure

    International Nuclear Information System (INIS)

    Scarpace, P.J.; Baresi, L.A.; Morley, J.E.

    1987-01-01

    Thermogenesis in brown adipose tissue (BAT) serves as a regulator of body temperature and weight maintenance. Thermogenesis can be stimulated by catecholamine activation of adenylate cyclase through the β-adrenergic receptor. To investigate the effects of sucrose feeding, food deprivation, and cold exposure on the β-adrenergic pathway, adenylate cyclase activity and β-adrenergic receptors were assessed in rat BAT after 2 wk of sucrose feeding, 2 days of food deprivation, or 2 days of cold exposure. β-Adrenergic receptors were identified in BAT using [ 125 I]iodocyanopindolol. Binding sites had the characteristics of mixed β 1 - and β 2 -type adrenergic receptors at a ratio of 60/40. After sucrose feeding or cold exposure, there was the expected increase in BAT mitochondrial mass as measured by total cytochrome-c oxidase activity but a decrease in β-adrenergic receptor density due to a loss of the β 1 -adrenergic subtype. This BAT β-adrenergic receptor downregulation was tissue specific, since myocardial β-adrenergic receptors were unchanged with either sucrose feeding or cold exposure. Forskolin-stimulated adenylate cyclase activity increased in BAT after sucrose feeding or cold exposure but not after food deprivation. These data suggest that in BAT, sucrose feeding or cold exposure result in downregulation of β-adrenergic receptors and that isoproterenol-stimulated adenylate cyclase activity was limited by receptor availability

  15. AmTAR2: Functional characterization of a honeybee tyramine receptor stimulating adenylyl cyclase activity.

    Science.gov (United States)

    Reim, Tina; Balfanz, Sabine; Baumann, Arnd; Blenau, Wolfgang; Thamm, Markus; Scheiner, Ricarda

    2017-01-01

    The biogenic monoamines norepinephrine and epinephrine regulate important physiological functions in vertebrates. Insects such as honeybees do not synthesize these neuroactive substances. Instead, they employ octopamine and tyramine for comparable physiological functions. These biogenic amines activate specific guanine nucleotide-binding (G) protein-coupled receptors (GPCRs). Based on pharmacological data obtained on heterologously expressed receptors, α- and β-adrenergic-like octopamine receptors are better activated by octopamine than by tyramine. Conversely, GPCRs forming the type 1 tyramine receptor clade (synonymous to octopamine/tyramine receptors) are better activated by tyramine than by octopamine. More recently, receptors were characterized which are almost exclusively activated by tyramine, thus forming an independent type 2 tyramine receptor clade. Functionally, type 1 tyramine receptors inhibit adenylyl cyclase activity, leading to a decrease in intracellular cAMP concentration ([cAMP] i ). Type 2 tyramine receptors can mediate Ca 2+ signals or both Ca 2+ signals and effects on [cAMP] i . We here provide evidence that the honeybee tyramine receptor 2 (AmTAR2), when heterologously expressed in flpTM cells, exclusively causes an increase in [cAMP] i . The receptor displays a pronounced preference for tyramine over octopamine. Its activity can be blocked by a series of established antagonists, of which mianserin and yohimbine are most efficient. The functional characterization of two tyramine receptors from the honeybee, AmTAR1 (previously named AmTYR1) and AmTAR2, which respond to tyramine by changing cAMP levels in opposite direction, is an important step towards understanding the actions of tyramine in honeybee behavior and physiology, particularly in comparison to the effects of octopamine. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. Hybrid energy storage systems utilizing redox active organic compounds

    Science.gov (United States)

    Wang, Wei; Xu, Wu; Li, Liyu; Yang, Zhenguo

    2015-09-08

    Redox flow batteries (RFB) have attracted considerable interest due to their ability to store large amounts of power and energy. Non-aqueous energy storage systems that utilize at least some aspects of RFB systems are attractive because they can offer an expansion of the operating potential window, which can improve on the system energy and power densities. One example of such systems has a separator separating first and second electrodes. The first electrode includes a first current collector and volume containing a first active material. The second electrode includes a second current collector and volume containing a second active material. During operation, the first source provides a flow of first active material to the first volume. The first active material includes a redox active organic compound dissolved in a non-aqueous, liquid electrolyte and the second active material includes a redox active metal.

  17. Activity-induced and developmental downregulation of the Nogo receptor

    DEFF Research Database (Denmark)

    Josephson, Anna; Trifunovski, Alexandra; Schéele, Camilla

    2003-01-01

    The three axon growth inhibitory proteins, myelin associated glycoprotein, oligodendrocyte-myelin glycoprotein and Nogo-A, can all bind to the Nogo-66 receptor (NgR). This receptor is expressed by neurons with high amounts in regions of high plasticity where Nogo expression is also high. We hypot...

  18. A bacterial tyrosine phosphatase inhibits plant pattern recognition receptor activation

    Science.gov (United States)

    Perception of pathogen-associated molecular patterns (PAMPs) by surface-localised pattern-recognition receptors (PRRs) is a key component of plant innate immunity. Most known plant PRRs are receptor kinases and initiation of PAMP-triggered immunity (PTI) signalling requires phosphorylation of the PR...

  19. Proteolytic regulation of Notch1 receptor activity in cancer

    NARCIS (Netherlands)

    van Tetering, Geert

    2011-01-01

    The Notch receptor is part of a highly conserved signaling pathway essential in development and disease in embryos and adults. Notch proteins coordinate cell-cell communication through receptor-ligand interactions between adjacent cells. First Notch is cleaved in the Golgi by furin at Site-1 (S1)

  20. Recent Progress on Cellulose-Based Electro-Active Paper, Its Hybrid Nanocomposites and Applications

    OpenAIRE

    Asif Khan; Zafar Abas; Heung Soo Kim; Jaehwan Kim

    2016-01-01

    We report on the recent progress and development of research into cellulose-based electro-active paper for bending actuators, bioelectronics devices, and electromechanical transducers. The cellulose electro-active paper is characterized in terms of its biodegradability, chirality, ample chemically modifying capacity, light weight, actuation capability, and ability to form hybrid nanocomposites. The mechanical, electrical, and chemical characterizations of the cellulose-based electro-active pa...

  1. Stereospecificity of oligonucleotide interactions revisited: no evidence for heterochiral hybridization and ribozyme/DNAzyme activity.

    Directory of Open Access Journals (Sweden)

    Kai Hoehlig

    Full Text Available A major challenge for the application of RNA- or DNA-oligonucleotides in biotechnology and molecular medicine is their susceptibility to abundant nucleases. One intriguing possibility to tackle this problem is the use of mirror-image (l-oligonucleotides. For aptamers, this concept has successfully been applied to even develop therapeutic agents, so-called Spiegelmers. However, for technologies depending on RNA/RNA or RNA/DNA hybridization, like antisense or RNA interference, it has not been possible to use mirror-image oligonucleotides because Watson-Crick base pairing of complementary strands is (thought to be stereospecific. Many scientists consider this a general principle if not a dogma. A recent publication proposing heterochiral Watson-Crick base pairing and sequence-specific hydrolysis of natural RNA by mirror-image ribozymes or DNAzymes (and vice versa prompted us to systematically revisit the stereospecificity of oligonucleotides hybridization and catalytic activity. Using hyperchromicity measurements we demonstrate that hybridization only occurs among homochiral anti-parallel complementary oligonucleotide strands. As expected, achiral PNA hybridizes to RNA and DNA irrespective of their chirality. In functional assays we could not confirm an alleged heterochiral hydrolytic activity of ribozymes or DNAzymes. Our results confirm a strict stereospecificity of oligonucleotide hybridization and clearly argue against the possibility to use mirror-image oligonucleotides for gene silencing or antisense applications.

  2. Peroxisome proliferator-activated receptor α agonist-induced down-regulation of hepatic glucocorticoid receptor expression in SD rats

    International Nuclear Information System (INIS)

    Chen Xiang; Li Ming; Sun Weiping; Bi Yan; Cai Mengyin; Liang Hua; Yu Qiuqiong; He Xiaoying; Weng Jianping

    2008-01-01

    It was reported that glucocorticoid production was inhibited by fenofibrate through suppression of type-1 11β-hydroxysteroid dehydrogenase gene expression in liver. The inhibition might be a negative-feedback regulation of glucocorticoid receptor (GR) activity by peroxisome proliferator-activated receptor alpha (PPARα), which is quickly induced by glucocorticoid in the liver. However, it is not clear if GR expression is changed by fenofibrate-induced PPARα activation. In this study, we tested this possibility in the liver of Sprague-Dawley rats. GR expression was reduced by fenofibrate in a time- and does-dependent manner. The inhibition was observed in liver, but not in fat and muscle. The corticosterone level in the blood was increased significantly by fenofibrate. These effects of fenofibrate were abolished by PPARα inhibitor MK886, suggesting that fenofibrate activated through PPARα. In conclusion, inhibition of GR expression may represent a new molecular mechanism for the negative feedback regulation of GR activity by PPARα

  3. Protease-activated receptor-2 activation exaggerates TRPV1-mediated cough in guinea pigs.

    Science.gov (United States)

    Gatti, Raffaele; Andre, Eunice; Amadesi, Silvia; Dinh, Thai Q; Fischer, Axel; Bunnett, Nigel W; Harrison, Selena; Geppetti, Pierangelo; Trevisani, Marcello

    2006-08-01

    A lowered threshold to the cough response frequently accompanies chronic airway inflammatory conditions. However, the mechanism(s) that from chronic inflammation results in a lowered cough threshold is poorly understood. Irritant agents, including capsaicin, resiniferatoxin, and citric acid, elicit cough in humans and in experimental animals through the activation of the transient receptor potential vanilloid 1 (TRPV1). Protease-activated receptor-2 (PAR2) activation plays a role in inflammation and sensitizes TRPV1 in cultured sensory neurons by a PKC-dependent pathway. Here, we have investigated whether PAR2 activation exaggerates TRPV1-dependent cough in guinea pigs and whether protein kinases are involved in the PAR2-induced cough modulation. Aerosolized PAR2 agonists (PAR2-activating peptide and trypsin) did not produce any cough per se. However, they potentiated citric acid- and resiniferatoxin-induced cough, an effect that was completely prevented by the TRPV1 receptor antagonist capsazepine. In contrast, cough induced by hypertonic saline, a stimulus that provokes cough in a TRPV1-independent manner, was not modified by aerosolized PAR2 agonists. The PKC inhibitor GF-109203X, the PKA inhibitor H-89, and the cyclooxygenase inhibitor indomethacin did not affect cough induced by TRPV1 agonists, but abated the exaggeration of this response produced by PAR2 agonists. In conclusion, PAR2 stimulation exaggerates TRPV1-dependent cough by activation of diverse mechanism(s), including PKC, PKA, and prostanoid release. PAR2 activation, by sensitizing TRPV1 in primary sensory neurons, may play a role in the exaggerated cough observed in certain airways inflammatory diseases such as asthma and chronic obstructive pulmonary disease.

  4. Characterization of human endothelial cell urokinase-type plasminogen activator receptor protein and messenger RNA

    DEFF Research Database (Denmark)

    Barnathan, E S; Kuo, A; Karikó, K

    1990-01-01

    Human umbilical vein endothelial cells in culture (HUVEC) express receptors for urokinase-type plasminogen activators (u-PA). The immunochemical nature of this receptor and its relationship to u-PA receptors expressed by other cell types is unknown. Cross-linking active site-blocked u-PA to HUVEC...... an endothelial cell cDNA library using the polymerase chain reaction (PCR) and oligonucleotide primers corresponding to the DNA sequence of the receptor cloned from transformed human fibroblasts (Roldan et al, EMBO J 9:467, 1990). The size of the cDNA (approximately 1,054 base pairs, bp) and the presence...

  5. Function of the cytoplasmic tail of human calcitonin receptor-like receptor in complex with receptor activity-modifying protein 2

    Energy Technology Data Exchange (ETDEWEB)

    Kuwasako, Kenji, E-mail: kuwasako@fc.miyazaki-u.ac.jp [Frontier Science Research Center, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692 (Japan); Kitamura, Kazuo; Nagata, Sayaka; Hikosaka, Tomomi [Division of Circulation and Body Fluid Regulation, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692 (Japan); Kato, Johji [Frontier Science Research Center, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692 (Japan)

    2010-02-12

    Receptor activity-modifying protein 2 (RAMP2) enables calcitonin receptor-like receptor (CRLR) to form an adrenomedullin (AM)-specific receptor. Here we investigated the function of the cytoplasmic C-terminal tail (C-tail) of human (h)CRLR by co-transfecting its C-terminal mutants into HEK-293 cells stably expressing hRAMP2. Deleting the C-tail from CRLR disrupted AM-evoked cAMP production or receptor internalization, but did not affect [{sup 125}I]AM binding. We found that CRLR residues 428-439 are required for AM-evoked cAMP production, though deleting this region had little effect on receptor internalization. Moreover, pretreatment with pertussis toxin (100 ng/mL) led to significant increases in AM-induced cAMP production via wild-type CRLR/RAMP2 complexes. This effect was canceled by deleting CRLR residues 454-457, suggesting Gi couples to this region. Flow cytometric analysis revealed that CRLR truncation mutants lacking residues in the Ser/Thr-rich region extending from Ser{sup 449} to Ser{sup 467} were unable to undergo AM-induced receptor internalization and, in contrast to the effect on wild-type CRLR, overexpression of GPCR kinases-2, -3 and -4 failed to promote internalization of CRLR mutants lacking residues 449-467. Thus, the hCRLR C-tail is crucial for AM-evoked cAMP production and internalization of the CRLR/RAMP2, while the receptor internalization is dependent on the aforementioned GPCR kinases, but not Gs coupling.

  6. Androgen receptor activation: a prospective therapeutic target for bladder cancer?

    Science.gov (United States)

    Mizushima, Taichi; Tirador, Kathleen A; Miyamoto, Hiroshi

    2017-03-01

    Patients with non-muscle-invasive or muscle-invasive bladder cancer undergoing surgery and currently available conventional therapy remain having a high risk of tumor recurrence or progression, respectively. Novel targeted molecular therapy is therefore expected to improve patient outcomes. Meanwhile, substantially higher incidence of bladder cancer in men has prompted research on androgen-mediated androgen receptor (AR) signaling in this malignancy. Indeed, preclinical evidence has suggested that AR signaling plays an important role in urothelial carcinogenesis and tumor outgrowth as well as resistance to some of the currently available conventional non-surgical therapies. Areas covered: We summarize and discuss available data suggesting the involvement of AR and its potential downstream targets in the development and progression of bladder cancer. Associations between AR signaling and sensitivity to cisplatin/doxorubicin or bacillus Calmette-Guérin treatment are also reviewed. Expert opinion: AR activation is likely to correlate with the promotion of urothelial carcinogenesis and cancer outgrowth as well as resistance to conventional therapies. Molecular therapy targeting the AR may thus provide effective chemopreventive and therapeutic approaches for urothelial cancer. Accordingly, bladder cancer can now be considered as an endocrine-related neoplasm. Clinical application of various anti-AR therapies available for AR-dependent prostate cancer to bladder cancer patients is anticipated.

  7. Recent Progress on Cellulose-Based Electro-Active Paper, Its Hybrid Nanocomposites and Applications.

    Science.gov (United States)

    Khan, Asif; Abas, Zafar; Kim, Heung Soo; Kim, Jaehwan

    2016-07-26

    We report on the recent progress and development of research into cellulose-based electro-active paper for bending actuators, bioelectronics devices, and electromechanical transducers. The cellulose electro-active paper is characterized in terms of its biodegradability, chirality, ample chemically modifying capacity, light weight, actuation capability, and ability to form hybrid nanocomposites. The mechanical, electrical, and chemical characterizations of the cellulose-based electro-active paper and its hybrid composites such as blends or coatings with synthetic polymers, biopolymers, carbon nanotubes, chitosan, and metal oxides, are explained. In addition, the integration of cellulose electro-active paper is highlighted to form various functional devices including but not limited to bending actuators, flexible speaker, strain sensors, energy harvesting transducers, biosensors, chemical sensors and transistors for electronic applications. The frontiers in cellulose paper devices are reviewed together with the strategies and perspectives of cellulose electro-active paper and cellulose nanocomposite research and applications.

  8. Recent Progress on Cellulose-Based Electro-Active Paper, Its Hybrid Nanocomposites and Applications

    Directory of Open Access Journals (Sweden)

    Asif Khan

    2016-07-01

    Full Text Available We report on the recent progress and development of research into cellulose-based electro-active paper for bending actuators, bioelectronics devices, and electromechanical transducers. The cellulose electro-active paper is characterized in terms of its biodegradability, chirality, ample chemically modifying capacity, light weight, actuation capability, and ability to form hybrid nanocomposites. The mechanical, electrical, and chemical characterizations of the cellulose-based electro-active paper and its hybrid composites such as blends or coatings with synthetic polymers, biopolymers, carbon nanotubes, chitosan, and metal oxides, are explained. In addition, the integration of cellulose electro-active paper is highlighted to form various functional devices including but not limited to bending actuators, flexible speaker, strain sensors, energy harvesting transducers, biosensors, chemical sensors and transistors for electronic applications. The frontiers in cellulose paper devices are reviewed together with the strategies and perspectives of cellulose electro-active paper and cellulose nanocomposite research and applications.

  9. Induction of aryl hydrocarbon receptor-mediated and estrogen receptor-mediated activities, and modulation of cell proliferation by dinaphthofurans

    Czech Academy of Sciences Publication Activity Database

    Vondráček, Jan; Chramostová, Kateřina; Plíšková, M.; Bláha, L.; Brack, W.; Kozubík, Alois; Machala, M.

    2004-01-01

    Roč. 23, č. 9 (2004), s. 2214-2220 ISSN 0730-7268 R&D Projects: GA ČR GA525/03/1527 Institutional research plan: CEZ:AV0Z5004920 Keywords : aryl hydrocarbon receptor-mediated activity * estrogenicity * intercellular communication inhibition Subject RIV: BO - Biophysics Impact factor: 2.121, year: 2004

  10. TiO2/carbon nanotube hybrid nanostructures: Solvothermal synthesis and their visible light photocatalytic activity

    International Nuclear Information System (INIS)

    Tian Lihong; Ye Liqun; Deng Kejian; Zan Ling

    2011-01-01

    MWCNT/TiO 2 hybrid nanostructures were prepared via solvothermal synthesis and sol-gel method with benzyl alcohol as a surfactant. As-prepared hybrid materials were characterized by X-ray diffraction, transmission electron microscopy, UV-vis diffuse reflectance spectra and X-ray photoelectron spectroscopy. The results showed that MWCNTs were uniformly decorated with anatase nanocrystals in solvothermal condition, but MWCNTs were embedded in a majority of TiO 2 nanoparticles by sol-gel method. When the weight ratio of MWCNTs to TiO 2 was 20%, MWCNT/TiO 2 hybrid nanostructures prepared by solvothermal synthesis exhibited higher visible-light-driven photocatalytic activity than that prepared by sol-gel method. Post-annealing of MWCNT/TiO 2 nanostructures at 400 deg. C resulted in the formation of the carbonaceous Ti-C bonds on the interface between TiO 2 and MWCNTs, which enhanced the photoabsorbance of the hybrid materials in the visible light region and improved the visible-light degradation efficiency of methylene blue. - Graphical abstract: MWCNT/TiO 2 nanostructures have been prepared by solvothermal method, which exhibited higher visible-light-driven photocatalytic activity than that prepared by sol-gel method. The carbonaceous Ti-C bonds on the interface between TiO 2 and MWCNTs enhanced the photoabsorbance of the hybrid materials in the visible light region. Highlights: → Anatase TiO 2 nanoparticles were anchored on CNTs surface uniformly via solvothermal method → The morphology facilitated the electron transfer between CNTs and TiO 2 → Ti-C bonds extended the absorption of MWCNT/TiO 2 to the whole visible light region. → The hybrid nanostructures showed enhanced visible-light induced photocatalytic activity.

  11. A Hybrid Estimator for Active/Reactive Power Control of Single-Phase Distributed Generation Systems with Energy Storage

    DEFF Research Database (Denmark)

    Pahlevani, Majid; Eren, Suzan; Guerrero, Josep M.

    2016-01-01

    This paper presents a new active/reactive power closed-loop control system for a hybrid renewable energy generation system used for single-phase residential/commercial applications. The proposed active/reactive control method includes a hybrid estimator, which is able to quickly and accurately es...

  12. Quantitative structure-activity relationships of selective antagonists of glucagon receptor using QuaSAR descriptors.

    Science.gov (United States)

    Manoj Kumar, Palanivelu; Karthikeyan, Chandrabose; Hari Narayana Moorthy, Narayana Subbiah; Trivedi, Piyush

    2006-11-01

    In the present paper, quantitative structure activity relationship (QSAR) approach was applied to understand the affinity and selectivity of a novel series of triaryl imidazole derivatives towards glucagon receptor. Statistically significant and highly predictive QSARs were derived for glucagon receptor inhibition by triaryl imidazoles using QuaSAR descriptors of molecular operating environment (MOE) employing computer-assisted multiple regression procedure. The generated QSAR models revealed that factors related to hydrophobicity, molecular shape and geometry predominantly influences glucagon receptor binding affinity of the triaryl imidazoles indicating the relevance of shape specific steric interactions between the molecule and the receptor. Further, QSAR models formulated for selective inhibition of glucagon receptor over p38 mitogen activated protein (MAP) kinase of the compounds in the series highlights that the same structural features, which influence the glucagon receptor affinity, also contribute to their selective inhibition.

  13. Differential Regulation of Receptor Activation and Agonist Selectivity by Highly Conserved Tryptophans in the Nicotinic Acetylcholine Receptor Binding Site

    OpenAIRE

    Williams, Dustin K.; Stokes, Clare; Horenstein, Nicole A.; Papke, Roger L.

    2009-01-01

    We have shown previously that a highly conserved Tyr in the nicotinic acetylcholine receptor (nAChR) ligand-binding domain (LBD) (α7 Tyr188 or α4 Tyr195) differentially regulates the activity of acetylcholine (ACh) and the α7-selective agonist 3-(4-hydroxy,2-methoxybenzylidene)anabaseine (4OH-GTS-21) in α4β2 and α7 nAChR. In this study, we mutated two highly conserved LBD Trp residues in human α7 and α4β2 and expressed the receptors in Xenopus laevis oocytes. α7 Re...

  14. Sulindac metabolites inhibit epidermal growth factor receptor activation and expression

    Directory of Open Access Journals (Sweden)

    Ahnen Dennis

    2005-01-01

    Full Text Available Abstract Background Regular use of nonsteroidal anti-inflammatory drugs (NSAIDs is associated with a decreased mortality from colorectal cancer (CRC. NSAIDs induce apoptotic cell death in colon cancer cells in vitro and inhibit growth of neoplastic colonic mucosa in vivo however, the biochemical mechanisms required for these growth inhibitory effects are not well defined. We previously reported that metabolites of the NSAID sulindac downregulate extracellular-signal regulated kinase 1/2 (ERK1/2 signaling and that this effect is both necessary and sufficient for the apoptotic effects of these drugs. The goal of this project was to specifically test the hypothesis that sulindac metabolites block activation and/or expression of the epidermal growth factor (EGF receptor (EGFR. Methods HT29 human colon cancer cells were treated with EGF, alone, or in the presence of sulindac sulfide or sulindac sulfone. Cells lysates were assayed by immunoblotting for phosphorylated EGFR (pEGFR, pY1068, total EGFR, phosphorylated ERK1/2 (pERK1/2, total ERK1/2, activated caspase-3, and α-tubulin. Results EGF treatment rapidly induced phosphorylation of both EGFR and ERK1/2 in HT29 colon cancer cells. Pretreatment with sulindac metabolites for 24 h blocked EGF-induced phosphorylation of both EGFR and ERK1/2 and decreased total EGFR protein expression. Under basal conditions, downregulation of pEGFR and total EGFR was detected as early as 12 h following sulindac sulfide treatment and persisted through at least 48 h. Sulindac sulfone induced downregulation of pEGFR and total EGFR was detected as early as 1 h and 24 h, respectively, following drug treatment, and persisted through at least 72 h. EGFR downregulation by sulindac metabolites was observed in three different CRC cell lines, occurred prior to the observed downregulation of pERK1/2 and induction of apoptosis by these drugs, and was not dependent of caspase activation. Conclusion These results suggest that

  15. Ligand-independent Thrombopoietin Mutant Receptor Requires Cell Surface Localization for Endogenous Activity*

    OpenAIRE

    Marty, Caroline; Chaligné, Ronan; Lacout, Catherine; Constantinescu, Stefan N.; Vainchenker, William; Villeval, Jean-Luc

    2009-01-01

    The activating W515L mutation in the thrombopoietin receptor (MPL) has been identified in primary myelofibrosis and essential thrombocythemia. MPL belongs to a subset of the cytokine receptor superfamily that requires the JAK2 kinase for signaling. We examined whether the ligand-independent MPLW515L mutant could signal intracellularly. Addition of the endoplasmic reticulum (ER) retention KDEL sequence to the receptor C terminus efficiently locked MPLW515L within its na...

  16. Molecular Vibration-Activity Relationship in the Agonism of Adenosine Receptors

    OpenAIRE

    Chee, Hyun Keun; Oh, S. June

    2013-01-01

    The molecular vibration-activity relationship in the receptor-ligand interaction of adenosine receptors was investigated by structure similarity, molecular vibration, and hierarchical clustering in a dataset of 46 ligands of adenosine receptors. The resulting dendrogram was compared with those of another kind of fingerprint or descriptor. The dendrogram result produced by corralled intensity of molecular vibrational frequency outperformed four other analyses in the current study of adenosine ...

  17. Overview of PV Wind hybrid system activities in Germany

    Energy Technology Data Exchange (ETDEWEB)

    Bopp, G.; Gabler, H.; Kiefer, K.; Preiser, K.; Wiemken, E. [Fraunhofer Institute for Solar Energy Systems ISE, Freiburg (Germany)

    1997-12-31

    Photovoltaic solar generators combined with diesel engines, in some cases additionally with wind energy converters, and battery energy storage are powering isolated mountain lodges, information centers in nature parks, isolated farms or dwellings all over Europe. A total of 300,000 buildings in Europe are estimated to be not connected to the public grid. This represents a major market potential for photovoltaic, as often photovoltaic power generation is less expensive than a connection to the electric utility. The Fraunhofer Institute for Solar Energy Systems ISE has planned, realized and monitored about 30 hybrid remote energy supply systems with PV generators typically around 5 kW for loads typically around 20 kWh per day. More than one hundred years of operational experience accumulated so far, are a sound foundation on which to draw an interim balance over problems solved and technical questions still under development. Room for further technical development is seen in the domain of system reliability and the reduction of operating costs as well as in the optimization of the utilization of the electric energy produced by the PV generator. [Espanol] Para la electrificacion en toda Europa de casas de campo en la montana, centros de informacion, parques naturales, granjas aisladas o conjuntos habitacionales, se estan usando generadores fotovoltaicos combinados con maquinas diesel, en algunos casos adicionalmente con convertidores de energia del viento y baterias para el almacenamiento de energia. Se estima que en Europa un total de 300,000 edificios no estan conectados a la red publica. Esto representa un gran mercado potencial para los sistemas fotovoltaicos, ya que a menudo la generacion fotovoltaica es menos costosa que una conexion a la empresa electrica. El Instituto Fraunhofer para Sistemas de Energia Solar ISE ha planeado, llevado a cabo y monitoreado alrededor de 30 sistemas hibridos remotos de suministro de energia con generadores fotovoltaicos

  18. Overview of PV Wind hybrid system activities in Germany

    Energy Technology Data Exchange (ETDEWEB)

    Bopp, G; Gabler, H; Kiefer, K; Preiser, K; Wiemken, E [Fraunhofer Institute for Solar Energy Systems ISE, Freiburg (Germany)

    1998-12-31

    Photovoltaic solar generators combined with diesel engines, in some cases additionally with wind energy converters, and battery energy storage are powering isolated mountain lodges, information centers in nature parks, isolated farms or dwellings all over Europe. A total of 300,000 buildings in Europe are estimated to be not connected to the public grid. This represents a major market potential for photovoltaic, as often photovoltaic power generation is less expensive than a connection to the electric utility. The Fraunhofer Institute for Solar Energy Systems ISE has planned, realized and monitored about 30 hybrid remote energy supply systems with PV generators typically around 5 kW for loads typically around 20 kWh per day. More than one hundred years of operational experience accumulated so far, are a sound foundation on which to draw an interim balance over problems solved and technical questions still under development. Room for further technical development is seen in the domain of system reliability and the reduction of operating costs as well as in the optimization of the utilization of the electric energy produced by the PV generator. [Espanol] Para la electrificacion en toda Europa de casas de campo en la montana, centros de informacion, parques naturales, granjas aisladas o conjuntos habitacionales, se estan usando generadores fotovoltaicos combinados con maquinas diesel, en algunos casos adicionalmente con convertidores de energia del viento y baterias para el almacenamiento de energia. Se estima que en Europa un total de 300,000 edificios no estan conectados a la red publica. Esto representa un gran mercado potencial para los sistemas fotovoltaicos, ya que a menudo la generacion fotovoltaica es menos costosa que una conexion a la empresa electrica. El Instituto Fraunhofer para Sistemas de Energia Solar ISE ha planeado, llevado a cabo y monitoreado alrededor de 30 sistemas hibridos remotos de suministro de energia con generadores fotovoltaicos

  19. New porphyrin-polyoxometalate hybrid materials: synthesis, characterization and investigation of catalytic activity in acetylation reactions.

    Science.gov (United States)

    Araghi, Mehdi; Mirkhani, Valiollah; Moghadam, Majid; Tangestaninejad, Shahram; Mohammdpoor-Baltork, Iraj

    2012-10-14

    New hybrid complexes based on covalent interaction between 5,10,15,20-tetrakis(4-aminophenyl)porphyrinatozinc(II) and 5,10,15,20-tetrakis(4-aminophenyl)porphyrinatotin(IV) chloride, and a Lindqvist-type polyoxometalate, Mo(6)O(19)(2-), were prepared. These new porphyrin-polyoxometalate hybrid materials were characterized by (1)H NMR, FT IR and UV-Vis spectroscopic methods and cyclic voltammetry. These spectro- and electrochemical studies provided several spectral data for synthesis of these compounds. Cyclic voltammetry showed the influence of the polyoxometalate on the redox process of the porphyrin ring. The catalytic activity of tin(IV)porphyrin-hexamolybdate hybrid material was investigated in the acetylation of alcohols and phenols with acetic anhydride. The reusability of this catalyst was also investigated.

  20. Identification of potential regional sources of atmospheric total gaseous mercury in Windsor, Ontario, Canada using hybrid receptor modeling

    Directory of Open Access Journals (Sweden)

    X. Xu

    2010-08-01

    Full Text Available Windsor (Ontario, Canada experiences trans-boundary air pollution as it is located on the border immediately downwind of industrialized regions of the United States of America. A study was conducted in 2007 to identify the potential regional sources of total gaseous mercury (TGM and investigate the effects of regional sources and other factors on seasonal variability of TGM concentrations in Windsor.

    TGM concentration was measured at the University of Windsor campus using a Tekran® 2537A Hg vapour analyzer. An annual mean of 2.02±1.63 ng/m3 was observed in 2007. The average TGM concentration was high in the summer (2.48±2.68 ng/m3 and winter (2.17±2.01 ng/m3, compared to spring (1.88±0.78 ng/m3 and fall (1.76±0.58 ng/m3. Hybrid receptor modeling potential source contribution function (PSCF was used by incorporating 72-h backward trajectories and measurements of TGM in Windsor. The results of PSCF were analyzed in conjunction with the Hg emissions inventory of North America (by state/province to identify regions affecting Windsor. In addition to annual modeling, seasonal PSCF modeling was also conducted. The potential source region was identified between 24–61° N and 51–143° W. Annual PSCF modeling identified major sources southwest of Windsor, stretching from Ohio to Texas. The emissions inventory also supported the findings, as Hg emissions were high in those regions. Results of seasonal PSCF modeling were analyzed to find the combined effects of regional sources, meteorological conditions, and surface re-emissions, on seasonal variability of Hg concentrations. It was found that the summer and winter highs of atmospheric Hg can be attributed to areas where large numbers of coal fired power plants are located in the USA. Weak atmospheric dispersion due to low winds and high re-emission from surfaces due to higher temperatures also contributed to high concentrations in

  1. Adenosine A2A Receptor Modulates the Activity of Globus Pallidus Neurons in Rats

    Directory of Open Access Journals (Sweden)

    Hui-Ling Diao

    2017-11-01

    Full Text Available The globus pallidus is a central nucleus in the basal ganglia motor control circuit. Morphological studies have revealed the expression of adenosine A2A receptors in the globus pallidus. To determine the modulation of adenosine A2A receptors on the activity of pallidal neurons in both normal and parkinsonian rats, in vivo electrophysiological and behavioral tests were performed in the present study. The extracellular single unit recordings showed that micro-pressure administration of adenosine A2A receptor agonist, CGS21680, regulated the pallidal firing activity. GABAergic neurotransmission was involved in CGS21680-induced modulation of pallidal neurons via a PKA pathway. Furthermore, application of two adenosine A2A receptor antagonists, KW6002 or SCH442416, mainly increased the spontaneous firing of pallidal neurons, suggesting that endogenous adenosine system modulates the activity of pallidal neurons through adenosine A2A receptors. Finally, elevated body swing test (EBST showed that intrapallidal microinjection of adenosine A2A receptor agonist/antagonist induced ipsilateral/contralateral-biased swing, respectively. In addition, the electrophysiological and behavioral findings also revealed that activation of dopamine D2 receptors by quinpirole strengthened KW6002/SCH442416-induced excitation of pallidal activity. Co-application of quinpirole with KW6002 or SCH442416 alleviated biased swing in hemi-parkinsonian rats. Based on the present findings, we concluded that pallidal adenosine A2A receptors may be potentially useful in the treatment of Parkinson's disease.

  2. The Power Quality Compensation Strategy for Power Distribution System Based on Hybrid Parallel Active Power Filters

    Directory of Open Access Journals (Sweden)

    Rachid DEHINI

    2010-12-01

    Full Text Available In this paper, the main aim is to confront the performance of shunt active power filter (SAPF and the shunt hybrid active power filter (SHAPF to achieve flexibility and reliability of the filter devices. Both of the two devices used the classical proportional-integral controller for pulse generation to trigger the inventers MOSFET’s. In the adopted hybrid active filter there is a passive power filter with high power rating to filter the low order harmonies and one active filter with low power rating to filter the other high order harmonies. In order to investigate the effectiveness of (SHAPF, the studies have been accomplished using simulation with the MATLAB-SIMULINK. The results show That (SHAPF is more effective than (SAPF, and has lower cost.

  3. Insulin receptor binding and protein kinase activity in muscles of trained rats

    International Nuclear Information System (INIS)

    Dohm, G.L.; Sinha, M.K.; Caro, J.F.

    1987-01-01

    Exercise has been shown to increase insulin sensitivity, and muscle is quantitatively the most important tissue of insulin action. Since the first step in insulin action is the binding to a membrane receptor, the authors postulated that exercise training would change insulin receptors in muscle and in this study they have investigated this hypothesis. Female rats initially weighing ∼ 100 g were trained by treadmill running for 2 h/day, 6 days/wk for 4 wk at 25 m/min (0 grade). Insulin receptors from vastus intermedius muscles were solubilized by homogenizing in a buffer containing 1% Triton X-100 and then partially purified by passing the soluble extract over a wheat germ agglutinin column. The 4 wk training regimen resulted in a 65% increase in citrate synthase activity in red vastus lateralis muscle, indicating an adaptation to exercise [ 125 I]. Insulin binding by the partially purified receptor preparations was approximately doubled in muscle of trained rats at all insulin concentrations, suggesting an increase in the number of receptors. Training did not alter insulin receptor structure as evidenced by electrophoretic mobility under reducing and nonreducing conditions. Basal insulin receptor protein kinase activity was higher in trained than untrained animals and this was likely due to the greater number of receptors. However, insulin stimulation of the protein kinase activity was depressed by training. These results demonstrate that endurance training does alter receptor number and function in muscle and these changes may be important in increasing insulin sensitivity after exercise training

  4. Purification of the active C5a receptor from human polymorphonuclear leukocytes as a receptor - G sub i complex

    Energy Technology Data Exchange (ETDEWEB)

    Rollins, T.E.; Siciliano, S.; Kobayashi, S.; Cianciarulo, D.N.; Bonilla-Argudo, V.; Collier, K.; Springer, M.S. (Merck Sharp and Dohme Research Lab., Rahway, NJ (United States))

    1991-02-01

    The authors have isolated, in an active state, the C5a receptor from human polymorphonuclear leukocytes. The purification was achieved in a single step using a C5a affinity column in which the C5a molecule was coupled to the resin through its N terminus. The purified receptor, like the crude solubilized molecule, exhibited a single class of high-affinity binding sites with a K{sub d} of 30 pM. Further, the binding of C5a retained its sensitivity to guanine nucleotides, implying that the purified receptor contained a guanine nucleotide-binding protein (G protein). SDS/PAGE revealed the presence of three polypeptides with molecular masses of 42, 40, and 36 kDa, which were determined to be the C5a-binding subunit and the {alpha} and {beta} subunits of G{sub i}, respectively. The 36- and 40-kDa polypeptides were identified by immunoblotting and by the ability of pertussis toxin to ADP-ribosylate the 40-kDa molecule. These results confirm their earlier hypothesis that the receptor exists as a complex with a G protein in the presence or absence of C5a. The tight coupling between the receptor and G protein should make possible the identification of the G protein(s) involved in the transduction pathways used by C5a to produce its many biological effects.

  5. Purification of the active C5a receptor from human polymorphonuclear leukocytes as a receptor - Gi complex

    International Nuclear Information System (INIS)

    Rollins, T.E.; Siciliano, S.; Kobayashi, S.; Cianciarulo, D.N.; Bonilla-Argudo, V.; Collier, K.; Springer, M.S.

    1991-01-01

    The authors have isolated, in an active state, the C5a receptor from human polymorphonuclear leukocytes. The purification was achieved in a single step using a C5a affinity column in which the C5a molecule was coupled to the resin through its N terminus. The purified receptor, like the crude solubilized molecule, exhibited a single class of high-affinity binding sites with a K d of 30 pM. Further, the binding of C5a retained its sensitivity to guanine nucleotides, implying that the purified receptor contained a guanine nucleotide-binding protein (G protein). SDS/PAGE revealed the presence of three polypeptides with molecular masses of 42, 40, and 36 kDa, which were determined to be the C5a-binding subunit and the α and β subunits of G i , respectively. The 36- and 40-kDa polypeptides were identified by immunoblotting and by the ability of pertussis toxin to ADP-ribosylate the 40-kDa molecule. These results confirm their earlier hypothesis that the receptor exists as a complex with a G protein in the presence or absence of C5a. The tight coupling between the receptor and G protein should make possible the identification of the G protein(s) involved in the transduction pathways used by C5a to produce its many biological effects

  6. Ionic liquid mediated stereoselective synthesis of alanine linked hybrid quinazoline-4(3H)-one derivatives perturbing the malarial reductase activity in folate pathway.

    Science.gov (United States)

    Patel, Tarosh S; Bhatt, Jaimin D; Vanparia, Satish F; Patel, Urmila H; Dixit, Ritu B; Chudasama, Chaitanya J; Patel, Bhavesh D; Dixit, Bharat C

    2017-12-15

    Grimmel's method was optimized as well as modified leading to the cyclization and incorporation of alanine linked sulphonamide in 4-quinazolin-(3H)-ones. Further, the generation of heterocyclic motif at position-3 of 4-quinazolinones was explored by synthesis of imines, which unfortunately led to an isomeric mixture of stereoisomers. The hurdle of diastereomers encountered on the path was eminently rectified by development of new rapid and reproducible methodology involving the use of imidazolium based ionic liquid as solvents as well as catalyst for cyclization as well as synthesis of imines in situ at position-3 leading to procurement of single E-isomer as the target hybrid heterocyclic molecules. The purity and presence of single isomer was also confirmed by HPLC and spectroscopic techniques. Further, the synthesized sulphonamide linked 4-quinazolin-(3H)-ones hybrids were screened for their antimalarial potency rendering potent entities (4b, 4c, 4 l, 4 t and 4u). The active hybrids were progressively screened for enzyme inhibitory efficacy against presumed receptor Pf-DHFR and h-DHFR computationally as well as in vitro, proving their potency as dihydrofolate reductase inhibitors. The ADME properties of these active molecules were also predicted to enhance the knowhow of the oral bioavailability, indicating good bioavailability of the active entities. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Analysis of the epidermal growth factor receptor specific transcriptome: effect of receptor expression level and an activating mutation

    DEFF Research Database (Denmark)

    Pedersen, Mikkel W; Pedersen, Nina; Damstrup, Lars

    2005-01-01

    moderately expressed or overexpressed at an in-itself transforming level. These changes were compared to those induced by the naturally occurring constitutively active variant EGFRvIII. This study provides novel insight on the activities and mechanisms of EGFRvIII and EGFR mediated transformation, as genes...... by interferons. Expression of this module was absent in the EGFRvIII-expressing cell line and the parental cell line. Treatment with the specific EGFR inhibitor AG1478 indicated that the regulations were primary, receptor-mediated events. Furthermore, activation of this module correlated with activation of STAT1...

  8. Regioselective synthesis of isoxazole-mercaptobenzimidazole hybrids and their in vivo analgesic and anti-inflammatory activity studies

    DEFF Research Database (Denmark)

    Kankala, Shravankumar; Kankala, Ranjith Kumar; Gundepaka, Prasad

    2013-01-01

    Regioselective synthesis of isoxazole-mercaptobenzimidazole hybrids and their efficiency in in vivo analgesic and anti-inflammatory activity was described. A comparison of structure-activity relationship for there compounds was also emphasized....

  9. 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.

  10. Root activity and soil feeding zones of some Bajra hybrids (Pennisetum typhoids Stapf.)

    International Nuclear Information System (INIS)

    Shriniwas

    1980-01-01

    Root activity and soil feeding zones of five bajra hybrids (Hybrid D-356, HB-3, HB-4, HB-1 and Bil-3B) were determined under natural field conditions by placement of 32 P labelled superphosphate enclosed in gelatinous capsules at different soil locations around the plant. Percent root activity varied significantly from one depth to another and it decreased with increase in depths and lateral distances. More than 44 percent of the root activity occurred in a soil feeding zone consisting of 0-15 cm depth having double of this much lateral distance. Percent root activity in HB-3 and HB-4 was almost found identical both horizontally and vertically. Hybrid D-356 and HB-1 approximated more than 38 percent root activity in a soil feeding zone of 0-15 cm in depth and 0-10 cm in lateral distance. 32 P placement in capsules appeared to hold promise over Hall's technique since it overcomes the differences caused by disturbance of the feeding activity of roots at the point of 32 P injection into the soil. (author)

  11. Shunt hybrid active power filter for harmonic mitigation: A practical ...

    Indian Academy of Sciences (India)

    2016-08-26

    Aug 26, 2016 ... The increasing importance of Power Quality problems has been responsible for several improvements in Active Power Filter (APF) typologies in the last decade. The increased cost and switching losses make a pure shunt APF economically impractical for high power applications. In higher power levels ...

  12. Reversal of metabolic disorders by pharmacological activation of bile acid receptors TGR5 and FXR

    Directory of Open Access Journals (Sweden)

    Kavita Jadhav

    2018-03-01

    Full Text Available Objectives: Activation of the bile acid (BA receptors farnesoid X receptor (FXR or G protein-coupled bile acid receptor (GPBAR1; TGR5 improves metabolic homeostasis. In this study, we aim to determine the impact of pharmacological activation of bile acid receptors by INT-767 on reversal of diet-induced metabolic disorders, and the relative contribution of FXR vs. TGR5 to INT-767's effects on metabolic parameters. Methods: Wild-type (WT, Tgr5−/−, Fxr−/−, Apoe−/− and Shp−/− mice were used to investigate whether and how BA receptor activation by INT-767, a semisynthetic agonist for both FXR and TGR5, could reverse diet-induced metabolic disorders. Results: INT-767 reversed HFD-induced obesity dependent on activation of both TGR5 and FXR and also reversed the development of atherosclerosis and non-alcoholic fatty liver disease (NAFLD. Mechanistically, INT-767 improved hypercholesterolemia by activation of FXR and induced thermogenic genes via activation of TGR5 and/or FXR. Furthermore, INT-767 inhibited several lipogenic genes and de novo lipogenesis in the liver via activation of FXR. We identified peroxisome proliferation-activated receptor γ (PPARγ and CCAAT/enhancer-binding protein α (CEBPα as novel FXR-regulated genes. FXR inhibited PPARγ expression by inducing small heterodimer partner (SHP whereas the inhibition of CEBPα by FXR was SHP-independent. Conclusions: BA receptor activation can reverse obesity, NAFLD, and atherosclerosis by specific activation of FXR or TGR5. Our data suggest that, compared to activation of FXR or TGR5 only, dual activation of both FXR and TGR5 is a more attractive strategy for treatment of common metabolic disorders. Keywords: Farnesoid X receptor, TGR5, Atherosclerosis, Obesity, NAFLD

  13. A Molecular Mechanism for Sequential Activation of a G Protein-Coupled Receptor

    DEFF Research Database (Denmark)

    Grundmann, Manuel; Tikhonova, Irina G; Hudson, Brian D

    2016-01-01

    Ligands targeting G protein-coupled receptors (GPCRs) are currently classified as either orthosteric, allosteric, or dualsteric/bitopic. Here, we introduce a new pharmacological concept for GPCR functional modulation: sequential receptor activation. A hallmark feature of this is a stepwise ligand...

  14. The minor binding pocket: a major player in 7TM receptor activation

    DEFF Research Database (Denmark)

    Rosenkilde, Mette Marie; Benned-Jensen, Tau; Frimurer, Thomas M.

    2010-01-01

    residue located in one of two adjacent positions. Here we argue that this minor binding pocket is important for receptor activation. Functional coupling of the receptors seems to be mediated through the hydrogen bond network located between the intracellular segments of these TMs, with the allosteric...... targeted in the development of functionally biased drugs....

  15. PKCζ regulates Notch receptor routing and activity in a Notch signaling-dependent manner

    NARCIS (Netherlands)

    Sjöqvist, M.; Antfolk, D.; Ferraris, S.; Rraklli, V.; Haga, C.; Antila, C.; Mutvei, A.; Imanishi, S.Y.; Holmberg, J.; Jin, S.; Eriksson, J.E.; Lendahl, U.; Sahlgren, C.M.

    Activation of Notch signaling requires intracellular routing of the receptor, but the mechanisms controlling the distinct steps in the routing process is poorly understood. We identify PKCζ as a key regulator of Notch receptor intracellular routing. When PKCζ was inhibited in the developing chick

  16. IMPROVED TUMOR CELL KILLING BY TRAIL REQUIRES SELECTIVE AND HIGH AFFINITY RECEPTOR ACTIVATION

    NARCIS (Netherlands)

    Szegezdi, Eva; van der Sloot, Almer M.; Alessandro, Natoni; Mahalingam, Devalingam; Cool, Robbert H.; Munoz, Ines G.; Montoya, Guillermo; Quax, Wim J.; Luis Serrano, Steven de Jong; Samali, Afshin; Wallach, D; Kovalenko, A; Feldman, M

    2011-01-01

    Apoptosis can be activated by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in a wide range of tumor cells, but not in non-transformed cells. TRAIL interaction with receptors DR4 or DR5 induces apoptosis, whereas DcR1, DcR2 and osteoprotegerin are decoy receptors for TRAIL. TRAIL

  17. Interaction between the p21ras GTPase activating protein and the insulin receptor

    NARCIS (Netherlands)

    Pronk, G.J.; Medema, R.H.; Burgering, B.M.T.; Clark, R.; McCormick, F.; Bos, J.L.

    1992-01-01

    We investigated the involvement of the p21ras-GTPase activating protein (GAP) in insulin-induced signal transduction. In cells overexpressing the insulin receptor, we did not observe association between GAP and the insulin receptor after insulin treatment nor the phosphorylation of GAP on tyrosine

  18. Distinct conformational changes in activated agonist-bound and agonist-free glycine receptor subunits

    DEFF Research Database (Denmark)

    Pless, Stephan Alexander; Lynch, Joseph W

    2009-01-01

    Ligand binding to Cys-loop receptors produces either global conformational changes that lead to activation or local conformational changes that do not. We found that the fluorescence of a fluorophore tethered to R271C in the extracellular M2 region of the alpha1 glycine receptor increases during ...

  19. Signaling cross-talk between peroxisome proliferator-activated receptor/retinoid X receptor and estrogen receptor through estrogen response elements.

    Science.gov (United States)

    Keller, H; Givel, F; Perroud, M; Wahli, W

    1995-07-01

    Peroxisome proliferator-activated receptors (PPARs) and retinoid X receptors (RXRs) are nuclear hormone receptors that are activated by fatty acids and 9-cis-retinoic acid, respectively. PPARs and RXRs form heterodimers that activate transcription by binding to PPAR response elements (PPREs) in the promoter of target genes. The PPREs described thus far consist of a direct tandem repeat of the AGGTCA core element with one intervening nucleotide. We show here that the vitellogenin A2 estrogen response element (ERE) can also function as a PPRE and is bound by a PPAR/RXR heterodimer. Although this heterodimer can bind to several other ERE-related palindromic response elements containing AGGTCA half-sites, only the ERE is able to confer transactivation of test reporter plasmids, when the ERE is placed either close to or at a distance from the transcription initiation site. Examination of natural ERE-containing promoters, including the pS2, very-low-density apolipoprotein II and vitellogenin A2 genes, revealed considerable differences in the binding of PPAR/RXR heterodimers to these EREs. In their natural promoter context, these EREs did not allow transcriptional activation by PPARs/RXRs. Analysis of this lack of stimulation of the vitellogenin A2 promoter demonstrated that PPARs/RXRs bind to the ERE but cannot transactivate due to a nonpermissive promoter structure. As a consequence, PPARs/RXRs inhibit transactivation by the estrogen receptor through competition for ERE binding. This is the first example of signaling cross-talk between PPAR/RXR and estrogen receptor.

  20. Effect of propofol on androgen receptor activity in prostate cancer cells.

    Science.gov (United States)

    Tatsumi, Kenichiro; Hirotsu, Akiko; Daijo, Hiroki; Matsuyama, Tomonori; Terada, Naoki; Tanaka, Tomoharu

    2017-08-15

    Androgen receptor is a nuclear receptor and transcription factor activated by androgenic hormones. Androgen receptor activity plays a pivotal role in the development and progression of prostate cancer. Although accumulating evidence suggests that general anesthetics, including opioids, affect cancer cell growth and impact patient prognosis, the effect of those drugs on androgen receptor in prostate cancer is not clear. The purpose of this study was to investigate the effect of the general anesthetic propofol on androgen receptor activity in prostate cancer cells. An androgen-dependent human prostate cancer cell line (LNCaP) was stimulated with dihydrotestosterone (DHT) and exposed to propofol. The induction of androgen receptor target genes was investigated using real-time reverse transcription polymerase chain reaction, and androgen receptor protein levels and localization patterns were analyzed using immunoblotting and immunofluorescence assays. The effect of propofol on the proliferation of LNCaP cells was analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Propofol significantly inhibited DHT-induced expression of androgen receptor target genes in a dose- and time-dependent manner, and immunoblotting and immunofluorescence assays indicated that propofol suppressed nuclear levels of androgen receptor proteins. Exposure to propofol for 24h suppressed the proliferation of LNCaP cells, whereas 4h of exposure did not exert significant effects. Together, our results indicate that propofol suppresses nuclear androgen receptor protein levels, and inhibits androgen receptor transcriptional activity and proliferation in LNCaP cells. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Alternative activation of macrophages and pulmonary fibrosis are modulated by scavenger receptor, macrophage receptor with collagenous structure.

    Science.gov (United States)

    Murthy, Shubha; Larson-Casey, Jennifer L; Ryan, Alan J; He, Chao; Kobzik, Lester; Carter, A Brent

    2015-08-01

    Alternative activation of alveolar macrophages is linked to fibrosis following exposure to asbestos. The scavenger receptor, macrophage receptor with collagenous structure (MARCO), provides innate immune defense against inhaled particles and pathogens; however, a receptor for asbestos has not been identified. We hypothesized that MARCO acts as an initial signaling receptor for asbestos, polarizes macrophages to a profibrotic M2 phenotype, and is required for the development of asbestos-induced fibrosis. Compared with normal subjects, alveolar macrophages isolated from patients with asbestosis express higher amounts of MARCO and have greater profibrotic polarization. Arginase 1 (40-fold) and IL-10 (265-fold) were higher in patients. In vivo, the genetic deletion of MARCO attenuated the profibrotic environment and pulmonary fibrosis in mice exposed to chrysotile. Moreover, alveolar macrophages from MARCO(-/-) mice polarize to an M1 phenotype, whereas wild-type mice have higher Ym1 (>3.0-fold) and nearly 7-fold more active TGF-β1 in bronchoalveolar lavage (BAL) fluid (BALF). Arg(432) and Arg(434) in domain V of MARCO are required for the polarization of macrophages to a profibrotic phenotype as mutation of these residues reduced FIZZ1 expression (17-fold) compared with cells expressing MARCO. These observations demonstrate that a macrophage membrane protein regulates the fibrotic response to lung injury and suggest a novel target for therapeutic intervention. © FASEB.

  2. Novel role for proteinase-activated receptor 2 (PAR2) in membrane trafficking of proteinase-activated receptor 4 (PAR4).

    Science.gov (United States)

    Cunningham, Margaret R; McIntosh, Kathryn A; Pediani, John D; Robben, Joris; Cooke, Alexandra E; Nilsson, Mary; Gould, Gwyn W; Mundell, Stuart; Milligan, Graeme; Plevin, Robin

    2012-05-11

    Proteinase-activated receptors 4 (PAR(4)) is a class A G protein-coupled receptor (GPCR) recognized through the ability of serine proteases such as thrombin and trypsin to mediate receptor activation. Due to the irreversible nature of activation, a fresh supply of receptor is required to be mobilized to the cell surface for responsiveness to agonist to be sustained. Unlike other PAR subtypes, the mechanisms regulating receptor trafficking of PAR(4) remain unknown. Here, we report novel features of the intracellular trafficking of PAR(4) to the plasma membrane. PAR(4) was poorly expressed at the plasma membrane and largely retained in the endoplasmic reticulum (ER) in a complex with the COPI protein subunit β-COP1. Analysis of the PAR(4) protein sequence identified an arginine-based (RXR) ER retention sequence located within intracellular loop-2 (R(183)AR → A(183)AA), mutation of which allowed efficient membrane delivery of PAR(4). Interestingly, co-expression with PAR(2) facilitated plasma membrane delivery of PAR(4), an effect produced through disruption of β-COP1 binding and facilitation of interaction with the chaperone protein 14-3-3ζ. Intermolecular FRET studies confirmed heterodimerization between PAR(2) and PAR(4). PAR(2) also enhanced glycosylation of PAR(4) and activation of PAR(4) signaling. Our results identify a novel regulatory role for PAR(2) in the anterograde traffic of PAR(4). PAR(2) was shown to both facilitate and abrogate protein interactions with PAR(4), impacting upon receptor localization and cell signal transduction. This work is likely to impact markedly upon the understanding of the receptor pharmacology of PAR(4) in normal physiology and disease.

  3. Transcriptional activation by the thyroid hormone receptor through ligand-dependent receptor recruitment and chromatin remodelling

    DEFF Research Database (Denmark)

    Grøntved, Lars; Waterfall, Joshua J; Kim, Dong Wook

    2015-01-01

    A bimodal switch model is widely used to describe transcriptional regulation by the thyroid hormone receptor (TR). In this model, the unliganded TR forms stable, chromatin-bound complexes with transcriptional co-repressors to repress transcription. Binding of hormone dissociates co...

  4. The angiotensin II type 1 receptor antagonist Losartan binds and activates bradykinin B2 receptor signaling

    DEFF Research Database (Denmark)

    Bonde, Marie Mi; Olsen, Kristine Boisen; Erikstrup, Niels

    2011-01-01

    The angiotensin II type 1 receptor (AT1R) blocker (ARB) Losartan has cardioprotective effects during ischemia-reperfusion injury and inhibits reperfusion arrhythmias -effects that go beyond the benefits of lowering blood pressure. The renin-angiotensin and kallikrein-kinin systems are intricately...

  5. DMPD: Proximal effects of Toll-like receptor activation in dendritic cells. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17142025 Proximal effects of Toll-like receptor activation in dendritic cells. Watt...) (.svg) (.html) (.csml) Show Proximal effects of Toll-like receptor activation in dendritic cells. PubmedID... 17142025 Title Proximal effects of Toll-like receptor activation in dendritic ce

  6. Charge transfer properties and photoelectrocatalytic activity of TiO{sub 2}/MWCNT hybrid

    Energy Technology Data Exchange (ETDEWEB)

    Jiang Liaochuan [Nano Science Research Center, School of Chemistry and Chemical Engineering, South China University of Technology, 381 Wushan Road, Guangzhou 510640 (China); Zhang Weide, E-mail: zhangwd@scut.edu.c [Nano Science Research Center, School of Chemistry and Chemical Engineering, South China University of Technology, 381 Wushan Road, Guangzhou 510640 (China)

    2010-12-15

    The vertically aligned multiwalled carbon nanotube (MWCNT) arrays on tantalum foils were successfully coated with TiO{sub 2} nanoparticles by a hydrothermal process. The prepared TiO{sub 2}/MWCNT hybrid was characterized by scanning electron microscopy and transmission electron microscopy. The charge transfer properties and photocatalytic degradation of rhodamine B with and without bias potential under UV irradiation were investigated. The MWCNTs promoted the separation of photoinduced carriers in the TiO{sub 2}, thus enhanced photocatalytic activity. Applying bias potential on the photoanode further enhanced its catalytic activity. The efficient charge transportation and high photoelectrocatalytic activity towards degradation of rhodamine B made this hybrid material promising for photocatalyst and for the development of photoelectrical devices.

  7. Hybrid Active-Passive Microwave Photonic Filter with High Quality Factor

    International Nuclear Information System (INIS)

    En-Ming, Xu; Xin-Liang, Zhang; Li-Na, Zhou; Yu, Zhang; De-Xiu, Huang

    2009-01-01

    A hybrid high quality factor (Q-factor) microwave photonic filter with a cascaded active filter and a passive filter is presented and experimentally demonstrated. The active infinite impulse response filter is realized by a recirculating delay line loop with a semiconductor optical amplifier, and a much narrower 3 dB bandwidth of response peaks can be achieved. A passive finite impulse response filter is realized by an unbalance Mach–Zehnder interferometer, and it is cascaded to select the desired filter frequencies and to suppress the intermediate peaks. Compared with the purely active filter scheme, the free spectrum range and the Q-factor of the hybrid structure can be doubled. Stable operation and a high Q-factor of 362 are experimentally demonstrated

  8. Chaotic system synchronization with an unknown master model using a hybrid HOD active control approach

    Energy Technology Data Exchange (ETDEWEB)

    Du Shengzhi [Department of EAD, ICT Faculty, Tshwane University of Technology, Pretoria 0001 (South Africa); French South Africa Technical Institute of Electronics (F' SATIE), Tshwane University of Technology, Pretoria 0001 (South Africa)], E-mail: dushengzhi@gmail.com; Wyk, Barend J. van; Qi Guoyuan; Tu Chunling [French South Africa Technical Institute of Electronics (F' SATIE), Tshwane University of Technology, Pretoria 0001 (South Africa)

    2009-11-15

    In this paper, a hybrid method using active control and a High Order Differentiator (HOD) methodology is proposed to synchronize chaotic systems. Compared to some traditional active control methods, this new method can synchronize chaotic systems where only output states of the master system are available, i.e. the system is considered a black box. The HOD is used to estimate the derivative information of the master system followed by an active control methodology relying on HOD information. The Qi hyperchaotic system is used to verify the performance of this hybrid method. The proposed method is also compared to some traditional methods. Experimental results show that the proposed method has high synchronization precision and speed and is robust against uncertainties in the master system. The circus implements of the proposed synchronizing scheme are included in this paper. The simulation results show the feasibility of the proposed scheme.

  9. Synthesis, antimalarial activity and molecular docking of hybrid 4-aminoquinoline-1,3,5-triazine derivatives.

    Science.gov (United States)

    Bhat, Hans Raj; Singh, Udaya Pratap; Thakur, Anjali; Kumar Ghosh, Surajit; Gogoi, Kabita; Prakash, Anil; Singh, Ramendra K

    2015-10-01

    A series of novel hybrid 4-aminoquinoline 1,3,5-triazine derivatives was synthesized in a five-steps reaction and evaluated for their in vitro antimalarial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (RKL-2) strains of Plasmodium falciparum. Entire synthetic derivatives showed higher antimalarial activity on the sensitive strain while two compounds, viz., 9a and 9c displayed good activity against both the strains of P. falciparum. The observed activity was further substantiated by docking study on both wild and qradruple mutant type P. falciparum dihydrofolate reductase-thymidylate synthase (pf-DHFR-TS). Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Hybridization of active and passive elements for planar photonic components and interconnects

    Science.gov (United States)

    Pearson, M.; Bidnyk, S.; Balakrishnan, A.

    2007-02-01

    The deployment of Passive Optical Networks (PON) for Fiber-to-the-Home (FTTH) applications currently represents the fastest growing sector of the telecommunication industry. Traditionally, FTTH transceivers have been manufactured using commodity bulk optics subcomponents, such as thin film filters (TFFs), micro-optic collimating lenses, TO-packaged lasers, and photodetectors. Assembling these subcomponents into a single housing requires active alignment and labor-intensive techniques. Today, the majority of cost reducing strategies using bulk subcomponents has been implemented making future reductions in the price of manufacturing FTTH transceivers unlikely. Future success of large scale deployments of FTTH depends on further cost reductions of transceivers. Realizing the necessity of a radically new packaging approach for assembly of photonic components and interconnects, we designed a novel way of hybridizing active and passive elements into a planar lightwave circuit (PLC) platform. In our approach, all the filtering components were monolithically integrated into the chip using advancements in planar reflective gratings. Subsequently, active components were passively hybridized with the chip using fully-automated high-capacity flip-chip bonders. In this approach, the assembly of the transceiver package required no active alignment and was readily suitable for large-scale production. This paper describes the monolithic integration of filters and hybridization of active components in both silica-on-silicon and silicon-on-insulator PLCs.

  11. Piezoelectric properties of the new generation active matrix hybrid (micro-nano) composites

    Energy Technology Data Exchange (ETDEWEB)

    Parali, Levent, E-mail: levent.parali@cbu.edu.tr [Department of Electronics and Automation, Celal Bayar University, Manisa (Turkey); Şabikoğlu, İsrafil [Department of Physics, Celal Bayar University, Manisa (Turkey); Kurbanov, Mirza A. [Institute of Physics, Academy of Sciences of Azerbaijan, Baku (Azerbaijan)

    2014-11-01

    Highlights: • We prepared hybrid structured piezocomposites. • We examine thermostimulated depolarization of piezocomposites. • We examine frequency characteristic of piezocomposites with SiO{sub 2} and BaTiO{sub 3}. • The piezocomposites can be used in acoustic applications at 5 Hz–40 kHz. - Abstract: A hybrid piezoelectric composite structure is obtained by addition of nano-sized BaTiO{sub 3}, SiO{sub 2} to the micro-sized PZT and polymers composition. Although the PZT material itself has excellent piezoelectric properties, PZT-based composite variety is limited. Piezoelectric properties of PZT materials can be varied with an acceptor or a donor added to the material. In addition, varieties of PZT-based sensors can be increased with doping polymers which have physical-mechanical, electrophysical, thermophysical and photoelectrical properties. The active matrix hybrid structure occurs when bringing together the unique piezoelectric properties of micro-sized PZT with electron trapping properties of nano-sized insulators (BaTiO{sub 3} or SiO{sub 2}), and their piezoelectric, mechanic and electromechanic properties significantly change. In this study, the relationship between the piezoelectric constant and the coupling factor values of microstructure (PZT–PVDF) and the hybrid structure (PZT–PVDF–BaTiO{sub 3}) composite are compared. The d{sub 33} value and the coupling factor of the hybrid structure have shown an average of 54 and 62% increase according to microstructure composite, respectively. In addition, the d{sub 33} value and the coupling factor of the hybrid structure (PZT–HDPE–SiO{sub 2}) have exhibited about 68 and 52% increase according to microstructure composite (PZT–HDPE), respectively.

  12. Active Fault Detection and Isolation for Hybrid Systems

    DEFF Research Database (Denmark)

    Gholami, Mehdi; Schiøler, Henrik; Bak, Thomas

    2009-01-01

    An algorithm for active fault detection and isolation is proposed. In order to observe the failure hidden due to the normal operation of the controllers or the systems, an optimization problem based on minimization of test signal is used. The optimization based method imposes the normal and faulty...... models predicted outputs such that their discrepancies are observable by passive fault diagnosis technique. Isolation of different faults is done by implementation a bank of Extended Kalman Filter (EKF) where the convergence criterion for EKF is confirmed by Genetic Algorithm (GA). The method is applied...

  13. Activation of peroxisome proliferator-activated receptor-α enhances fatty acid oxidation in human adipocytes

    International Nuclear Information System (INIS)

    Lee, Joo-Young; Hashizaki, Hikari; Goto, Tsuyoshi; Sakamoto, Tomoya; Takahashi, Nobuyuki; Kawada, Teruo

    2011-01-01

    Highlights: → PPARα activation increased mRNA expression levels of adipocyte differentiation marker genes and GPDH activity in human adipocytes. → PPARα activation also increased insulin-dependent glucose uptake in human adipocytes. → PPARα activation did not affect lipid accumulation in human adipocytes. → PPARα activation increased fatty acid oxidation through induction of fatty acid oxidation-related genes in human adipocytes. -- Abstract: Peroxisome proliferator-activated receptor-α (PPARα) is a key regulator for maintaining whole-body energy balance. However, the physiological functions of PPARα in adipocytes have been unclarified. We examined the functions of PPARα using human multipotent adipose tissue-derived stem cells as a human adipocyte model. Activation of PPARα by GW7647, a potent PPARα agonist, increased the mRNA expression levels of adipocyte differentiation marker genes such as PPARγ, adipocyte-specific fatty acid-binding protein, and lipoprotein lipase and increased both GPDH activity and insulin-dependent glucose uptake level. The findings indicate that PPARα activation stimulates adipocyte differentiation. However, lipid accumulation was not changed, which is usually observed when PPARγ is activated. On the other hand, PPARα activation by GW7647 treatment induced the mRNA expression of fatty acid oxidation-related genes such as CPT-1B and AOX in a PPARα-dependent manner. Moreover, PPARα activation increased the production of CO 2 and acid soluble metabolites, which are products of fatty acid oxidation, and increased oxygen consumption rate in human adipocytes. The data indicate that activation of PPARα stimulates both adipocyte differentiation and fatty acid oxidation in human adipocytes, suggesting that PPARα agonists could improve insulin resistance without lipid accumulation in adipocytes. The expected effects of PPARα activation are very valuable for managing diabetic conditions accompanied by obesity, because

  14. GABA-B receptor activation and conflict behavior

    International Nuclear Information System (INIS)

    Ketelaars, C.E.J.; Bollen, E.L.; Rigter, H.; Bruinvels, J.

    1988-01-01

    Baclofen and oxazepam enhance extinction of conflict behavior in the Geller-Seifter test while baclofen and diazepam release punished behavior in Vogel's conflict test. In order to investigate the possibility that the effect of the selective GABA-B receptor agonist baclofen is mediated indirectly via the GABA-A/benzodiazepine receptor complex, the effect of pretreatment of rats with baclofen on [ 3 H]-diazepam binding to washed and unwashed cortical and cerebellar membranes of rats has been studied. Baclofen pretreatment increase Bmax in washed cerebellar membranes when bicuculline was present in the incubation mixture. No effect was seen in cortical membranes. The present results render it unlikely that the effect of baclofen on extinction of conflict behavior and punished drinking is mediated via the GABA-A/benzodiazepine receptor complex. 50 references, 1 figure, 4 tables

  15. The insulin and IGF1 receptor kinase domains are functional dimers in the activated state

    Science.gov (United States)

    Cabail, M. Zulema; Li, Shiqing; Lemmon, Eric; Bowen, Mark E.; Hubbard, Stevan R.; Miller, W. Todd

    2015-03-01

    The insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R) are highly related receptor tyrosine kinases with a disulfide-linked homodimeric architecture. Ligand binding to the receptor ectodomain triggers tyrosine autophosphorylation of the cytoplasmic domains, which stimulates catalytic activity and creates recruitment sites for downstream signalling proteins. Whether the two phosphorylated tyrosine kinase domains within the receptor dimer function independently or cooperatively to phosphorylate protein substrates is not known. Here we provide crystallographic, biophysical and biochemical evidence demonstrating that the phosphorylated kinase domains of IR and IGF1R form a specific dimeric arrangement involving an exchange of the juxtamembrane region proximal to the kinase domain. In this dimer, the active position of α-helix C in the kinase N lobe is stabilized, which promotes downstream substrate phosphorylation. These studies afford a novel strategy for the design of small-molecule IR agonists as potential therapeutic agents for type 2 diabetes.

  16. The dopamine D2 receptor can directly recruit and activate GRK2 without G protein activation.

    Science.gov (United States)

    Pack, Thomas F; Orlen, Margo I; Ray, Caroline; Peterson, Sean M; Caron, Marc G

    2018-04-20

    The dopamine D2 receptor (D2R) is a G protein-coupled receptor (GPCR) that is critical for many central nervous system functions. The D2R carries out these functions by signaling through two transducers: G proteins and β-arrestins (βarrs). Selectively engaging either the G protein or βarr pathway may be a way to improve drugs targeting GPCRs. The current model of GPCR signal transduction posits a chain of events where G protein activation ultimately leads to βarr recruitment. GPCR kinases (GRKs), which are regulated by G proteins and whose kinase action facilitates βarr recruitment, bridge these pathways. Therefore, βarr recruitment appears to be intimately tied to G protein activation via GRKs. Here we sought to understand how GRK2 action at the D2R would be disrupted when G protein activation is eliminated and the effect of this on βarr recruitment. We used two recently developed biased D2R mutants that can preferentially interact either with G proteins or βarrs as well as a βarr-biased D2R ligand, UNC9994. With these functionally selective tools, we investigated the mechanism whereby the βarr-preferring D2R achieves βarr pathway activation in the complete absence of G protein activation. We describe how direct, G protein-independent recruitment of GRK2 drives interactions at the βarr-preferring D2R and also contributes to βarr recruitment at the WT D2R. Additionally, we found an additive interaction between the βarr-preferring D2R mutant and UNC9994. These results reveal that the D2R can directly recruit GRK2 without G protein activation and that this mechanism may have relevance to achieving βarr-biased signaling. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

  17. A multiscale computational approach to dissect early events in the Erb family receptor mediated activation, differential signaling, and relevance to oncogenic transformations.

    Science.gov (United States)

    Liu, Yingting; Purvis, Jeremy; Shih, Andrew; Weinstein, Joshua; Agrawal, Neeraj; Radhakrishnan, Ravi

    2007-06-01

    We describe a hierarchical multiscale computational approach based on molecular dynamics simulations, free energy-based molecular docking simulations, deterministic network-based kinetic modeling, and hybrid discrete/continuum stochastic dynamics protocols to study the dimer-mediated receptor activation characteristics of the Erb family receptors, specifically the epidermal growth factor receptor (EGFR). Through these modeling approaches, we are able to extend the prior modeling of EGF-mediated signal transduction by considering specific EGFR tyrosine kinase (EGFRTK) docking interactions mediated by differential binding and phosphorylation of different C-terminal peptide tyrosines on the RTK tail. By modeling signal flows through branching pathways of the EGFRTK resolved on a molecular basis, we are able to transcribe the effects of molecular alterations in the receptor (e.g., mutant forms of the receptor) to differing kinetic behavior and downstream signaling response. Our molecular dynamics simulations show that the drug sensitizing mutation (L834R) of EGFR stabilizes the active conformation to make the system constitutively active. Docking simulations show preferential characteristics (for wildtype vs. mutant receptors) in inhibitor binding as well as preferential enhancement of phosphorylation of particular substrate tyrosines over others. We find that in comparison to the wildtype system, the L834R mutant RTK preferentially binds the inhibitor erlotinib, as well as preferentially phosphorylates the substrate tyrosine Y1068 but not Y1173. We predict that these molecular level changes result in preferential activation of the Akt signaling pathway in comparison to the Erk signaling pathway for cells with normal EGFR expression. For cells with EGFR over expression, the mutant over activates both Erk and Akt pathways, in comparison to wildtype. These results are consistent with qualitative experimental measurements reported in the literature. We discuss these

  18. Improved hybrid isolator with maglev actuator integrated in air spring for active-passive isolation of ship machinery vibration

    Science.gov (United States)

    Li, Yan; He, Lin; Shuai, Chang-geng; Wang, Chun-yu

    2017-10-01

    A hybrid isolator consisting of maglev actuator and air spring is proposed and developed for application in active-passive vibration isolation system of ship machinery. The dynamic characteristics of this hybrid isolator are analyzed and tested. The stability and adaptability of this hybrid isolator to shock and swing in the marine environment are improved by a compliant gap protection technique and a disengageable suspended structure. The functions of these new engineering designs are proved by analytical verification and experimental validation of the designed stiffness of such a hybrid isolator, and also by shock adaptability testing of the hybrid isolator. Finally, such hybrid isolators are installed in an engineering mounting loaded with a 200-kW ship diesel generator, and the broadband and low-frequency sinusoidal isolation performance is tested.

  19. Human Blood Feeding Activity of Female Hybrids between Culex pipiens pipiens and Culex pipiens quinquefasciatus(Diptera: Culicidae)

    OpenAIRE

    Yoshii, Manabu; Mine, Mariko; Kurokawa, Kenji; Oda, Tsutomu; Kato, Katsutomo; Ogawa, Yasunori; Eshita, Yuuki; Uchida, Keikichi

    2007-01-01

    Human blood feeding activity was examined in females of hybrids between Culex pipiens pipiens and Culex pipiens quinquefasciatus during long photoperiod at 25℃. Blood feeding rates of hybrids were lower than in Culex pipiens quinquefasciatus and Culex pipiens pallens, and higher than in Culex pipiens pipiens, because no females fed on human blood in Culex pipiens pipiens.

  20. Effect of photoperiod on blood feeding activity of female hybrids between Culex pipiens pipiens and Culex pipiens quinquefasciatus (Diptera: Culicidae)

    OpenAIRE

    Kurokawa, Kenji; Yoshii, Manabu; Oda, Tsutomu; Kato, Katsutomo; Uchida, Keikichi; Eshita, Yuki; Tahara, Hiroyuki; Mine, Mariko; Ogawa, Yasunori

    2004-01-01

    Blood feeding activity was examined in females of hybrids (F1) between Culex pipiens pipiens and Culex pipiens quinquefasciatus in long and short photoperiods at 2l℃ to examine the effect of photoperiod on blood feeding rate. Blood feeding rates (F1) were lower in short photoperiods than in long photoperiods. From this, it seems that the hybrids show diapause.

  1. Characterization of the single transmembrane domain of human receptor activity-modifying protein 3 in adrenomedullin receptor internalization

    International Nuclear Information System (INIS)

    Kuwasako, Kenji; Kitamura, Kazuo; Nagata, Sayaka; Nozaki, Naomi; Kato, Johji

    2012-01-01

    Highlights: ► RAMP3 mediates CLR internalization much less effectively than does RAMP2. ► The RAMP3 TMD participates in the negative regulation of CLR/RAMP3 internalization. ► A new strategy of promoting internalization and resensitization of the receptor was found. -- Abstract: Two receptor activity-modifying proteins (RAMP2 and RAMP3) enable calcitonin receptor-like receptor (CLR) to function as two heterodimeric receptors (CLR/RAMP2 and CLR/RAMP3) for adrenomedullin (AM), a potent cardiovascular protective peptide. Following AM stimulation, both receptors undergo rapid internalization through a clathrin-dependent pathway, after which CLR/RAMP3, but not CLR/RAMP2, can be recycled to the cell surface for resensitization. However, human (h)RAMP3 mediates CLR internalization much less efficiently than does hRAMP2. Therefore, the molecular basis of the single transmembrane domain (TMD) and the intracellular domain of hRAMP3 during AM receptor internalization was investigated by transiently transfecting various RAMP chimeras and mutants into HEK-293 cells stably expressing hCLR. Flow cytometric analysis revealed that substituting the RAMP3 TMD with that of RAMP2 markedly enhanced AM-induced internalization of CLR. However, this replacement did not enhance the cell surface expression of CLR, [ 125 I]AM binding affinity or AM-induced cAMP response. More detailed analyses showed that substituting the Thr 130 –Val 131 sequence in the RAMP3 TMD with the corresponding sequence (Ile 157 –Pro 158 ) from RAMP2 significantly enhanced AM-mediated CLR internalization. In contrast, substituting the RAMP3 target sequence with Ala 130 –Ala 131 did not significantly affect CLR internalization. Thus, the RAMP3 TMD participates in the negative regulation of CLR/RAMP3 internalization, and the aforementioned introduction of the Ile–Pro sequence into the RAMP3 TMD may be a strategy for promoting receptor internalization/resensitization.

  2. The Role of Stat3 Activation in Androgen Receptor Signaling and Prostate Cancer

    National Research Council Canada - National Science Library

    Gao, Allen C

    2006-01-01

    .... The experiments proposed in this application are based upon the hypothesis that Stat3 activation alters androgen receptor signaling pathways which in turn results in the loss of growth control in prostate cancer cells...

  3. The Role of Stat3 Activation in Androgen Receptor Signaling and Prostate Cancer

    National Research Council Canada - National Science Library

    Gao, Allen

    2004-01-01

    .... The experiments proposed in this application are based upon the hypothesis that stat3 activation alters androgen receptor signaling pathways, that in turn results in the loss of growth control in prostate cancer cells...

  4. The Role of Stat3 Activation in Androgen Receptor Signaling and Prostate Cancer

    National Research Council Canada - National Science Library

    Gao, Allen

    2002-01-01

    .... The experiments proposed in this application are based upon the hypothesis that Stat3 activation alters androgen receptor signaling pathways, that in turn results in the loss of growth control in prostate cancer cells...

  5. The Role of Stat3 Activation in Androgen Receptor Signaling and Prostate Cancer

    National Research Council Canada - National Science Library

    Gao, Allen C

    2005-01-01

    .... The experiments proposed in this application are based upon the hypothesis that Stat3 activation alters androgen receptor signaling pathways, that in turn results in the loss of growth control in prostate cancer cells...

  6. The Role of Stat3 Activation in Androgen Receptor Signaling and Prostate Cancer

    National Research Council Canada - National Science Library

    Gao, Allen

    2003-01-01

    .... The experiments proposed in this application are based upon the hypothesis that Stat3 activation alters androgen receptor signaling pathways, that in turn results in the loss of growth control in prostate cancer cells...

  7. Chronic regulation of colonic epithelial secretory function by activation of G protein-coupled receptors.

    LENUS (Irish Health Repository)

    Toumi, F

    2011-02-01

    Enteric neurotransmitters that act at G protein-coupled receptors (GPCRs) are well known to acutely promote epithelial Cl(-) and fluid secretion. Here we examined if acute GPCR activation might have more long-term consequences for epithelial secretory function.

  8. Phorbol ester-induced serine phosphorylation of the insulin receptor decreases its tyrosine kinase activity.

    Science.gov (United States)

    Takayama, S; White, M F; Kahn, C R

    1988-03-05

    The effect of 12-O-tetradecanoylphorbol-13-acetate (TPA) on the function of the insulin receptor was examined in intact hepatoma cells (Fao) and in solubilized extracts purified by wheat germ agglutinin chromatography. Incubation of ortho[32P]phosphate-labeled Fao cells with TPA increased the phosphorylation of the insulin receptor 2-fold after 30 min. Analysis of tryptic phosphopeptides from the beta-subunit of the receptor by reverse-phase high performance liquid chromatography and determination of their phosphoamino acid composition suggested that TPA predominantly stimulated phosphorylation of serine residues in a single tryptic peptide. Incubation of the Fao cells with insulin (100 nM) for 1 min stimulated 4-fold the phosphorylation of the beta-subunit of the insulin receptor. Prior treatment of the cells with TPA inhibited the insulin-stimulated tyrosine phosphorylation by 50%. The receptors extracted with Triton X-100 from TPA-treated Fao cells and purified on immobilized wheat germ agglutinin retained the alteration in kinase activity and exhibited a 50% decrease in insulin-stimulated tyrosine autophosphorylation and phosphotransferase activity toward exogenous substrates. This was due primarily to a decrease in the Vmax for these reactions. TPA treatment also decreased the Km of the insulin receptor for ATP. Incubation of the insulin receptor purified from TPA-treated cells with alkaline phosphatase decreased the phosphate content of the beta-subunit to the control level and reversed the inhibition, suggesting that the serine phosphorylation of the beta-subunit was responsible for the decreased tyrosine kinase activity. Our results support the notion that the insulin receptor is a substrate for protein kinase C in the Fao cell and that the increase in serine phosphorylation of the beta-subunit of the receptor produced by TPA treatment inhibited tyrosine kinase activity in vivo and in vitro. These data suggest that protein kinase C may regulate the function

  9. Bovine cumulus-granulosa cells contain biologically active retinoid receptors that can respond to retinoic acid

    Directory of Open Access Journals (Sweden)

    Malayer Jerry

    2003-11-01

    Full Text Available Abstract Retinoids, a class of compounds that include retinol and its metabolite, retinoic acid, are absolutely essential for ovarian steroid production, oocyte maturation, and early embryogenesis. Previous studies have detected high concentrations of retinol in bovine large follicles. Further, administration of retinol in vivo and supplementation of retinoic acid during in vitro maturation results in enhanced embryonic development. In the present study, we hypothesized that retinoids administered either in vivo previously or in vitro can exert receptor-mediated effects in cumulus-granulosa cells. Total RNA extracted from in vitro cultured cumulus-granulosa cells was subjected to reverse transcription polymerase chain reaction (RT-PCR and mRNA expression for retinol binding protein (RBP, retinoic acid receptor alpha (RARalpha, retinoic acid receptor beta (RARbeta, retinoic acid receptor gamma (RARgamma, retinoid X receptor alpha (RXRalpha, retinoid X receptor beta (RXRbeta, retinaldehyde dehydrogenase-2 (RALDH-2, and peroxisome proliferator activated receptor gamma (PPARgamma. Transcripts were detected for RBP, RARalpha, RARgamma, RXRalpha, RXRbeta, RALDH-2, and PPARgamma. Expression of RARbeta was not detected in cumulus-granulosa cells. Using western blotting, immunoreactive RARalpha, and RXRbeta protein was also detected in bovine cumulus-granulosa cells. The biological activity of these endogenous retinoid receptors was tested using a transient reporter assay using the pAAV-MCS-betaRARE-Luc vector. Addition of 0.5 and 1 micro molar all-trans retinoic acid significantly (P trans retinol stimulated a mild increase in reporter activity, however, the increase was not statistically significant. Based on these results we conclude that cumulus cells contain endogenously active retinoid receptors and may also be competent to synthesize retinoic acid using the precursor, retinol. These results also indirectly provide evidence that retinoids

  10. Differential Requirement of the Extracellular Domain in Activation of Class B G Protein-coupled Receptors.

    Science.gov (United States)

    Zhao, Li-Hua; Yin, Yanting; Yang, Dehua; Liu, Bo; Hou, Li; Wang, Xiaoxi; Pal, Kuntal; Jiang, Yi; Feng, Yang; Cai, Xiaoqing; Dai, Antao; Liu, Mingyao; Wang, Ming-Wei; Melcher, Karsten; Xu, H Eric

    2016-07-15

    G protein-coupled receptors (GPCRs) from the secretin-like (class B) family are key players in hormonal homeostasis and are important drug targets for the treatment of metabolic disorders and neuronal diseases. They consist of a large N-terminal extracellular domain (ECD) and a transmembrane domain (TMD) with the GPCR signature of seven transmembrane helices. Class B GPCRs are activated by peptide hormones with their C termini bound to the receptor ECD and their N termini bound to the TMD. It is thought that the ECD functions as an affinity trap to bind and localize the hormone to the receptor. This in turn would allow the hormone N terminus to insert into the TMD and induce conformational changes of the TMD to activate downstream signaling. In contrast to this prevailing model, we demonstrate that human class B GPCRs vary widely in their requirement of the ECD for activation. In one group, represented by corticotrophin-releasing factor receptor 1 (CRF1R), parathyroid hormone receptor (PTH1R), and pituitary adenylate cyclase activating polypeptide type 1 receptor (PAC1R), the ECD requirement for high affinity hormone binding can be bypassed by induced proximity and mass action effects, whereas in the other group, represented by glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R), the ECD is required for signaling even when the hormone is covalently linked to the TMD. Furthermore, the activation of GLP-1R by small molecules that interact with the intracellular side of the receptor is dependent on the presence of its ECD, suggesting a direct role of the ECD in GLP-1R activation. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  11. EPO-independent functional EPO receptor in breast cancer enhances estrogen receptor activity and promotes cell proliferation

    International Nuclear Information System (INIS)

    Reinbothe, Susann; Larsson, Anna-Maria; Vaapil, Marica; Wigerup, Caroline; Sun, Jianmin; Jögi, Annika; Neumann, Drorit; Rönnstrand, Lars; Påhlman, Sven

    2014-01-01

    Highlights: • New anti-human EPOR antibody confirms full-length EPOR expression in breast cancer cells. • Proliferation of breast cancer cells is not affected by rhEPO treatment in vitro. • EPOR knockdown impairs proliferation of ERa positive breast cancer cells. • EPOR knockdown reduces AKT phosphorylation and ERa activity. - Abstract: The main function of Erythropoietin (EPO) and its receptor (EPOR) is the stimulation of erythropoiesis. Recombinant human EPO (rhEPO) is therefore used to treat anemia in cancer patients. However, clinical trials have indicated that rhEPO treatment might promote tumor progression and has a negative effect on patient survival. In addition, EPOR expression has been detected in several cancer forms. Using a newly produced anti-EPOR antibody that reliably detects the full-length isoform of the EPOR we show that breast cancer tissue and cells express the EPOR protein. rhEPO stimulation of cultured EPOR expressing breast cancer cells did not result in increased proliferation, overt activation of EPOR (receptor phosphorylation) or a consistent activation of canonical EPOR signaling pathway mediators such as JAK2, STAT3, STAT5, or AKT. However, EPOR knockdown experiments suggested functional EPO receptors in estrogen receptor positive (ERα + ) breast cancer cells, as reduced EPOR expression resulted in decreased proliferation. This effect on proliferation was not seen in ERα negative cells. EPOR knockdown decreased ERα activity further supports a mechanism by which EPOR affects proliferation via ERα-mediated mechanisms. We show that EPOR protein is expressed in breast cancer cells, where it appears to promote proliferation by an EPO-independent mechanism in ERα expressing breast cancer cells

  12. EPO-independent functional EPO receptor in breast cancer enhances estrogen receptor activity and promotes cell proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Reinbothe, Susann; Larsson, Anna-Maria; Vaapil, Marica; Wigerup, Caroline [Department of Laboratory Medicine, Translational Cancer Research, Medicon Village, Lund University, SE-223 81 Lund (Sweden); CREATE Health, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv (Israel); Sun, Jianmin [Department of Laboratory Medicine, Translational Cancer Research, Medicon Village, Lund University, SE-223 81 Lund (Sweden); Jögi, Annika [Department of Laboratory Medicine, Translational Cancer Research, Medicon Village, Lund University, SE-223 81 Lund (Sweden); CREATE Health, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv (Israel); Neumann, Drorit [Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv (Israel); Rönnstrand, Lars [Department of Laboratory Medicine, Translational Cancer Research, Medicon Village, Lund University, SE-223 81 Lund (Sweden); Påhlman, Sven, E-mail: sven.pahlman@med.lu.se [Department of Laboratory Medicine, Translational Cancer Research, Medicon Village, Lund University, SE-223 81 Lund (Sweden); CREATE Health, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv (Israel)

    2014-02-28

    Highlights: • New anti-human EPOR antibody confirms full-length EPOR expression in breast cancer cells. • Proliferation of breast cancer cells is not affected by rhEPO treatment in vitro. • EPOR knockdown impairs proliferation of ERa positive breast cancer cells. • EPOR knockdown reduces AKT phosphorylation and ERa activity. - Abstract: The main function of Erythropoietin (EPO) and its receptor (EPOR) is the stimulation of erythropoiesis. Recombinant human EPO (rhEPO) is therefore used to treat anemia in cancer patients. However, clinical trials have indicated that rhEPO treatment might promote tumor progression and has a negative effect on patient survival. In addition, EPOR expression has been detected in several cancer forms. Using a newly produced anti-EPOR antibody that reliably detects the full-length isoform of the EPOR we show that breast cancer tissue and cells express the EPOR protein. rhEPO stimulation of cultured EPOR expressing breast cancer cells did not result in increased proliferation, overt activation of EPOR (receptor phosphorylation) or a consistent activation of canonical EPOR signaling pathway mediators such as JAK2, STAT3, STAT5, or AKT. However, EPOR knockdown experiments suggested functional EPO receptors in estrogen receptor positive (ERα{sup +}) breast cancer cells, as reduced EPOR expression resulted in decreased proliferation. This effect on proliferation was not seen in ERα negative cells. EPOR knockdown decreased ERα activity further supports a mechanism by which EPOR affects proliferation via ERα-mediated mechanisms. We show that EPOR protein is expressed in breast cancer cells, where it appears to promote proliferation by an EPO-independent mechanism in ERα expressing breast cancer cells.

  13. Hybrid magnetic mechanism for active locomotion based on inchworm motion

    International Nuclear Information System (INIS)

    Kim, Sung Hoon; Hashi, Shuichiro; Ishiyama, Kazushi

    2013-01-01

    Magnetic robots have been studied in the past. Insect-type micro-robots are used in various biomedical applications; researchers have developed inchworm micro-robots for endoscopic use. A biological inchworm has a looping locomotion gait. However, most inchworm micro-robots depend on a general bending, or bellows, motion. In this paper, we introduce a new robotic mechanism using magnetic force and torque control in a rotating magnetic field for a looping gait. The proposed robot is controlled by the magnetic torque, attractive force, and body mechanisms (two stoppers, flexible body, and different frictional legs). The magnetic torque generates a general bending motion. In addition, the attractive force and body mechanisms produce the robot’s looping motion within a rotating magnetic field and without the use of an algorithm for field control. We verified the device’s performance and analyzed the motion through simulations and various experiments. The robot mechanism can be applied to active locomotion for various medical robots, such as wireless endoscopes. (technical note)

  14. (Bio)hybrid materials based on optically active particles

    Science.gov (United States)

    Reitzig, Manuela; Härtling, Thomas; Opitz, Jörg

    2014-03-01

    In this contribution we provide an overview of current investigations on optically active particles (nanodiamonds, upconversion phospors) for biohybrid and sensing applications. Due to their outstanding properties nanodiamonds gain attention in various application elds such as microelectronics, optical monitoring, medicine, and biotechnology. Beyond the typical diamond properties such as high thermal conductivity and extreme hardness, the carbon surface and its various functional groups enable diverse chemical and biological surface functionalization. At Fraunhofer IKTS-MD we develop a customization of material surfaces via integration of chemically modi ed nanodiamonds at variable surfaces, e.g bone implants and pipelines. For the rst purpose, nanodiamonds are covalently modi ed at their surface with amino or phosphate functionalities that are known to increase adhesion to bone or titanium alloys. The second type of surface is approached via mechanical implementation into coatings. Besides nanodiamonds, we also investigate the properties of upconversion phosphors. In our contribution we show how upconversion phosphors are used to verify sterilization processes via a change of optical properties due to sterilizing electron beam exposure.

  15. Environmental polycyclic aromatic hydrocarbons affect androgen receptor activation in vitro

    DEFF Research Database (Denmark)

    Vinggaard, Anne Marie; Hnida, Christina; Larsen, John Christian

    2000-01-01

    Nine structurally different polycyclic aromatic hydrocarbons (PAHs) were tested for their ability to either agonize or antagonize the human androgen receptor (hAR) in a sensitive reporter gene assay based on CHO cells transiently cotransfected with a hAR vector and an MMTV-LUC vector. Benz...

  16. Activated carbon/manganese dioxide hybrid electrodes for high performance thin film supercapacitors

    Science.gov (United States)

    Jang, Yunseok; Jo, Jeongdai; Jang, Hyunjung; Kim, Inyoung; Kang, Dongwoo; Kim, Kwang-Young

    2014-06-01

    We combine the activated carbon (AC) and the manganese dioxide (MnO2) in a AC/MnO2 hybrid electrode to overcome the low capacitance of activated carbon and MnO2 by exploiting the large surface area of AC and the fast reversible redox reaction of MnO2. An aqueous permanganate (MnO4 -) is converted to MnO2 on the surface of the AC electrode by dipping the AC electrode into an aqueous permanganate solution. The AC/MnO2 hybrid electrode is found to display superior specific capacitance of 290 F/g. This shows that supercapacitors classified as electric double layer capacitors and pseudocapacitors can be combined together.

  17. Design of Hybrid Nanostructural Arrays to Manipulate SERS-Active Substrates by Nanosphere Lithography.

    Science.gov (United States)

    Zhao, Xiaoyu; Wen, Jiahong; Zhang, Mengning; Wang, Dunhui; Wang, Yaxin; Chen, Lei; Zhang, Yongjun; Yang, Jinghai; Du, Youwei

    2017-03-01

    An easy-handling and low-cost method is utilized to controllably fabricate nanopattern arrays as the surface-enhanced Raman scattering (SERS) active substrates with high density of SERS-active areas (hot spots). A hybrid silver array of nanocaps and nanotriangles are prepared by combining magnetron sputtering and plasma etching. By adjusting the etching time of polystyrene (PS) colloid spheres array in silver nanobowls, the morphology of the arrays can be easily manipulated to control the formation and distribution of hot spots. The experimental results show that the hybrid nanostructural arrays have large enhancement factor, which is estimated to be seven times larger than that in the array of nanocaps and three times larger than that in the array of nanorings and nanoparticles. According to the results of finite-difference time-domain simulation, the excellent SERS performance of this array is ascribed to the high density of hot spots and enhanced electromagnetic field.

  18. Reciprocal regulation of platelet responses to P2Y and thromboxane receptor activation.

    Science.gov (United States)

    Barton, J F; Hardy, A R; Poole, A W; Mundell, S J

    2008-03-01

    Thromboxane A(2) and ADP are two major platelet agonists that stimulate two sets of G protein-coupled receptors to activate platelets. Although aggregation responses to ADP and thromboxane desensitize, there are no reports currently addressing whether activation by one agonist may heterologously desensitize responses to the other. To demonstrate whether responses to ADP or U46619 may be modulated by prior treatment of platelets with the alternate agonist, revealing a level of cross-desensitization between receptor systems. Here we show that pretreatment of platelets with either agonist substantially desensitizes aggregation responses to the other agonist. Calcium responses to thromboxane receptor activation are desensitized by preactivation of P2Y(1) but not P2Y(12) receptors. This heterologous desensitization is mediated by a protein kinase C (PKC)-independent mechanism. Reciprocally, calcium responses to ADP are desensitized by pretreatment of platelets with the thromboxane analogue, U46619, and P2Y(12)-mediated inhibition of adenylate cyclase is also desensitized by pretreatment with U46619. In this direction, desensitization is comprised of two components, a true heterologous component that is PKC-independent, and a homologous component that is mediated through stimulated release of dense granule ADP. This study reveals cross-desensitization between ADP and thromboxane receptor signaling in human platelets. Cross-desensitization is mediated by protein kinases, involving PKC-dependent and independent pathways, and indicates that alterations in the activation state of one receptor may have effects upon the sensitivity of the other receptor system.

  19. Sch proteins are localized on endoplasmic reticulum membranes and are redistributed after tyrosine kinase receptor activation

    DEFF Research Database (Denmark)

    Lotti, L V; Lanfrancone, L; Migliaccio, E

    1996-01-01

    area of the cell and mostly associated with the cytosolic side of rough endoplasmic reticulum membranes. Upon epidermal growth factor treatment and receptor tyrosine kinase activation, the immunolabeling became peripheral and was found to be associated with the cytosolic surface of the plasma membrane....... The rough endoplasmic reticulum localization of Shc proteins in unstimulated cells and their massive recruitment to the plasma membrane, endocytic structures, and peripheral cytosol following receptor tyrosine kinase activation could account for multiple putative functions of the adaptor protein....

  20. 5-HT7 receptor activation: procognitive and antiamnesic effects.

    Science.gov (United States)

    Meneses, A; Perez-Garcia, G; Liy-Salmeron, G; Ponce-López, T; Lacivita, E; Leopoldo, M

    2015-02-01

    The serotonin (5-hydroxytryptamine (5-HT)) 5-HT7 receptor is localized in brain areas mediating memory; however, the role of this receptor on memory remains little explored. First, demonstrating the associative nature of Pavlovian/instrumental autoshaping (P/I-A) task, rats were exposed (three sessions) to CS-US (Pavlovian autoshaping), truly random control, free operant, and presentations of US or CS, and they were compared with rats trained-tested for one session to the P/I-A procedure. Also, effects of the 5-HT7 receptor agonist LP-211 administered intraperitoneally after training was determined on short- (1.5 h) and long-term memory 24 and 48 h) and on scopolamine-induced memory impairment and cAMP production. Autoshaping and its behavioral controls were studied. Other animals were subjected to an autoshaping training session and immediately afterwards were given (intraperitoneal) vehicle or LP-211 (0.1-10 mg/kg) and/or scopolamine (0.2 mg/kg) and tested for short-term memory (STM) and long-term memory (LTM); their brains were extracted for the cAMP ELISA immunoassay. P/I-A group produced the higher %CR. LP-211 did not affect STM; nonetheless, at 0.5 and 1.0 mg/kg, it improved LTM. The 5-HT7 receptor antagonist SB-269970 (SB; 10.0 mg/kg) alone had no effect; nevertheless, the LP-211 (1.0 mg/kg) LTM facilitation was reversed by SB. The scopolamine (0.2 mg/kg) induced-decrement in CR was accompanied by significant increased cAMP production. The scopolamine-induced decrement in CR and increments in cAMP were significantly attenuated by LP-211. Autoshaping is a reliable associative learning task whose consolidation is facilitated by the 5-HT7 receptor agonist LP-211.

  1. Activation of intracellular angiotensin AT2 receptors induces rapid cell death in human uterine leiomyosarcoma cells

    DEFF Research Database (Denmark)

    Zhao, Yi; Lützen, Ulf; Fritsch, Jürgen

    2015-01-01

    The presence of AT2 receptors in mitochondria and their role in NO generation and cell aging were recently demonstrated in various human and mouse non-tumour cells. We investigated the intracellular distribution of AT2 receptors including their presence in mitochondria and the role in the induction...... agonist, Compound 21 (C21) penetrates the cell membrane of quiescent SK-UT-1 cells, activates intracellular AT2 receptors and induces rapid cell death; approximately 70% of cells died within 24 h. The cells, which escaped from the cell death, displayed activation of the mitochondrial apoptotic pathway, i...

  2. Expression of an insulin/interleukin-1 receptor antagonist hybrid gene in insulin-producing cell lines (HIT-T15 and NIT-1) confers resistance against interleukin-1-induced nitric oxide production.

    Science.gov (United States)

    Welsh, N; Bendtzen, K; Welsh, M

    1995-01-01

    A hybrid gene consisting of the insulin gene enhancer/promoter region, the signal sequence, the insulin B- and C-chains, and the human interleukin-1 receptor antagonist (IL-1ra) gene was constructed. This hybrid gene was transfected together with the pSV2-neo construct into the insulin-producing cell lines HIT-T15 and NIT-1. One of the geneticin-selected clones, HITra2, expressed a 1.4-kb mRNA, which hybridized both to insulin and IL-1ra-cDNA in Northern blot analysis. Three proteins, with the mol wt 23, 17, and 14 kD, were immunoprecipitated with anti-IL-1ra antibodies from [35S]methionine-labeled HITra2 cells. Both at a low and at a high glucose concentration, 4-5 ng of IL-1ra/10(6) cells (ELISA) was released from these cells. On the other hand, a high glucose concentration evoked a three-fold increase in the release of insulin, suggesting that IL-1ra was released constitutively. Measured by nitrite production, transfected HIT, and NIT-1 cells exhibited a more than 10-fold decrease in IL-1 beta sensitivity. Since the conditioned culture media from the HITra2 cells exhibited an anti-IL-1 beta activity of only 0.5 U/ml, and mixed culture of HITra2 cells and isolated rat islets prevented IL-1 beta induced inhibition of insulin release, it is likely that IL-1ra acts locally at the cell surface. It is concluded that expression of a hybrid insulin/IL-1ra gene confers resistance to IL-1 and that this technique may be used to elucidate the role of IL-1 in autoimmune disorders such as insulin-dependent diabetes mellitus. Images PMID:7706480

  3. Activation of sigma-1 receptor chaperone in the treatment of neuropsychiatric diseases and its clinical implication

    Directory of Open Access Journals (Sweden)

    Kenji Hashimoto

    2015-01-01

    Full Text Available Endoplasmic reticulum (ER protein sigma-1 receptor represents unique chaperone activity in the central nervous system, and it exerts a potent influence on a number of neurotransmitter systems. Several lines of evidence suggest that activation of sigma-1 receptor plays a role in the pathophysiology of neuropsychiatric diseases, as well as in the mechanisms of some therapeutic drugs and neurosteroids. Preclinical studies showed that some selective serotonin reuptake inhibitors (SSRIs; fluvoxamine, fluoxetine, excitalopram, donepezil, and ifenprodil act as sigma-1 receptor agonists. Furthermore, sigma-1 receptor agonists could improve the N-methyl-D-aspartate (NMDA antagonist phencyclidine (PCP-induced cognitive deficits in mice. A study using positron emission tomography have demonstrated that an oral administration of fluvoxamine or donepezil could bind to sigma-1 receptor in the healthy human brain, suggesting that sigma-1 receptor might be involved in the therapeutic mechanisms of these drugs. Moreover, case reports suggest that sigma-1 receptor agonists, including fluvoxamine, and ifenprodil, may be effective in the treatment of cognitive impairment in schizophrenia, delirium in elderly people, and flashbacks in post-traumatic stress disorder. In this review article, the author would like to discuss the clinical implication of sigma-1 receptor agonists, including endogenous neurosteroids, in the neuropsychiatric diseases.

  4. Proteinase-activated receptors - mediators of early and delayed normal tissue radiation responses

    International Nuclear Information System (INIS)

    Hauer-Jensen, M.

    2003-01-01

    Proteinase-activated receptors (PARs) are G-protein coupled receptors that are activated by proteolytic exposure of a receptor-tethered ligand. The discovery of this receptor family represents one of the most intriguing recent developments in signal transduction. PARs are involved in the regulation of many normal and pathophysiological processes, notably inflammatory and fibroproliferative responses to injury. Preclinical studies performed in our laboratory suggest that proteinase-activated receptor-1 (PAR-1) plays a critical role in the mechanism of chronicity of radiation fibrosis, while proteinase-activated receptor-2 (PAR-2) may mediate important fibroproliferative responses in irradiated intestine. Specifically, activation of PAR-1 by thrombin, and PAR-2 by pancreatic trypsin and mast cell proteinases, appears to be involved in acute radiation-induced inflammation, as well as in subsequent extracellular matrix deposition, leading to the development of intestinal wall fibrosis and clinical complications. Pharmacological modulators of PAR-1 or PAR-2 expression or activation would be potentially useful as preventive or therapeutic agents in patients who receive radiation therapy, especially if blockade could be targeted to specific tissues or cellular compartments

  5. Sulfhydryl group content of chicken progesterone receptor: effect of oxidation on DNA binding activity

    International Nuclear Information System (INIS)

    Peleg, S.; Schrader, W.T.; O'Malley, B.W.

    1988-01-01

    DNA binding activity of chicken progesterone receptor B form (PRB) and A form (PRA) has been examined. This activity is strongly dependent upon the presence of thiols in the buffer. Stability studies showed that PRB was more sensitive to oxidation that was PRA. Receptor preparations were fractionated by DNA-cellulose chromatography to DNA-positive and DNA-negative subpopulations, and sulfhydryl groups were quantified on immunopurified receptor by labeling with [ 3 H]-N-ethylmaleimide. Labeling of DNA-negative receptors with [ 3 H]-N-ethylmaleimide showed 21-23 sulfhydryl groups on either PRA or PRB form when the proteins were reduced and denatured. A similar number was seen without reduction if denatured DNA-positive receptor species were tested. In contrast, the DNA-negative PRB had only 10-12 sulfhydryl groups detectable without reduction. A similar number (12-13 sulfhydryl groups) was found for PRA species that lost DNA binding activity after exposure to a nonreducing environment in vitro. The authors conclude that the naturally occurring receptor forms unable to bind to DNA, as well as receptor forms that have lost DNA binding activity due to exposure to nonreducing environment in vitro, contain 10-12 oxidized cysteine residues, likely present as disulfide bonds. Since they were unable to reduce the disulfide bonds when the native DNA-negative receptor proteins were treated with dithiothreitol (DTT), they speculate that irreversible loss of DNA binding activity of receptor in vitro is due to oxidation of cysteine residues that are not accessible to DTT in the native state

  6. Life cycle cost analysis of single slope hybrid (PV/T) active solar still

    International Nuclear Information System (INIS)

    Kumar, Shiv; Tiwari, G.N.

    2009-01-01

    This paper presents the life cycle cost analysis of the single slope passive and hybrid photovoltaic (PV/T) active solar stills, based on the annual performance at 0.05 m water depth. Effects of various parameters, namely interest rate, life of the system and the maintenance cost have been taken into account. The comparative cost of distilled water produced from passive solar still (Rs. 0.70/kg) is found to be less than hybrid (PV/T) active solar still (Rs. 1.93/kg) for 30 years life time of the systems. The payback periods of the passive and hybrid (PV/T) active solar still are estimated to be in the range of 1.1-6.2 years and 3.3-23.9 years, respectively, based on selling price of distilled water in the range of Rs. 10/kg to Rs. 2/kg. The energy payback time (EPBT) has been estimated as 2.9 and 4.7 years, respectively. (author)

  7. Genotype-Dependent Difference in 5-HT2C Receptor-Induced Hypolocomotion: Comparison with 5-HT2A Receptor Functional Activity

    Directory of Open Access Journals (Sweden)

    Darya V. Bazovkina

    2015-01-01

    Full Text Available In the present study behavioral effects of the 5-HT2C serotonin receptor were investigated in different mouse strains. The 5-HT2C receptor agonist MK-212 applied intraperitoneally induced significant dose-dependent reduction of distance traveled in the open field test in CBA/Lac mice. This effect was receptor-specific because it was inhibited by the 5-HT2C receptor antagonist RS102221. To study the role of genotype in 5-HT2C receptor-induced hypolocomotion, locomotor activity of seven inbred mouse strains was measured after MK-212 acute treatment. We found that the 5-HT2C receptor stimulation by MK-212 decreased distance traveled in the open field test in CBA/Lac, C57Bl/6, C3H/He, and ICR mice, whereas it failed to affect locomotor activity in DBA/2J, Asn, and Balb/c mice. We also compared the interstrain differences in functional response to 5-HT2C and 5-HT2A receptors activation measured by the quantification of receptor-mediated head-twitches. These experiments revealed significant positive correlation between 5-HT2C and 5-HT2A receptors functional responses for all investigated mouse strains. Moreover, we found that 5-HT2A receptor activation with DOI did not change locomotor activity in CBA/Lac mice. Taken together, our data indicate the implication of 5-HT2C receptors in regulation of locomotor activity and suggest the shared mechanism for functional responses mediated by 5-HT2C and 5-HT2A receptors.

  8. 14CO2-fixation and nitrate reductase activity in vivo in relation to hybrid vigour in maize

    International Nuclear Information System (INIS)

    Balasubramanian, V.; Shanthakumari, P.; Sinha, S.K.

    1977-01-01

    Dry matter accumulation in maize shoots, leaf area, 14 CO 2 -fixation and nitrate reductase activity in vivo were measured in the field grown heterotic hybrid CM 400x CM 300 and its inbred parents CM 300 and CM 400 from seedling to maturity. Rates of dry matter accumulation and leaf area development were higher in the hybrid during the initial vegetative phase than in the inbreds. The hybrid had more absolute level of 14 CO 2 -fixation and nitrate reductase activity, although the rates of these processes on unit weight basis were not higher than those of inbreds. It is concluded that the rapid development of leaf area in hybrids during the early stages of vegetative growth is probably important for hybrid vigour. (author)

  9. Preparation of AgBr@SiO{sub 2} core@shell hybrid nanoparticles and their bactericidal activity

    Energy Technology Data Exchange (ETDEWEB)

    Li, Yuanyuan [Key Laboratory for Special Functional Materials of Ministry of Education, Henan University, Kaifeng 475004 (China); Yang, Lisu [Key Laboratory for Special Functional Materials of Ministry of Education, Henan University, Kaifeng 475004 (China); Henna Sports School, Zhengzhou 450045 (China); Zhao, Yanbao, E-mail: yanbaozhao@126.com [Key Laboratory for Special Functional Materials of Ministry of Education, Henan University, Kaifeng 475004 (China); Li, Binjie; Sun, Lei; Luo, Huajuan [Key Laboratory for Special Functional Materials of Ministry of Education, Henan University, Kaifeng 475004 (China)

    2013-04-01

    AgBr@SiO{sub 2} core@shell hybrid nanoparticles (NPs) were successfully prepared by sol-gel method. Their morphology and structure were characterized by transmission electron microscopy (TEM) and X-ray diffraction (XRD). The hybrid NPs are predominantly spherical in shape, with an average diameter of 180–200 nm, and each NP contains one inorganic core. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the hybrid NPs were examined against Staphylococcus aureus (S. aureus), Pseudomonas aeruginosa (P. aeruginosa) and Escherichia coli (E. coli), respectively. Results indicated that the AgBr@SiO{sub 2} NPs had excellent antibacterial activity. - Highlights: ► Presents a novel antibacterial agent “AgBr@ SiO{sub 2} NPs”. ► AgBr@SiO{sub 2} hybrid NPs could provide long-term antimicrobial effect. ► AgBr@SiO{sub 2} hybrid NPs have excellent antibacterial activity.

  10. Activation of dopamine D3 receptors inhibits reward-related learning induced by cocaine.

    Science.gov (United States)

    Kong, H; Kuang, W; Li, S; Xu, M

    2011-03-10

    Memories of learned associations between the rewarding properties of drugs and environmental cues contribute to craving and relapse in humans. The mesocorticolimbic dopamine (DA) system is involved in reward-related learning induced by drugs of abuse. DA D3 receptors are preferentially expressed in mesocorticolimbic DA projection areas. Genetic and pharmacological studies have shown that DA D3 receptors suppress locomotor-stimulant effects of cocaine and reinstatement of cocaine-seeking behaviors. Activation of the extracellular signal-regulated kinase (ERK) induced by acute cocaine administration is also inhibited by D3 receptors. How D3 receptors modulate cocaine-induced reward-related learning and associated changes in cell signaling in reward circuits in the brain, however, have not been fully investigated. In the present study, we show that D3 receptor mutant mice exhibit potentiated acquisition of conditioned place preference (CPP) at low doses of cocaine compared to wild-type mice. Activation of ERK and CaMKIIα, but not the c-Jun N-terminal kinase and p38, in the nucleus accumbens, amygdala and prefrontal cortex is also potentiated in D3 receptor mutant mice compared to that in wild-type mice following CPP expression. These results support a model in which D3 receptors modulate reward-related learning induced by low doses of cocaine by inhibiting activation of ERK and CaMKIIα in reward circuits in the brain. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

  11. Tonically Active α5GABAA Receptors Reduce Motoneuron Excitability and Decrease the Monosynaptic Reflex

    Directory of Open Access Journals (Sweden)

    Martha Canto-Bustos

    2017-09-01

    Full Text Available Motoneurons, the final common path of the Central Nervous System (CNS, are under a complex control of its excitability in order to precisely translate the interneuronal pattern of activity into skeletal muscle contraction and relaxation. To fulfill this relevant function, motoneurons are provided with a vast repertoire of receptors and channels, including the extrasynaptic GABAA receptors which have been poorly investigated. Here, we confirmed that extrasynaptic α5 subunit-containing GABAA receptors localize with choline acetyltransferase (ChAT positive cells, suggesting that these receptors are expressed in turtle motoneurons as previously reported in rodents. In these cells, α5GABAA receptors are activated by ambient GABA, producing a tonic shunt that reduces motoneurons’ membrane resistance and affects their action potential firing properties. In addition, α5GABAA receptors shunted the synaptic excitatory inputs depressing the monosynaptic reflex (MSR induced by activation of primary afferents. Therefore, our results suggest that α5GABAA receptors may play a relevant physiological role in motor control.

  12. Class A scavenger receptor promotes osteoclast differentiation via the enhanced expression of receptor activator of NF-{kappa}B (RANK)

    Energy Technology Data Exchange (ETDEWEB)

    Takemura, Kenichi [Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556 (Japan); Department of Orthopaedic and Neuro-Musculoskeletal Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto (Japan); Sakashita, Naomi; Fujiwara, Yukio; Komohara, Yoshihiro; Lei, XiaoFeng; Ohnishi, Koji [Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556 (Japan); Suzuki, Hiroshi [National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Hokkaido (Japan); Kodama, Tatsuhiko [Department of Molecular Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo (Japan); Mizuta, Hiroshi [Department of Orthopaedic and Neuro-Musculoskeletal Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto (Japan); Takeya, Motohiro, E-mail: takeya@kumamoto-u.ac.jp [Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556 (Japan)

    2010-01-22

    Osteoclasts originate from bone marrow monocyte/macrophage lineage cells, and their differentiation depends on macrophage colony-stimulating factor (M-CSF) and receptor activator nuclear factor kappa B (RANK) ligand. Class A scavenger receptor (SR-A) is one of the principal functional molecules of macrophages, and its level of expression declines during osteoclast differentiation. To investigate the role of SR-A in osteoclastogenesis, we examined pathological changes in femoral bone and the expression levels of osteoclastogenesis-related molecules in SR-A{sup -/-} mice. The femoral osseous density of SR-A{sup -/-} mice was higher than that of SR-A{sup +/+} mice, and the number of multinucleated osteoclasts was significantly decreased. An in vitro differentiation assay revealed that the differentiation of multinucleated osteoclasts from bone marrow-derived progenitor cells is impaired in SR-A{sup -/-} mice. Elimination of SR-A did not alter the expression level of the M-CSF receptor, c-fms; however, the expression levels of RANK and RANK-related osteoclast-differentiation molecules such as nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1) and microphthalmia-associated transcription factor (MITF) significantly decreased. Furthermore, acetylated low-density lipoprotein (AcLDL), an SR-A ligand, significantly increased the expression level of RANK and MITF during osteoclast differentiation. These data indicate that SR-A promotes osteoclastogenesis via augmentation of the expression level of RANK and its related molecules.

  13. Self-phosphorylation of epidermal growth factor receptor: evidence for a model of intermolecular allosteric activation

    International Nuclear Information System (INIS)

    Yarden, Y.; Schlessinger, J.

    1987-01-01

    The membrane receptor for epidermal growth factor (EGF) is a 170,000 dalton glycoprotein composed of an extracellular EGF-binding domain and a cytoplasmic kinase domain connected by a stretch of 23 amino acids traversing the plasma membrane. The binding of EGF to the extracellular domain activates the cytoplasmic kinase function even in highly purified preparations of EGF receptor, suggesting that the activation occurs exclusively within the EGF receptor moiety. Conceivably, kinase activation may require the transfer of a conformational change through the single transmembrane region from the ligand binding domain to the cytoplasmic kinase region. Alternatively, ligand-induced receptor-receptor interactions may activate the kinase and thus bypass this requirement. Both mechanisms were contrasted by employing independent experimental approaches. On the basis of these results, an allosteric aggregation model is formulated for the activation of the cytoplasmic kinase function of the receptor by EGF. This model may be relevant to the mechanism by which the mitogenic signal of EGF is transferred across the membrane

  14. Carbobenzoxy amino acids: Structural requirements for cholecystokinin receptor antagonist activity

    International Nuclear Information System (INIS)

    Maton, P.N.; Sutliff, V.E.; Jensen, R.T.; Gardner, J.D.

    1985-01-01

    The authors used dispersed acini prepared from guinea pig pancreas to examine 28 carbobenzoxy (CBZ) amino acids for their abilities to function as cholecystokinin receptor antagonists. All amino acid derivatives tested, except for CBZ-alanine, CBZ-glycine, and N alpha-CBZ- lysine, were able to inhibit the stimulation of amylase secretion caused by the C-terminal octapeptide of cholecystokinin. In general, there was a good correlation between the ability of a carbobenzoxy amino acid to inhibit stimulated amylase secretion and the ability of the amino acid derivative to inhibit binding of 125 I-cholecystokinin. The inhibition of cholecystokinin-stimulated amylase secretion was competitive, fully reversible, and specific for those secretagogues that interact with the cholecystokinin receptor. The potencies with which the various carbobenzoxy amino acids inhibited the action of cholecystokinin varied 100-fold and CBZ-cystine was the most potent cholecystokinin receptor antagonist. This variation in potency was primarily but not exclusively a function of the hydrophobicity of the amino acid side chain

  15. Interaction of active compounds from Aegle marmelos CORREA with histamine-1 receptor

    Science.gov (United States)

    Nugroho, Agung Endro; Agistia, Dany Dwi; Tegar, Maulana; Purnomo, Hari

    2013-01-01

    The aim of this study is to determine the affinity of six active compounds of Aegle Marmelos Correa, they are (E, R)-Marmin, skimmianine, (S)-aegeline, aurapten, zeorin, and dustanin as antihistamines in histamine H1 receptor in comparison to cetirizin, diphenhydramine and chlorpheniramine as ligands comparison. Previously, in the in vitro study marmin obviously antagonized the histamine H1 receptor in a competitive manner. Methods: molecular docking to determine the interaction of ligand binding to its receptor. Lower docking score indicates more stable binding to that protein. Results: Marmin, skimmianine, aegeline, aurapten, zeorin, and dustanin were potential to develop as antihistamine agents, especially as histamine H1 receptor antagonists by interacting with amino acid residues, Asp107, Lys179, Lys191, Asn198, and Trp428 of histamine H1 receptor. Conclusions: Based on molecular docking, Amino acid residues involved in ligand protein interactions were Asp107, Lys179, Lys191, Asn198, and Trp428. PMID:23750086

  16. Pharmacology of the hypothermic response to 5-HT1A receptor activation in humans.

    Science.gov (United States)

    Lesch, K P; Poten, B; Söhnle, K; Schulte, H M

    1990-01-01

    The selective 5-HT1A receptor ligand ipsapirone (IPS) caused dose-related hypothermia in humans. The response was attenuated by the nonselective 5-HT1/2 receptor antagonist metergoline and was completely antagonized by the nonselective beta-adrenoceptor antagonist pindolol, which interacts stereoselectively with the 5-HT1A receptor. The selective beta 1-adrenergic antagonist betaxolol had no effect. The findings indicate that IPS-induced hypothermia specifically involves activation of (presynaptic) 5-HT1A receptors. Therefore, the hypothermic response to IPS may provide a convenient in vivo paradigma to assess the function of the presynaptic 5-HT receptor in affective disorders and its involvement in the effects of psychotropic drugs.

  17. Attenuation of eph receptor kinase activation in cancer cells by coexpressed ephrin ligands.

    Directory of Open Access Journals (Sweden)

    Giulia Falivelli

    Full Text Available The Eph receptor tyrosine kinases mediate juxtacrine signals by interacting "in trans" with ligands anchored to the surface of neighboring cells via a GPI-anchor (ephrin-As or a transmembrane segment (ephrin-Bs, which leads to receptor clustering and increased kinase activity. Additionally, soluble forms of the ephrin-A ligands released from the cell surface by matrix metalloproteases can also activate EphA receptor signaling. Besides these trans interactions, recent studies have revealed that Eph receptors and ephrins coexpressed in neurons can also engage in lateral "cis" associations that attenuate receptor activation by ephrins in trans with critical functional consequences. Despite the importance of the Eph/ephrin system in tumorigenesis, Eph receptor-ephrin cis interactions have not been previously investigated in cancer cells. Here we show that in cancer cells, coexpressed ephrin-A3 can inhibit the ability of EphA2 and EphA3 to bind ephrins in trans and become activated, while ephrin-B2 can inhibit not only EphB4 but also EphA3. The cis inhibition of EphA3 by ephrin-B2 implies that in some cases ephrins that cannot activate a particular Eph receptor in trans can nevertheless inhibit its signaling ability through cis association. We also found that an EphA3 mutation identified in lung cancer enhances cis interaction with ephrin-A3. These results suggest a novel mechanism that may contribute to cancer pathogenesis by attenuating the tumor suppressing effects of Eph receptor signaling pathways activated by ephrins in trans.

  18. Interactions of ligands with active and inactive conformations of the dopamine D2 receptor.

    Science.gov (United States)

    Malmberg, A; Mohell, N; Backlund Höök, B; Johansson, A M; Hacksell, U; Nordvall, G

    1998-04-10

    The affinities of 19 pharmacologically diverse dopamine D2 receptor ligands were determined for the active and inactive conformations of cloned human dopamine D2 receptors expressed in Ltk cells. The agonist [3H]quinpirole was used to selectively label the guanine nucleotide-binding protein-coupled, active receptor conformation. The antagonist [3H]raclopride, in the presence of the non-hydrolysable GTP-analogue Gpp(NH)p and sodium ions and in the absence of magnesium ions, was used to label the free inactive receptor conformation. The intrinsic activities of the ligands were determined in a forskolin-stimulated cyclic AMP assay using the same cells. An excellent correlation was shown between the affinity ratios (KR/KRG) of the ligands for the two receptor conformations and their intrinsic activity (r=0.96). The ligands included eight structurally related and enantiopure 2-aminotetralin derivatives; the enantiomers of 5-hydroxy-2-(dipropylamino)tetralin, 5-methoxy-2-(dipropylamino)tetralin, 5-fluoro-2-(dipropylamino)tetralin and 2-(dipropylamino)tetralin. The (S)-enantiomers behaved as full agonists in the cyclic AMP assay and displayed a large KR/KRG ratio. The (R)-enantiomers were classified as partial agonists and had lower ratios. The structure-affinity relationships of these compounds at the active and the inactive receptor conformations were analysed separately, and used in conjunction with a homology based receptor model of the dopamine D2 receptor. This led to proposed binding modes for agonists, antagonists and partial agonists in the 2-aminotetralin series. The concepts used in this study should be of value in the design of ligands with predetermined affinity and intrinsic activity.

  19. The role and regulation of the peroxisome proliferator activated receptor alpha in human liver

    NARCIS (Netherlands)

    Kersten, Sander; Stienstra, Rinke

    2017-01-01

    The peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor that is abundantly expressed in liver. PPARα is activated by fatty acids and various other lipid species, as well as by a class of chemicals referred to as peroxisome proliferators. Studies in mice

  20. The soluble urokinase plasminogen activator receptor and its fragments in venous ulcers

    DEFF Research Database (Denmark)

    Ahmad, Anwar; Saha, Prakash; Evans, Colin

    2015-01-01

    OBJECTIVE: Activation of proteolytic mechanisms at the cell surface through the activity of urokinase-type plasminogen activator (uPA) bound to its receptor, uPAR, is an important process in wound healing. The soluble forms of uPAR (suPAR and its fragments I, II, and III) have nonproteolytic func...

  1. Synthesis of hybrid cellulose nanocomposite bonded with dopamine SiO2/TiO2 and its antimicrobial activity

    Science.gov (United States)

    Ramesh, Sivalingam; Kim, Gwang-Hoon; Kim, Jaehwan; Kim, Joo-Hyung

    2015-04-01

    Organic-inorganic hybrid material based cellulose was synthesized by the sol-gel approach. The explosion of activity in this area in the past decade has made tremendous progress in industry or academic both fundamental understanding of sol-gel process and applications of new functionalized hybrid materials. In this present research work, we focused on cellulose-dopamine functionalized SiO2/TiO2 hybrid nanocomposite by sol-gel process. The cellulose-dopamine hybrid nanocomposite was synthesized via γ-aminopropyltriethoxysilane (γ-APTES) coupling agent by in-situ sol-gel process. The chemical structure of cellulose-amine functionalized dopamine bonding to cellulose structure with covalent cross linking hybrids was confirmed by FTIR spectral analysis. The morphological analysis of cellulose-dopamine nanoSiO2/TiO2 hybrid nanocomposite materials was characterized by XRD, SEM and TEM. From this different analysis results indicate that the optical transparency, thermal stability, control morphology of cellulose-dopamine-SiO2/TiO2 hybrid nanocomposite. Furthermore cellulose-dopamine-SiO2/TiO2 hybrid nanocomposite was tested against pathogenic bacteria for antimicrobial activity.

  2. Tumorigenesis induced by the HHV8-encoded chemokine receptor requires ligand modulation of high constitutive activity

    DEFF Research Database (Denmark)

    Holst, P J; Rosenkilde, M M; Manfra, D

    2001-01-01

    sarcoma (KS). Here we demonstrate that several lines of mice carrying mutated receptors deficient in either constitutive activity or chemokine regulation fail to develop KS-like disease. In addition, animals expressing a receptor that preserves chemokine binding and constitutive activity but that does...... not respond to agonist stimulation have a much lower incidence of angiogenic lesions and tumors. These results indicate that induction of the KS-like disease in transgenic mice by ORF74 requires not only high constitutive signaling activity but also modulation of this activity by endogenous chemokines....

  3. Protease activated receptors (PARS) mediation in gyroxin biological activity; Mediacao dos receptores ativados por proteases (PARs) em atividades biologicas da giroxina

    Energy Technology Data Exchange (ETDEWEB)

    Silva, Jose Alberto Alves da

    2009-07-01

    Gyroxin is a serine protease enzyme from the South American rattlesnake (Crotalus durissus terrificus) venom; it is only partially characterized and has multiple activities. Gyroxin induces blood coagulation, blood pressure decrease and a neurotoxic behavior named barrel rotation. The mechanisms involved in this neurotoxic activity are not known. Whereas gyroxin is a member of enzymes with high potential to become a new drug with clinical applications such as thrombin, batroxobin, ancrod, tripsyn and kalicrein, it is important to find out how gyroxin works. The analysis on agarose gel electrophoresis and circular dichroism confirmed the molecules' integrity and purity. The gyroxin intravenous administration in mice proved its neurotoxicity (barrel rotation). In vivo studies employing intravital microscopy proved that gyroxin induces vasodilation with the participation of protease activated receptors (PARs), nitric oxide and Na+K+ATPase. The leukocytes' adherence and rolling counting indicated that gyroxin has no pro inflammatory activity. Gyroxin induced platelet aggregation, which was blocked by inhibitors of PAR1 and PAR4 receptors (SCH 79797 and tcY-NH{sub 2}, respectively). Finally, it was proved that the gyroxin temporarily alter the permeability of the blood brain barrier (BBB). Our study has shown that both the protease-activated receptors and nitric oxide are mediators involved in the biological activities of gyroxin. (author)

  4. Silver nanoparticles containing hybrid polymer microgels with tunable surface plasmon resonance and catalytic activity

    Energy Technology Data Exchange (ETDEWEB)

    Ajmal, Muhammad; Siddiq, Mohammad [Quaid-I-Azam University, Islamabad (Pakistan); Farooqi, Zahoor Hussain [University of the Punjab, Lahore (Pakistan)

    2013-11-15

    Multi-responsive poly(N-isopropylacrylamide-methacrylic acid-acrylamide) [P(NIPAM-MAA-AAm)] copolymer microgel was prepared by free radical emulsion polymerization. Silver nanoparticles were fabricated inside the microgel network by in-situ reduction of silver nitrate. Swelling and deswelling behavior of the pure microgels was studied under various conditions of pH and temperature using dynamic light scattering. A red shift was observed in surface plasmon resonance wavelength of Ag nanoparticles with pH induced swelling of hybrid microgel. The catalytic activity of the hybrid system was investigated by monitoring the reduction of p-nitrophenol under different conditions of temperature and amount of catalysts. For this catalytic reaction a time delay of 8 to 10min was observed at room temperature, which was reduced to 2 min at high temperature due to swelling of microgels, which facilitated diffusion of reactants to catalyst surface and increased rate of reaction.

  5. Hybrid Modulation of Bidirectional Three-Phase Dual-Active-Bridge DC Converters for Electric Vehicles

    Directory of Open Access Journals (Sweden)

    Yen-Ching Wang

    2016-06-01

    Full Text Available Bidirectional power converters for electric vehicles (EVs have received much attention recently, due to either grid-supporting requirements or emergent power supplies. This paper proposes a hybrid modulation of the three-phase dual-active bridge (3ΦDAB converter for EV charging systems. The designed hybrid modulation allows the converter to switch its modulation between phase-shifted and trapezoidal modes to increase the conversion efficiency, even under light-load conditions. The mode transition is realized in a real-time manner according to the charging or discharging current. The operation principle of the converter is analyzed in different modes and thus design considerations of the modulation are derived. A lab-scaled prototype circuit with a 48V/20Ah LiFePO4 battery is established to validate the feasibility and effectiveness.

  6. Activation of peroxisome proliferator-activated receptor-{alpha} enhances fatty acid oxidation in human adipocytes

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Joo-Young; Hashizaki, Hikari; Goto, Tsuyoshi; Sakamoto, Tomoya; Takahashi, Nobuyuki [Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011 (Japan); Kawada, Teruo, E-mail: fat@kais.kyoto-u.ac.jp [Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011 (Japan)

    2011-04-22

    Highlights: {yields} PPAR{alpha} activation increased mRNA expression levels of adipocyte differentiation marker genes and GPDH activity in human adipocytes. {yields} PPAR{alpha} activation also increased insulin-dependent glucose uptake in human adipocytes. {yields} PPAR{alpha} activation did not affect lipid accumulation in human adipocytes. {yields} PPAR{alpha} activation increased fatty acid oxidation through induction of fatty acid oxidation-related genes in human adipocytes. -- Abstract: Peroxisome proliferator-activated receptor-{alpha} (PPAR{alpha}) is a key regulator for maintaining whole-body energy balance. However, the physiological functions of PPAR{alpha} in adipocytes have been unclarified. We examined the functions of PPAR{alpha} using human multipotent adipose tissue-derived stem cells as a human adipocyte model. Activation of PPAR{alpha} by GW7647, a potent PPAR{alpha} agonist, increased the mRNA expression levels of adipocyte differentiation marker genes such as PPAR{gamma}, adipocyte-specific fatty acid-binding protein, and lipoprotein lipase and increased both GPDH activity and insulin-dependent glucose uptake level. The findings indicate that PPAR{alpha} activation stimulates adipocyte differentiation. However, lipid accumulation was not changed, which is usually observed when PPAR{gamma} is activated. On the other hand, PPAR{alpha} activation by GW7647 treatment induced the mRNA expression of fatty acid oxidation-related genes such as CPT-1B and AOX in a PPAR{alpha}-dependent manner. Moreover, PPAR{alpha} activation increased the production of CO{sub 2} and acid soluble metabolites, which are products of fatty acid oxidation, and increased oxygen consumption rate in human adipocytes. The data indicate that activation of PPAR{alpha} stimulates both adipocyte differentiation and fatty acid oxidation in human adipocytes, suggesting that PPAR{alpha} agonists could improve insulin resistance without lipid accumulation in adipocytes. The expected

  7. GPCR-I-TASSER: A Hybrid Approach to G Protein-Coupled Receptor Structure Modeling and the Application to the Human Genome.

    Science.gov (United States)

    Zhang, Jian; Yang, Jianyi; Jang, Richard; Zhang, Yang

    2015-08-04

    Experimental structure determination remains difficult for G protein-coupled receptors (GPCRs). We propose a new hybrid protocol to construct GPCR structure models that integrates experimental mutagenesis data with ab initio transmembrane (TM) helix assembly simulations. The method was tested on 24 known GPCRs where the ab initio TM-helix assembly procedure constructed the correct fold for 20 cases. When combined with weak homology and sparse mutagenesis restraints, the method generated correct folds for all the tested cases with an average Cα root-mean-square deviation 2.4 Å in the TM regions. The new hybrid protocol was applied to model all 1,026 GPCRs in the human genome, where 923 have a high confidence score and are expected to have correct folds; these contain many pharmaceutically important families with no previously solved structures, including Trace amine, Prostanoids, Releasing hormones, Melanocortins, Vasopressin, and Neuropeptide Y receptors. The results demonstrate new progress on genome-wide structure modeling of TM proteins. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. Activation of the kinin B1 receptor attenuates melanoma tumor growth and metastasis.

    Directory of Open Access Journals (Sweden)

    Patricia Dillenburg-Pilla

    Full Text Available Melanoma is a very aggressive tumor that does not respond well to standard therapeutic approaches, such as radio- and chemotherapies. Furthermore, acquiring the ability to metastasize in melanoma and many other tumor types is directly related to incurable disease. The B1 kinin receptor participates in a variety of cancer-related pathophysiological events, such as inflammation and angiogenesis. Therefore, we investigated whether this G protein-coupled receptor plays a role in tumor progression. We used a murine melanoma cell line that expresses the kinin B1 receptor and does not express the kinin B2 receptor to investigate the precise contribution of activation of the B1 receptor in tumor progression and correlated events using various in vitro and in vivo approaches. Activation of the kinin B1 receptor in the absence of B2 receptor inhibits cell migration in vitro and decreases tumor formation in vivo. Moreover, tumors formed from cells stimulated with B1-specific agonist showed several features of decreased aggressiveness, such as smaller size and infiltration of inflammatory cells within the tumor area, higher levels of pro-inflammatory cytokines implicated in the host anti-tumor immune response, lower number of cells undergoing mitosis, a poorer vascular network, no signs of invasion of surrounding tissues or metastasis and increased animal survival. Our findings reveal that activation of the kinin B1 receptor has a host protective role during murine melanoma tumor progression, suggesting that the B1 receptor could be a new anti-tumor GPCR and provide new opportunities for therapeutic targeting.

  9. Activation of synaptic and extrasynaptic glycine receptors by taurine in preoptic hypothalamic neurons.

    Science.gov (United States)

    Bhattarai, Janardhan Prasad; Park, Soo Joung; Chun, Sang Woo; Cho, Dong Hyu; Han, Seong Kyu

    2015-11-03

    Taurine is an essential amino-sulfonic acid having a fundamental function in the brain, participating in both cell volume regulation and neurotransmission. Using a whole cell voltage patch clamp technique, the taurine-activated neurotransmitter receptors in the preoptic hypothalamic area (PHA) neurons were investigated. In the first set of experiments, different concentrations of taurine were applied on PHA neurons. Taurine-induced responses were concentration-dependent. Taurine-induced currents were action potential-independent and sensitive to strychnine, suggesting the involvement of glycine receptors. In addition, taurine activated not only α-homomeric, but also αβ-heteromeric glycine receptors in PHA neurons. Interestingly, a low concentration of taurine (0.5mM) activated glycine receptors, whereas a higher concentration (3mM) activated both glycine and gamma-aminobutyric acid A (GABAA) receptors in PHA neurons. These results suggest that PHA neurons are influenced by taurine and respond via glycine and GABAA receptors. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  10. 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.

  11. Activation of GLP-1 Receptor Promotes Bone Marrow Stromal Cell Osteogenic Differentiation through β-Catenin

    Directory of Open Access Journals (Sweden)

    Jingru Meng

    2016-04-01

    Full Text Available Glucagon-like peptide 1 (GLP-1 plays an important role in regulating bone remodeling, and GLP-1 receptor agonist shows a positive relationship with osteoblast activity. However, GLP-1 receptor is not found in osteoblast, and the mechanism of GLP-1 receptor agonist on regulating bone remodeling is unclear. Here, we show that the GLP-1 receptor agonist exendin-4 (Ex-4 promoted bone formation and increased bone mass and quality in a rat unloading-induced bone loss model. These functions were accompanied by an increase in osteoblast number and serum bone formation markers, while the adipocyte number was decreased. Furthermore, GLP-1 receptor was detected in bone marrow stromal cells (BMSCs, but not in osteoblast. Activation of GLP-1 receptor by Ex-4 promoted the osteogenic differentiation and inhibited BMSC adipogenic differentiation through regulating PKA/β-catenin and PKA/PI3K/AKT/GSK3β signaling. These findings reveal that GLP-1 receptor regulates BMSC osteogenic differentiation and provide a molecular basis for therapeutic potential of GLP-1 against osteoporosis.

  12. Mood states, sympathetic activity, and in vivo beta-adrenergic receptor function in a normal population.

    Science.gov (United States)

    Yu, Bum-Hee; Kang, Eun-Ho; Ziegler, Michael G; Mills, Paul J; Dimsdale, Joel E

    2008-01-01

    The purpose of this study was to examine the relationship between mood states and beta-adrenergic receptor function in a normal population. We also examined if sympathetic nervous system activity is related to mood states or beta-adrenergic receptor function. Sixty-two participants aged 25-50 years were enrolled in this study. Mood states were assessed using the Profile of Mood States (POMS). Beta-adrenergic receptor function was determined using the chronotropic 25 dose isoproterenol infusion test. Level of sympathetic nervous system activity was estimated from 24-hr urine norepinephrine excretion. Higher tension-anxiety, depression-dejection, and anger-hostility were related to decreased beta-adrenergic receptor sensitivity (i.e., higher chronotropic 25 dose values), but tension-anxiety was the only remaining independent predictor of beta-adrenergic receptor function after controlling for age, gender, ethnicity, and body mass index (BMI). Urinary norepinephrine excretion was unrelated to either mood states or beta-adrenergic receptor function. These findings replicate previous reports that anxiety is related to decreased (i.e., desensitized) beta-adrenergic receptor sensitivity, even after controlling for age, gender, ethnicity, and body mass index.

  13. Analgesic tone conferred by constitutively active mu opioid receptors in mice lacking β-arrestin 2

    Directory of Open Access Journals (Sweden)

    Hales Tim G

    2011-04-01

    Full Text Available Abstract Hedonic reward, dependence and addiction are unwanted effects of opioid analgesics, linked to the phasic cycle of μ opioid receptor activation, tolerance and withdrawal. In vitro studies of recombinant G protein coupled receptors (GPCRs over expressed in cell lines reveal an alternative tonic signaling mechanism that is independent of agonist. Such studies demonstrate that constitutive GPCR signaling can be inhibited by inverse agonists but not by neutral antagonists. However, ligand-independent activity has been difficult to examine in vivo, at the systems level, due to relatively low levels of constitutive activity of most GPCRs including μ receptors, often necessitating mutagenesis or pharmacological manipulation to enhance basal signaling. We previously demonstrated that the absence of β-arrestin 2 (β-arr2 augments the constitutive coupling of μ receptors to voltage-activated Ca2+ channels in primary afferent dorsal root ganglion neurons from β-arr2-/- mice. We used this in vitro approach to characterize neutral competitive antagonists and inverse agonists of the constitutively active wild type μ receptors in neurons. We administered these agents to β-arr2-/- mice to explore the role of constitutive μ receptor activity in nociception and hedonic tone. This study demonstrates that the induction of constitutive μ receptor activity in vivo in β-arr2-/- mice prolongs tail withdrawal from noxious heat, a phenomenon that was reversed by inverse agonists, but not by antagonists that lack negative efficacy. By contrast, the aversive effects of inverse agonists were similar in β-arr2-/- and β-arr2+/+ mice, suggesting that hedonic tone was unaffected.

  14. 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”.

  15. How does high-frequency sound or vibration activate vestibular receptors?

    Science.gov (United States)

    Curthoys, I S; Grant, J W

    2015-03-01

    The mechanism by which vestibular neural phase locking occurs and how it relates to classical otolith mechanics is unclear. Here, we put forward the hypothesis that sound and vibration both cause fluid pressure waves in the inner ear and that it is these pressure waves which displace the hair bundles on vestibular receptor hair cells and result in activation of type I receptor hair cells and phase locking of the action potentials in the irregular vestibular afferents, which synapse on type I receptors. This idea has been suggested since the early neural recordings and recent results give it greater credibility.

  16. Molecular simulation of receptors of physiologically active compounds for purposes of medical chemistry

    Science.gov (United States)

    Baskin, Igor I.; Palyulin, Vladimir A.; Zefirov, Nikolai S.

    2009-06-01

    The general strategy of the molecular simulation of biological receptors and their interaction with ligands is considered. The procedures for construction of 3D protein models, molecular docking, evaluation of model quality, determination of the free energy of protein binding with ligands are discussed. The methods of molecular design of new medicaments based on molecular models of biological targets: virtual screening and de novo design, are presented. Examples of the above-listed approaches for the simulation of a number of pharmacologically significant receptors, analysis of receptor-ligand interactions and design of new biologically active organic compounds are given.

  17. Molecular simulation of receptors of physiologically active compounds for purposes of medical chemistry

    International Nuclear Information System (INIS)

    Baskin, Igor I; Palyulin, Vladimir A; Zefirov, Nikolai S

    2009-01-01

    The general strategy of the molecular simulation of biological receptors and their interaction with ligands is considered. The procedures for construction of 3D protein models, molecular docking, evaluation of model quality, determination of the free energy of protein binding with ligands are discussed. The methods of molecular design of new medicaments based on molecular models of biological targets: virtual screening and de novo design, are presented. Examples of the above-listed approaches for the simulation of a number of pharmacologically significant receptors, analysis of receptor-ligand interactions and design of new biologically active organic compounds are given.

  18. Molecular simulation of receptors of physiologically active compounds for purposes of medical chemistry

    Energy Technology Data Exchange (ETDEWEB)

    Baskin, Igor I; Palyulin, Vladimir A; Zefirov, Nikolai S [Department of Chemistry, M.V. Lomonosov Moscow State University, Moscow (Russian Federation)

    2009-06-30

    The general strategy of the molecular simulation of biological receptors and their interaction with ligands is considered. The procedures for construction of 3D protein models, molecular docking, evaluation of model quality, determination of the free energy of protein binding with ligands are discussed. The methods of molecular design of new medicaments based on molecular models of biological targets: virtual screening and de novo design, are presented. Examples of the above-listed approaches for the simulation of a number of pharmacologically significant receptors, analysis of receptor-ligand interactions and design of new biologically active organic compounds are given.

  19. Rheumatic Disease: Protease-Activated Receptor-2 in Synovial Joint Pathobiology

    Directory of Open Access Journals (Sweden)

    Kendal McCulloch

    2018-05-01

    Full Text Available Protease-activated receptor-2 (PAR2 is one member of a small family of transmembrane, G-protein-coupled receptors. These receptors are activated via cleavage of their N terminus by serine proteases (e.g., tryptase, unveiling an N terminus tethered ligand which binds to the second extracellular loop of the receptor. Increasing evidence has emerged identifying key pathophysiological roles for PAR2 in both rheumatoid arthritis (RA and osteoarthritis (OA. Importantly, this includes both pro-inflammatory and destructive roles. For example, in murine models of RA, the associated synovitis, cartilage degradation, and subsequent bone erosion are all significantly reduced in the absence of PAR2. Similarly, in experimental models of OA, PAR2 disruption confers protection against cartilage degradation, subchondral bone osteosclerosis, and osteophyte formation. This review focuses on the role of PAR2 in rheumatic disease and its potential as an important therapeutic target for treating pain and joint degradation.

  20. Thyroid hormone and retinoic acid nuclear receptors: specific ligand-activated transcription factors

    International Nuclear Information System (INIS)

    Brtko, J.

    1998-01-01

    Transcriptional regulation by both the thyroid hormone and the vitamin A-derived 'retinoid hormones' is a critical component in controlling many aspects of higher vertebrate development and metabolism. Their functions are mediated by nuclear receptors, which comprise a large super-family of ligand-inducible transcription factors. Both the thyroid hormone and the retinoids are involved in a complex arrangement of physiological and development responses in many tissues of higher vertebrates. The functions of 3,5,3'-triiodothyronine (T 3 ), the thyromimetically active metabolite of thyroxine as well as all-trans retinoic acid, the biologically active vitamin A metabolite are mediated by nuclear receptor proteins that are members of the steroid/thyroid/retinoid hormone receptor family. The functions of all members of the receptor super family are discussed. (authors)

  1. Mechanical stress activates NMDA receptors in the absence of agonists

    OpenAIRE

    Maneshi, Mohammad Mehdi; Maki, Bruce; Gnanasambandam, Radhakrishnan; Belin, Sophie; Popescu, Gabriela K.; Sachs, Frederick; Hua, Susan Z.

    2017-01-01

    While studying the physiological response of primary rat astrocytes to fluid shear stress in a model of traumatic brain injury (TBI), we found that shear stress induced Ca2+ entry. The influx was inhibited by MK-801, a specific pore blocker of N-Methyl-D-aspartic acid receptor (NMDAR) channels, and this occurred in the absence of agonists. Other NMDA open channel blockers ketamine and memantine showed a similar effect. The competitive glutamate antagonists AP5 and GluN2B-selective inhibitor i...

  2. Structural motifs of importance for the constitutive activity of the orphan 7TM receptor EBI2: analysis of receptor activation in the absence of an agonist

    DEFF Research Database (Denmark)

    Benned-Jensen, Tau; Rosenkilde, Mette M

    2008-01-01

    were identified by a systematic mutational analysis of 29 residues in EBI2. The cAMP response element-binding protein transcription factor was used as a measure of receptor activity and was correlated to the receptor surface expression. PheVI:13 (Phe257), and the neighboring CysVI:12 (Cys256......, but not to Lys, decreased the constitutive activity more than 7-fold compared with wt EBI2. IleIII:03 (Ile106) is located only 4 A from ArgII:20, and a favorable electrostatic interaction with ArgII:20 was created by introduction of Glu in III:03, given that the activity increased to 4.4-fold of that wt EBI2...

  3. Acutely increasing δGABAA receptor activity impairs memory and inhibits synaptic plasticity in the hippocampus

    Science.gov (United States)

    Whissell, Paul D.; Eng, Dave; Lecker, Irene; Martin, Loren J.; Wang, Dian-Shi; Orser, Beverley A.

    2013-01-01

    Extrasynaptic γ-aminobutyric acid type A (GABAA) receptors that contain the δ subunit (δGABAA receptors) are expressed in several brain regions including the dentate gyrus (DG) and CA1 subfields of the hippocampus. Drugs that increase δGABAA receptor activity have been proposed as treatments for a variety of disorders including insomnia, epilepsy and chronic pain. Also, long-term pretreatment with the δGABAA receptor–preferring agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) enhances discrimination memory and increases neurogenesis in the DG. Despite the potential therapeutic benefits of such treatments, the effects of acutely increasing δGABAA receptor activity on memory behaviors remain unknown. Here, we studied the effects of THIP (4 mg/kg, i.p.) on memory performance in wild-type (WT) and δGABAA receptor null mutant (Gabrd−/−) mice. Additionally, the effects of THIP on long-term potentiation (LTP), a molecular correlate of memory, were studied within the DG and CA1 subfields of the hippocampus using electrophysiological recordings of field potentials in hippocampal slices. The results showed that THIP impaired performance in the Morris water maze, contextual fear conditioning and object recognition tasks in WT mice but not Gabrd−/− mice. Furthermore, THIP inhibited LTP in hippocampal slices from WT but not Gabrd−/− mice, an effect that was blocked by GABAA receptor antagonist bicuculline. Thus, acutely increasing δGABAA receptor activity impairs memory behaviors and inhibits synaptic plasticity. These results have important implications for the development of therapies aimed at increasing δGABAA receptor activity. PMID:24062648

  4. Acutely increasing δGABAA receptor activity impairs memory and inhibits synaptic plasticity in the hippocampus

    Directory of Open Access Journals (Sweden)

    Paul David Whissell

    2013-09-01

    Full Text Available Extrasynaptic γ-aminobutyric acid type A (GABAA receptors that contain the δ subunit (δGABAA receptors are expressed in several brain regions including the dentate gyrus (DG and CA1 subfields of the hippocampus. Drugs that increase δGABAA receptor activity have been proposed as treatments for a variety of disorders including insomnia, epilepsy and chronic pain. Also, long-term pretreatment with the δGABAA receptor–preferring agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP enhances discrimination memory and increases neurogenesis in the DG. Despite the potential therapeutic benefits of such treatments, the effects of acutely increasing δGABAA receptor activity on memory behaviors remain unknown. Here, we studied the effects of THIP (4 mg/kg, i.p. on memory performance in wild-type (WT and δGABAA receptor null mutant (Gabrd–/– mice. Additionally, the effects of THIP on long-term potentiation (LTP, a molecular correlate of memory, were studied within the DG and CA1 subfields of the hippocampus using electrophysiological recordings of field potentials in hippocampal slices. The results showed that THIP impaired performance in the Morris water maze, contextual fear conditioning and object recognition tasks in WT mice but not Gabrd–/– mice. Furthermore, THIP inhibited LTP in hippocampal slices from WT but not Gabrd–/– mice, an effect that was blocked by GABAA receptor antagonist bicuculline. Thus, acutely increasing δGABAA receptor activity impairs memory behaviors and inhibits synaptic plasticity. These results have important implications for the development of therapies aimed at increasing δGABAA receptor activity.

  5. Cow's milk increases the activities of human nuclear receptors peroxisome proliferator-activated receptors alpha and delta and retinoid X receptor alpha involved in the regulation of energy homeostasis, obesity, and inflammation.

    Science.gov (United States)

    Suhara, W; Koide, H; Okuzawa, T; Hayashi, D; Hashimoto, T; Kojo, H

    2009-09-01

    The nuclear peroxisome proliferator-activated receptors (PPAR) have been shown to play crucial roles in regulating energy homeostasis including lipid and carbohydrate metabolism, inflammatory responses, and cell proliferation, differentiation, and survival. Because PPAR agonists have the potential to prevent or ameliorate diseases such as hyperlipidemia, diabetes, atherosclerosis, and obesity, we have explored new natural agonists for PPAR. For this purpose, cow's milk was tested for agonistic activity toward human PPAR subtypes using a reporter gene assay. Milk increased human PPARalpha activity in a dose-dependent manner with a 3.2-fold increase at 0.5% (vol/vol). It also enhanced human PPARdelta activity in a dose-dependent manner with an 11.5-fold increase at 0.5%. However, it only slightly affected human PPARgamma activity. Ice cream, butter, and yogurt also increased the activities of PPARalpha and PPARdelta, whereas vegetable cream affected activity of PPARdelta but not PPARalpha. Skim milk enhanced the activity of PPAR to a lesser degree than regular milk. Milk and fresh cream increased the activity of human retinoid X receptor (RXR)alpha as well as PPARalpha and PPARdelta, whereas neither affected vitamin D3 receptor, estrogen receptors alpha and beta, or thyroid receptors alpha and beta. Both milk and fresh cream were shown by quantitative real-time PCR to increase the quantity of mRNA for uncoupling protein 2 (UCP2), an energy expenditure gene, in a dose-dependent manner. The increase in UCP2 mRNA was found to be reduced by treatment with PPARdelta-short interfering (si)RNA. This study unambiguously clarified at the cellular level that cow's milk increased the activities of human PPARalpha, PPARdelta, and RXRalpha. The possible role in enhancing the activities of PPARalpha, PPARdelta, and RXRalpha, and the health benefits of cow's milk were discussed.

  6. Histamine induces microglia activation and dopaminergic neuronal toxicity via H1 receptor activation.

    Science.gov (United States)

    Rocha, Sandra M; Saraiva, Tatiana; Cristóvão, Ana C; Ferreira, Raquel; Santos, Tiago; Esteves, Marta; Saraiva, Cláudia; Je, Goun; Cortes, Luísa; Valero, Jorge; Alves, Gilberto; Klibanov, Alexander; Kim, Yoon-Seong; Bernardino, Liliana

    2016-06-04

    Histamine is an amine widely known as a peripheral inflammatory mediator and as a neurotransmitter in the central nervous system. Recently, it has been suggested that histamine acts as an innate modulator of microglial activity. Herein, we aimed to disclose the role of histamine in microglial phagocytic activity and reactive oxygen species (ROS) production and to explore the consequences of histamine-induced neuroinflammation in dopaminergic (DA) neuronal survival. The effect of histamine on phagocytosis was assessed both in vitro by using a murine N9 microglial cell line and primary microglial cell cultures and in vivo. Cells were exposed to IgG-opsonized latex beads or phosphatidylserine (PS) liposomes to evaluate Fcγ or PS receptor-mediated microglial phagocytosis, respectively. ROS production and protein levels of NADPH oxidases and Rac1 were assessed as a measure of oxidative stress. DA neuronal survival was evaluated in vivo by counting the number of tyrosine hydroxylase-positive neurons in the substantia nigra (SN) of mice. We found that histamine triggers microglial phagocytosis via histamine receptor 1 (H1R) activation and ROS production via H1R and H4R activation. By using apocynin, a broad NADPH oxidase (Nox) inhibitor, and Nox1 knockout mice, we found that the Nox1 signaling pathway is involved in both phagocytosis and ROS production induced by histamine in vitro. Interestingly, both apocynin and annexin V (used as inhibitor of PS-induced phagocytosis) fully abolished the DA neurotoxicity induced by the injection of histamine in the SN of adult mice in vivo. Blockade of H1R protected against histamine-induced Nox1 expression and death of DA neurons in vivo. Overall, our results highlight the relevance of histamine in the modulation of microglial activity that ultimately may interfere with neuronal survival in the context of Parkinson's disease (PD) and, eventually, other neurodegenerative diseases which are accompanied by microglia

  7. Molecular characterization of the receptor binding structure-activity relationships of influenza B virus hemagglutinin.

    Science.gov (United States)

    Carbone, V; Kim, H; Huang, J X; Baker, M A; Ong, C; Cooper, M A; Li, J; Rockman, S; Velkov, T

    2013-01-01

    Selectivity of α2,6-linked human-like receptors by B hemagglutinin (HA) is yet to be fully understood. This study integrates binding data with structure-recognition models to examine the impact of regional-specific sequence variations within the receptor-binding pocket on selectivity and structure activity relationships (SAR). The receptor-binding selectivity of influenza B HAs corresponding to either B/Victoria/2/1987 or the B/Yamagata/16/88 lineages was examined using surface plasmon resonance, solid-phase ELISA and gel-capture assays. Our SAR data showed that the presence of asialyl sugar units is the main determinant of receptor preference of α2,6 versus α2,3 receptor binding. Changes to the type of sialyl-glycan linkage present on receptors exhibit only a minor effect upon binding affinity. Homology-based structural models revealed that structural properties within the HA pocket, such as a glyco-conjugate at Asn194 on the 190-helix, sterically interfere with binding to avian receptor analogs by blocking the exit path of the asialyl sugars. Similarly, naturally occurring substitutions in the C-terminal region of the 190-helix and near the N-terminal end of the 140-loop narrows the horizontal borders of the binding pocket, which restricts access of the avian receptor analog LSTa. This study helps bridge the gap between ligand structure and receptor recognition for influenza B HA; and provides a consensus SAR model for the binding of human and avian receptor analogs to influenza B HA.

  8. Exercise reduces adipose tissue via cannabinoid receptor type 1 which is regulated by peroxisome proliferator-activated receptor

    International Nuclear Information System (INIS)

    Yan Zhencheng; Liu Daoyan; Zhang Lili; Shen Chenyi; Ma Qunli; Cao Tingbing; Wang Lijuan; Nie Hai; Zidek, Walter; Tepel, Martin; Zhu Zhiming

    2007-01-01

    Obesity is one major cardiovascular risk factor. We tested effects of endurance exercise on cannabinoid receptor type 1 (CB1) and peroxisome proliferator-activated receptor-δ (PPAR-δ)-dependent pathways in adipose tissue. Male Wistar rats were randomly assigned to standard laboratory chow or a high-fat diet without and with regular endurance exercise. Exercise in rats on high-fat diet significantly reduced visceral fat mass, blood pressure, and adipocyte size (each p < 0.05). Adipocyte hypertrophy induced by high-fat diet was accompanied by increased CB1 expression in adipose tissue, whereas exercise significantly reduced CB1 expression (each p < 0.05). CB1 receptor expression and adipocyte differentiation were directly regulated by PPAR-δ. Adipocyte hypertrophy induced by high-fat diet was accompanied by reduced PPAR-δ. Furthermore, selective silencing of PPAR-δ by RNA interference in 3T3-L1-preadipocyte cells significantly increased CB1 expression from 1.00 ± 0.06 (n = 3) to 1.91 ± 0.06 (n = 3; p < 0.01) and increased adipocyte differentiation, whereas adenovirus-mediated overexpression of PPAR-δ significantly reduced CB1 expression to 0.39 ± 0.03 (n = 3; p < 0.01) and reduced adipocyte differentiation. In the presence of the CB1 antagonist rimonabant adipocyte differentiation in stimulated 3T3 L1 preadipocyte cells was significantly reduced. The study indicates that high-fat diet-induced hypertrophy of adipocytes is associated with increased CB1 receptor expression which is directly regulated by PPAR-δ. Both CB1 and PPAR-δ are intimately involved in therapeutic interventions against a most important cardiovascular risk factor

  9. Natural compounds regulate energy metabolism by the modulating the activity of lipid-sensing nuclear receptors.

    Science.gov (United States)

    Goto, Tsuyoshi; Kim, Young-Il; Takahashi, Nobuyuki; Kawada, Teruo

    2013-01-01

    Obesity causes excess fat accumulation in various tissues, most notoriously in the adipose tissue, along with other insulin-responsive organs such as skeletal muscle and the liver, which predisposes an individual to the development of metabolic abnormalities. The molecular mechanisms underlying obesity-induced metabolic abnormalities have not been completely elucidated; however, in recent years, the search for therapies to prevent the development of obesity and obesity-associated metabolic disorders has increased. It is known that several nuclear receptors, when activated by specific ligands, regulate carbohydrate and lipid metabolism at the transcriptional level. The expression of lipid metabolism-related enzymes is directly regulated by the activity of various nuclear receptors via their interaction with specific response elements in promoters of those genes. Many natural compounds act as ligands of nuclear receptors and regulate carbohydrate and lipid metabolism by regulating the activities of these nuclear receptors. In this review, we describe our current knowledge of obesity, the role of lipid-sensing nuclear receptors in energy metabolism, and several examples of food factors that act as agonists or antagonists of nuclear receptors, which may be useful for the management of obesity and the accompanying energy metabolism abnormalities. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. MMP activity in the hybrid layer detected with in situ zymography.

    Science.gov (United States)

    Mazzoni, A; Nascimento, F D; Carrilho, M; Tersariol, I; Papa, V; Tjäderhane, L; Di Lenarda, R; Tay, F R; Pashley, D H; Breschi, L

    2012-05-01

    Dentinal proteases are believed to play an important role in the degradation of hybrid layers (HL). This study investigated the HL gelatinolytic activity by in situ zymography and functional enzyme activity assay. The hypotheses were that HLs created by an etch-and-rinse adhesive exhibit active gelatinolytic activity, and MMP-2 and -9 activities in dentin increase during adhesive procedures. Etched-dentin specimens were bonded with Adper Scotchbond 1XT and restored with composite. Adhesive/dentin interface slices were placed on microscope slides, covered with fluorescein-conjugated gelatin, and observed with a multi-photon confocal microscope after 24 hrs. Human dentin powder aliquots were prepared and assigned to the following treatments: A, untreated; B, etched with 10% phosphoric acid; or C, etched with 10% phosphoric acid and mixed with Scotchbond 1XT. The MMP-2 and -9 activities of extracts of dentin powder were measured with functional enzyme assays. Intense and continuous enzyme activity was detected at the bottom of the HL, while that activity was more irregular in the upper HL. Both acid-etching and subsequent adhesive application significantly increased MMP-2 and -9 activities (p < 0.05). The results demonstrate, for the first time, intrinsic MMP activity in the HL, and intense activation of matrix-bound MMP activity with both etching and adhesive application.

  11. Telmisartan prevents weight gain and obesity through activation of peroxisome proliferator-activated receptor-delta-dependent pathways

    DEFF Research Database (Denmark)

    He, Hongbo; Yang, Dachun; Ma, Liqun

    2010-01-01

    Telmisartan shows antihypertensive and several pleiotropic effects that interact with metabolic pathways. In the present study we tested the hypothesis that telmisartan prevents adipogenesis in vitro and weight gain in vivo through activation of peroxisome proliferator-activated receptor (PPAR)-d...

  12. Conformation guides molecular efficacy in docking screens of activated β-2 adrenergic G protein coupled receptor.

    Science.gov (United States)

    Weiss, Dahlia R; Ahn, SeungKirl; Sassano, Maria F; Kleist, Andrew; Zhu, Xiao; Strachan, Ryan; Roth, Bryan L; Lefkowitz, Robert J; Shoichet, Brian K

    2013-05-17

    A prospective, large library virtual screen against an activated β2-adrenergic receptor (β2AR) structure returned potent agonists to the exclusion of inverse-agonists, providing the first complement to the previous virtual screening campaigns against inverse-agonist-bound G protein coupled receptor (GPCR) structures, which predicted only inverse-agonists. In addition, two hits recapitulated the signaling profile of the co-crystal ligand with respect to the G protein and arrestin mediated signaling. This functional fidelity has important implications in drug design, as the ability to predict ligands with predefined signaling properties is highly desirable. However, the agonist-bound state provides an uncertain template for modeling the activated conformation of other GPCRs, as a dopamine D2 receptor (DRD2) activated model templated on the activated β2AR structure returned few hits of only marginal potency.

  13. Peroxisome Proliferator-activated Receptor gamma Regulates Expression of the Anti-lipolytic G-protein-coupled Receptor 81 (GPR81/Gpr81)

    NARCIS (Netherlands)

    Jeninga, E.H.; Bugge, A.; Nielsen, R.; Kersten, A.H.; Hamers, N.; Dani, C.; Wabitsch, M.; Berger, R.; Stunnenberg, H.G.; Mandrup, S.; Kalkhoven, E.

    2009-01-01

    The ligand-inducible nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) plays a key role in the differentiation, maintenance, and function of adipocytes and is the molecular target for the insulin-sensitizing thiazoledinediones (TZDs). Although a number of PPAR gamma

  14. Peptides derived from specific interaction sites of the fibroblast growth factor 2 - FGF receptor complexes induce receptor activation and signaling

    DEFF Research Database (Denmark)

    Manfè, Valentina; Kochoyan, Artur; Bock, Elisabeth

    2010-01-01

    J. Neurochem. (2010) 10.1111/j.1471-4159.2010.06718.x Abstract Basic fibroblast growth factor (FGF2, bFGF) is the most extensively studied member of the FGF family and is involved in neurogenesis, differentiation, neuroprotection, and synaptic plasticity in the CNS. FGF2 executes its pleiotropic...... biologic actions by binding, dimerizing, and activating FGF receptors (FGFRs). The present study reports the physiologic impact of various FGF2-FGFR1 contact sites employing three different synthetic peptides, termed canofins, designed based on structural analysis of the interactions between FGF2 and FGFR1...

  15. Effect of ozone on the performance of a hybrid ceramic membrane-biological activated carbon process.

    Science.gov (United States)

    Guo, Jianning; Hu, Jiangyong; Tao, Yi; Zhu, Jia; Zhang, Xihui

    2014-04-01

    Two hybrid processes including ozonation-ceramic membrane-biological activated carbon (BAC) (Process A) and ceramic membrane-BAC (Process B) were compared to treat polluted raw water. The performance of hybrid processes was evaluated with the removal efficiencies of turbidity, ammonia and organic matter. The results indicated that more than 99% of particle count was removed by both hybrid processes and ozonation had no significant effect on its removal. BAC filtration greatly improved the removal of ammonia. Increasing the dissolved oxygen to 30.0 mg/L could lead to a removal of ammonia with concentrations as high as 7.80 mg/L and 8.69 mg/L for Processes A and B, respectively. The average removal efficiencies of total organic carbon and ultraviolet absorbance at 254 nm (UV254, a parameter indicating organic matter with aromatic structure) were 49% and 52% for Process A, 51% and 48% for Process B, respectively. Some organic matter was oxidized by ozone and this resulted in reduced membrane fouling and increased membrane flux by 25%-30%. However, pre-ozonation altered the components of the raw water and affected the microorganisms in the BAC, which may impact the removals of organic matter and nitrite negatively. Copyright © 2014 The Research Centre for Eco-Environmental Sciences, Chinese Academy of Sciences. Published by Elsevier B.V. All rights reserved.

  16. Reactivation of desensitized formyl peptide receptors by platelet activating factor: a novel receptor cross talk mechanism regulating neutrophil superoxide anion production.

    Directory of Open Access Journals (Sweden)

    Huamei Forsman

    Full Text Available Neutrophils express different chemoattractant receptors of importance for guiding the cells from the blood stream to sites of inflammation. These receptors communicate with one another, a cross talk manifested as hierarchical, heterologous receptor desensitization. We describe a new receptor cross talk mechanism, by which desensitized formyl peptide receptors (FPRdes can be reactivated. FPR desensitization is induced through binding of specific FPR agonists and is reached after a short period of active signaling. The mechanism that transfers the receptor to a non-signaling desensitized state is not known, and a signaling pathway has so far not been described, that transfers FPRdes back to an active signaling state. The reactivation signal was generated by PAF stimulation of its receptor (PAFR and the cross talk was uni-directional. LatrunculinA, an inhibitor of actin polymerization, induced a similar reactivation of FPRdes as PAF while the phosphatase inhibitor CalyculinA inhibited reactivation, suggesting a role for the actin cytoskeleton in receptor desensitization and reactivation. The activated PAFR could, however, reactivate FPRdes also when the cytoskeleton was disrupted prior to activation. The receptor cross talk model presented prophesies that the contact on the inner leaflet of the plasma membrane that blocks signaling between the G-protein and the FPR is not a point of no return; the receptor cross-talk from the PAFRs to the FPRdes initiates an actin-independent signaling pathway that turns desensitized receptors back to a signaling state. This represents a novel mechanism for amplification of neutrophil production of reactive oxygen species.

  17. Structural mechanism of ligand activation in human calcium-sensing receptor

    Energy Technology Data Exchange (ETDEWEB)

    Geng, Yong; Mosyak, Lidia; Kurinov, Igor; Zuo, Hao; Sturchler, Emmanuel; Cheng, Tat Cheung; Subramanyam, Prakash; Brown, Alice P.; Brennan, Sarah C.; Mun, Hee-chang; Bush, Martin; Chen, Yan; Nguyen, Trang X.; Cao, Baohua; Chang, Donald D.; Quick, Matthias; Conigrave, Arthur D.; Colecraft, Henry M.; McDonald, Patricia; Fan, Qing R.

    2016-07-19

    Human calcium-sensing receptor (CaSR) is a G-protein-coupled receptor (GPCR) that maintains extracellular Ca2+homeostasis through the regulation of parathyroid hormone secretion. It functions as a disulfide-tethered homodimer composed of three main domains, the Venus Flytrap module, cysteine-rich domain, and seven-helix transmembrane region. Here, we present the crystal structures of the entire extracellular domain of CaSR in the resting and active conformations. We provide direct evidence that L-amino acids are agonists of the receptor. In the active structure, L-Trp occupies the orthosteric agonist-binding site at the interdomain cleft and is primarily responsible for inducing extracellular domain closure to initiate receptor activation. Our structures reveal multiple binding sites for Ca2+and PO43-ions. Both ions are crucial for structural integrity of the receptor. While Ca2+ions stabilize the active state, PO43-ions reinforce the inactive conformation. The activation mechanism of CaSR involves the formation of a novel dimer interface between subunits.

  18. A Novel Hybrid Model for Drawing Trace Reconstruction from Multichannel Surface Electromyographic Activity.

    Science.gov (United States)

    Chen, Yumiao; Yang, Zhongliang

    2017-01-01

    Recently, several researchers have considered the problem of reconstruction of handwriting and other meaningful arm and hand movements from surface electromyography (sEMG). Although much progress has been made, several practical limitations may still affect the clinical applicability of sEMG-based techniques. In this paper, a novel three-step hybrid model of coordinate state transition, sEMG feature extraction and gene expression programming (GEP) prediction is proposed for reconstructing drawing traces of 12 basic one-stroke shapes from multichannel surface electromyography. Using a specially designed coordinate data acquisition system, we recorded the coordinate data of drawing traces collected in accordance with the time series while 7-channel EMG signals were recorded. As a widely-used time domain feature, Root Mean Square (RMS) was extracted with the analysis window. The preliminary reconstruction models can be established by GEP. Then, the original drawing traces can be approximated by a constructed prediction model. Applying the three-step hybrid model, we were able to convert seven channels of EMG activity recorded from the arm muscles into smooth reconstructions of drawing traces. The hybrid model can yield a mean accuracy of 74% in within-group design (one set of prediction models for all shapes) and 86% in between-group design (one separate set of prediction models for each shape), averaged for the reconstructed x and y coordinates. It can be concluded that it is feasible for the proposed three-step hybrid model to improve the reconstruction ability of drawing traces from sEMG.

  19. A peptide antagonist of the ErbB1 receptor inhibits receptor activation, tumor cell growth and migration in vitro and xenograft tumor growth in vivo

    DEFF Research Database (Denmark)

    Xu, Ruodan; Povlsen, Gro Klitgaard; Soroka, Vladislav

    2010-01-01

    The epidermal growth factor family of receptor tyrosine kinases (ErbBs) plays essential roles in tumorigenesis and cancer disease progression, and therefore has become an attractive target for structure-based drug design. ErbB receptors are activated by ligand-induced homo- and heterodimerization...... constitutes part of the dimerization arm of ErbB3. Inherbin3 binds to the extracellular domains of all four ErbB receptors, with the lowest peptide binding affinity for ErbB4. Inherbin3 functions as an antagonist of epidermal growth factor (EGF)-ErbB1 signaling. We show that Inherbin3 inhibits EGF-induced Erb....... Structural studies have revealed that ErbB receptor dimers are stabilized by receptor-receptor interactions, primarily mediated by a region in the second extracellular domain, termed the "dimerization arm". The present study is the first biological characterization of a peptide, termed Inherbin3, which...

  20. ALK receptor activation, ligands and therapeutic targeting in glioblastoma and in other cancers

    International Nuclear Information System (INIS)

    Wellstein, Anton

    2012-01-01

    The intracellular anaplastic lymphoma kinase (ALK) fragment shows striking homology with members of the insulin receptor family and was initially identified as an oncogenic fusion protein resulting from a translocation in lymphoma and more recently in a range of cancers. The full-length ALK transmembrane receptor of ~220 kDa was identified based on this initial work. This tyrosine kinase receptor and its ligands, the growth factors pleiotrophin (PTN) and midkine (MK) are highly expressed during development of the nervous system and other organs. Each of these genes has been implicated in malignant progression of different tumor types and shown to alter phenotypes as well as signal transduction in cultured normal and tumor cells. Beyond its role in cancer, the ALK receptor pathway is thought to contribute to nervous system development, function, and repair, as well as metabolic homeostasis and the maintenance of tissue regeneration. ALK receptor activity in cancer can be up-regulated by amplification, overexpression, ligand binding, mutations in the intracellular domain of the receptor and by activity of the receptor tyrosine phosphatase PTPRz. Here we discuss the evidence for ligand control of ALK activity as well as the potential prognostic and therapeutic implications from gene expression and functional studies. An analysis of 18 published gene expression data sets from different cancers shows that overexpression of ALK, its smaller homolog LTK (leukocyte tyrosine kinase) and the ligands PTN and MK in cancer tissues from patients correlate significantly with worse course and outcome of the disease. This observation together with preclinical functional studies suggests that this pathway could be a valid therapeutic target for which complementary targeting strategies with small molecule kinase inhibitors as well as antibodies to ligands or the receptors may be used.

  1. Increased dopamine D1 receptor binding in the human mesocortical system following central cholinergic activation

    International Nuclear Information System (INIS)

    Fedi, M.; Berkovic, S.F.; Tochon-Danguy, H.J.; Reutens, D.C.

    2002-01-01

    Full text: The interaction between the cholinergic and dopaminergic system has been implicated in many pathological processes including, Alzheimer's disease, schizophrenia and drug addiction. Little is known about the control of dopamine (DA) release following central cholinergic activation in humans, but experimental studies suggest that endogenously released Acetylcholine (ACh) achieved by the administration of cholinesterase inhibitors, can increase dopamine efflux in different regions of the brain. This leads to the activation of different types of post-synaptic dopaminergic receptors which belong to the family of G-protein coupled receptors (GPCRs). A common paradigm of the GPCRs desensitization is that agonist-induced receptor signaling is rapidly attenuated by receptor internalisation. Several experiments have shown that the activation of Dl receptors in acute conditions leads, within minutes, to translocation of the receptor from the surface of the neurons to the endosomal compartment in the cytoplasm and increased receptor turnover. To assess changes in Dl receptor density following an intravenous infusion of the selective cholinesterase inhibitor physostigmine salicylate (PHY), we studied eleven normal subjects (10 male and 1 female, mean age 36.1 and 61617; 9.9) using [11C]-SCH23390 and PET The binding potential (BP) for SCH23390 was significantly (p 0.05). There was no statistically significant difference between baseline and physostigmine Kl ratio (p>0.05) suggesting that BP changes observed were not secondary to regional blood flow changes or to an order effect of the scans. Copyright (2002) The Australian and New Zealand Society of Nuclear Medicine Inc

  2. Dysregulation of gene expression within the peroxisome proliferator activated receptor pathway in morbidly obese patients.

    Science.gov (United States)

    Hindle, A Katharine; Koury, Jadd; McCaffrey, Tim; Fu, Sidney W; Brody, Fred

    2009-06-01

    The causes of obesity are multifactorial but may include dysregulation of a family of related genes, such as the peroxisome proliferator activated receptor gamma (PPARgamma). When activated, the PPARgamma pathway promotes lipid metabolism. This study used microarray technology to evaluate differential gene expression profiles in obese patients undergoing bariatric surgery. The study enrolled six morbidly obese patients with a body mass index (BMI) exceeding 35 and four nonobese individuals. Blood samples were stabilized in PaxGene tubes (PreAnalytiX), and total RNA was extracted. Next, 100 ng of total RNA was amplified and labeled using the Ovation RNA Amplification System V2 with the Ovation whole-blood reagent (NuGen) before it was hybridized to an Affymetrix (Santa Clara, CA) focus array containing more than 8,500 verified genes. The data were analyzed using an analysis of variance (ANOVA) (p < 0.05) in the GeneSpring program, and potential pathways were identified with the Ingenuity program. Real-time quantitative reverse transcriptase-polymerase chain reaction was used to validate the array data. A total of 97 upregulated genes and 125 downregulated genes were identified. More than a 1.5-fold change was identified between the morbidly obese patients and the control subjects for a cluster of dysregulated genes involving pathways regulating cell metabolism and lipid formation. Specifically, the PPARgamma pathway showed a plethora of dysregulated genes including tumor necrosis factor-alpha (TNFalpha). In morbidly obese patients, TNFalpha expression was increased (upregulated) 1.6-fold. These findings were confirmed using quantitative polymerase chain reaction with a 2.8-fold change. Microarrays are a powerful tool for identifying biomarkers indicating morbid obesity by analyzing differential gene expression profiles. This study confirms the association of PPARgamma with morbid obesity. Also, these findings in blood support previous work documented in tissue

  3. 5-HT1A receptors modulate small-conductance Ca2+-activated K+ channels

    DEFF Research Database (Denmark)

    Grunnet, Morten; Jespersen, Thomas; Perrier, Jean-François

    2004-01-01

    Small-conductance calcium-activated potassium channels (SK) are responsible for the medium afterhyperpolarisation (mAHP) following action potentials in neurons. Here we tested the ability of serotonin (5-HT) to modulate the activity of SK channels by coexpressing 5-HT1A receptors with different...

  4. 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

  5. Morphine withdrawal enhances constitutive μ-opioid receptor activity in the ventral tegmental area

    NARCIS (Netherlands)

    Meye, F.J.; van Zessen, R.; Smidt, M.P.; Adan, R.A.H.; Ramakers, G.M.J.

    2012-01-01

    μ-opioid receptors (MORs) in the ventral tegmental area (VTA) are pivotally involved in addictive behavior. While MORs are typically activated by opioids, they can also become constitutively active in the absence of any agonist. In the current study, we present evidence that MOR constitutive

  6. Prediction of in vitro and in vivo oestrogen receptor activity using hierarchical clustering

    Science.gov (United States)

    In this study, hierarchical clustering classification models were developed to predict in vitro and in vivo oestrogen receptor (ER) activity. Classification models were developed for binding, agonist, and antagonist in vitro ER activity and for mouse in vivo uterotrophic ER bindi...

  7. Identification of a second putative receptor of platelet activating factor on human polymorphonuclear leukocytes

    International Nuclear Information System (INIS)

    Hwang, S.B.

    1987-01-01

    Due to multiple molecular species of platelet activating factor (PAF) and the existence of high affinity binding sites in a variety of cells and tissues, possible existence of PAF receptor subtypes has been suggested. This report shows differences between specific PAF receptors on human leukocytes and platelets. Human PMN leukocyte membranes showed high affinity binding sites for PAF with an equilibrium dissociation constant (Kd) of 4.7 (+/- 1.4) x 10 -10 M. The maximal number (B/sub max/) of receptor sites was estimated to be 3.13 (+/- 1.4) x 10 -13 mol/mg protein. They compared the relative potencies of several PAF agonists and receptor antagonists between human platelet and human leukocyte membranes. One antagonist (Ono-6240) was found to be 8 times less potent at inhibiting the [ 3 H]PAF specific receptor binding to human leukocytes than to human platelets. Mg 2+ , Ca 2+ and K + ions potentiated the [ 3 H]PAF specific binding in both systems. Na + ions inhibited the [ 3 H]PAF specific binding to human platelets but showed no effects in human leukocytes. K + ions decreased the Mg 2+ -potentiated [ 3 H]PAF binding in human leukocytes but showed no effects in human platelets. These results suggest that the PAF specific receptors in human leukocytes are different structurally and possibly functionally from the receptors identified in human platelets

  8. Peroxisome proliferator-activated receptor α activation induces hepatic steatosis, suggesting an adverse effect.

    Directory of Open Access Journals (Sweden)

    Fang Yan

    Full Text Available Non-alcoholic fatty liver disease (NAFLD is characterized by hepatic triglyceride accumulation, ranging from steatosis to steatohepatitis and cirrhosis. NAFLD is a risk factor for cardiovascular diseases and is associated with metabolic syndrome. Antihyperlipidemic drugs are recommended as part of the treatment for NAFLD patients. Although fibrates activate peroxisome proliferator-activated receptor α (PPARα, leading to the reduction of serum triglyceride levels, the effects of these drugs on NAFLD remain controversial. Clinical studies have reported that PPARα activation does not improve hepatic steatosis. In the present study, we focused on exploring the effect and mechanism of PPARα activation on hepatic triglyceride accumulation and hepatic steatosis. Male C57BL/6J mice, Pparα-null mice and HepG2 cells were treated with fenofibrate, one of the most commonly used fibrate drugs. Both low and high doses of fenofibrate were administered. Hepatic steatosis was detected through oil red O staining and electron microscopy. Notably, in fenofibrate-treated mice, the serum triglyceride levels were reduced and the hepatic triglyceride content was increased in a dose-dependent manner. Oil red O staining of liver sections demonstrated that fenofibrate-fed mice accumulated abundant neutral lipids. Fenofibrate also increased the intracellular triglyceride content in HepG2 cells. The expression of sterol regulatory element-binding protein 1c (SREBP-1c and the key genes associated with lipogenesis were increased in fenofibrate-treated mouse livers and HepG2 cells in a dose-dependent manner. However, the effect was strongly impaired in Pparα-null mice treated with fenofibrate. Fenofibrate treatment induced mature SREBP-1c expression via the direct binding of PPARα to the DR1 motif of the SREBP-1c gene. Taken together, these findings indicate the molecular mechanism by which PPARα activation increases liver triglyceride accumulation and suggest an

  9. Dithiothreitol activation of the insulin receptor/kinase does not involve subunit dissociation of the native α2β2 insulin receptor subunit complex

    International Nuclear Information System (INIS)

    Sweet, L.J.; Wilden, P.A.; Pessin, J.E.

    1986-01-01

    The subunit composition of the dithiothreitol- (DTT) activated insulin receptor/kinase was examined by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis and gel filtration chromatography under denaturing or nondenaturing conditions. Pretreatment of 32 P-labeled insulin receptors with 50 mM DTT followed by gel filtration chromatography in 0.1% SDS demonstrated the dissociation of the α 2 β 2 insulin receptor complex (M/sub r/ 400,000) into the monomeric 95,000 β subunit. In contrast, pretreatment of the insulin receptors with 1-50 mM DTT followed by gel filtration chromatography in 0.1% Triton X-100 resulted in no apparent alteration in mobility compared to the untreated insulin receptors. Resolution of this complex by nonreducing SDS-polyacrylamide gel electrophoresis and autoradiography demonstrated the existence of the α 2 β 2 heterotetrameric complex with essentially no αβ heterodimeric or free monomeric β subunit species present. This suggests that the insulin receptor can reoxidize into the M/sub r/ 400,000 complex after the removal of DTT by gel filtration chromatography. To prevent reoxidation, the insulin receptors were pretreated with 50 mM DTT. Under the conditions the insulin receptors migrated as the M/sub r/ 400,000 α 2 β 2 complex. These results demonstrate that treatment of the insulin receptors with high concentrations of DTT, followed by removal of DTT by gel filtration, results in reoxidation of the reduced α 2 β 2 insulin receptor complex. Further, these results document that although the DTT stimulation of the insulin receptor/kinase does involve reduction of the insulin receptor subunits, it does not result in dissociation of the native α 2 β 2 insulin receptor subunit complex

  10. A new hybrid observer based rotor imbalance vibration control via passive autobalancer and active bearing actuation

    Science.gov (United States)

    Jung, DaeYi; DeSmidt, Hans

    2018-02-01

    Many researchers have explored the use of active bearings, such as non-contact Active Magnetic Bearings (AMB), to control imbalance vibration in rotor systems. Meanwhile, the advantages of a passive Auto-balancer device (ABD) eliminating the imbalance effect of rotor without using other active means have been recently studied. This paper develops a new hybrid imbalance vibration control approach for an ABD-rotor system supported by a normal passive bearing in augmented with an AMB to enhance the balancing and vibration isolation capabilities. Essentially, an ABD consists of several freely moving eccentric balancing masses mounted on the rotor, which, at supercritical operating speeds, act to cancel the rotor's imbalance at steady-state. However, due to the inherent nonlinearity of the ABD, the potential for other, non-synchronous limit-cycle behavior exists resulting in increased rotor vibration. To address this, the algorithm of proposed hybrid control is designed to guarantee globally asymptotic stability of the synchronous balanced condition. This algorithm also incorporates with a "Luenberger-like" observer that continuously estimates the states of a balancer ball circulating around within ABD. In particular, it is shown that the balanced equilibrium can be made globally attractive under the hybrid control strategy, and that the control power levels of AMB are significantly reduced via the addition of the ABD because the control is designed such that it is only switched on for the abnormal operation of ABD and will be disengaged otherwise. Moreover, unlike other imbalance vibration control applications based upon ABD such as rotor speed regulator [21,22], this approach enables the controller to achieve the desirable performance without altering rotor speed once the rotor initially reaches the target speed. These applications are relevant to limited power applications such as in satellite reaction wheels, flywheel energy storage batteries or CD-ROM application.

  11. Passive, active, and hybrid mode-locking in a self-optimized ultrafast diode laser

    Science.gov (United States)

    Alloush, M. Ali; Pilny, Rouven H.; Brenner, Carsten; Klehr, Andreas; Knigge, Andrea; Tränkle, Günther; Hofmann, Martin R.

    2018-02-01

    Semiconductor lasers are promising sources for generating ultrashort pulses. They are directly electrically pumped, allow for a compact design, and therefore they are cost-effective alternatives to established solid-state systems. Additionally, their emission wavelength depends on the bandgap which can be tuned by changing the semiconductor materials. Theoretically, the obtained pulse width can be few tens of femtoseconds. However, the generated pulses are typically in the range of several hundred femtoseconds only. Recently, it was shown that by implementing a spatial light modulator (SLM) for phase and amplitude control inside the resonator the optical bandwidth can be optimized. Consequently, by using an external pulse compressor shorter pulses can be obtained. We present a Fourier-Transform-External-Cavity setup which utilizes an ultrafast edge-emitting diode laser. The used InGaAsP diode is 1 mm long and emits at a center wavelength of 850 nm. We investigate the best conditions for passive, active and hybrid mode-locking operation using the method of self-adaptive pulse shaping. For passive mode-locking, the bandwidth is increased from 2.34 nm to 7.2 nm and ultrashort pulses with a pulse width of 216 fs are achieved after external pulse compression. For active and hybrid mode-locking, we also increased the bandwidth. It is increased from 0.26 nm to 5.06 nm for active mode-locking and from 3.21 nm to 8.7 nm for hybrid mode-locking. As the pulse width is strongly correlated with the bandwidth of the laser, we expect further reduction in the pulse duration by increasing the bandwidth.

  12. Synthesis and characterization of a new porphyrin-polyoxometalate hybrid material and investigation of its catalytic activity.

    Science.gov (United States)

    Araghi, Mehdi; Mirkhani, Valiollah; Moghadam, Majid; Tangestaninejad, Shahram; Mohammdpoor-Baltork, Iraj

    2012-03-14

    In the present work, the preparation of a new organic-inorganic hybrid material in which tetrakis(p-aminophenylporphyrin) is covalently linked to a Lindqvist structure of polyoxometalate, is reported. This new porphyrin-polyoxometalate hybrid material was characterized by (1)H NMR, FT-IR and UV-Vis spectroscopic methods and cyclic voltammetry. These spectro- and electrochemical studies provided spectral data of the synthesis of this compound. Cyclic voltammetry showed the influence of the porphyrin on the redox process of the polyoxometalate. The catalytic activity of this hybrid material was investigated in the alkene epoxidation with NaIO(4).

  13. Protection against methamphetamine-induced neurotoxicity to neostriatal dopaminergic neurons by adenosine receptor activation.

    Science.gov (United States)

    Delle Donne, K T; Sonsalla, P K

    1994-12-01

    Methamphetamine (METH)-induced neurotoxicity to nigrostriatal dopaminergic neurons in experimental animals appears to have a glutamatergic component because blockade of N-methyl-D-aspartate receptors prevents the neuropathologic consequences. Because adenosine affords neuroprotection against various forms of glutamate-mediated neuronal damage, the present studies were performed to investigate whether adenosine plays a protective role in METH-induced toxicity. METH-induced decrements in neostriatal dopamine content and tyrosine hydroxylase activity in mice were potentiated by concurrent treatment with caffeine, a nonselective adenosine antagonist that blocks both A1 and A2 adenosine receptors. In contrast, chronic treatment of mice with caffeine through their drinking water for 4 weeks, which increased the number of adenosine A1 receptors in the neostriatum and frontal cortex, followed by drug washout, prevented the neurochemical changes produced by the treatment of mice with METH treatment. In contrast, this treatment did not prevent 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine-induced dopaminergic neurotoxicity. Furthermore, concurrent administration of cyclopentyladenosine, an adenosine A1 receptor agonist, attenuated the METH-induced neurochemical changes. This protection by cyclopentyladenosine was blocked by cyclopentyltheophylline, an A1 receptor antagonist. These results indicate that activation of A1 receptors can protect against METH-induced neurotoxicity in mice.

  14. Castor oil induces laxation and uterus contraction via ricinoleic acid activating prostaglandin EP3 receptors.

    Science.gov (United States)

    Tunaru, Sorin; Althoff, Till F; Nüsing, Rolf M; Diener, Martin; Offermanns, Stefan

    2012-06-05

    Castor oil is one of the oldest drugs. When given orally, it has a laxative effect and induces labor in pregnant females. The effects of castor oil are mediated by ricinoleic acid, a hydroxylated fatty acid released from castor oil by intestinal lipases. Despite the wide-spread use of castor oil in conventional and folk medicine, the molecular mechanism by which ricinoleic acid acts remains unknown. Here we show that the EP(3) prostanoid receptor is specifically activated by ricinoleic acid and that it mediates the pharmacological effects of castor oil. In mice lacking EP(3) receptors, the laxative effect and the uterus contraction induced via ricinoleic acid are absent. Although a conditional deletion of the EP(3) receptor gene in intestinal epithelial cells did not affect castor oil-induced diarrhea, mice lacking EP(3) receptors only in smooth-muscle cells were unresponsive to this drug. Thus, the castor oil metabolite ricinoleic acid activates intestinal and uterine smooth-muscle cells via EP(3) prostanoid receptors. These findings identify the cellular and molecular mechanism underlying the pharmacological effects of castor oil and indicate a role of the EP(3) receptor as a target to induce laxative effects.

  15. Lipidated alpha-Peptide/beta-Peptoid Hybrids with Potent Antiinflammatory Activity

    DEFF Research Database (Denmark)

    Skovbakke, Sarah L.; Larsen, Camilla J.; Heegaard, Peter M. H.

    2015-01-01

    is dependent on the length and position of the lipid element(s). The resulting lead compound, Pam-(Lys-beta NSpe)(6)-NH2, blocks LPS-induced cytokine secretion with a potency comparable to that of polymyxin B. The mode of action of this HDP mimic appears not to involve direct LPS interaction since it......, in contrast to polymyxin B, displayed only minor activity in the Limulus amebocyte lysate assay. Flow cytometry data showed specific interaction of a fluorophore-labeled lipidated a-peptide/beta-peptoid hybrid with monocytes and granulocytes indicating a cellular target expressed by these leukocyte subsets....

  16. Mechanisms of integrin-vascular endothelial growth factor receptor cross-activation in angiogenesis.

    Science.gov (United States)

    Mahabeleshwar, Ganapati H; Feng, Weiyi; Reddy, Kumar; Plow, Edward F; Byzova, Tatiana V

    2007-09-14

    The functional responses of endothelial cells are dependent on signaling from peptide growth factors and the cellular adhesion receptors, integrins. These include cell adhesion, migration, and proliferation, which, in turn, are essential for more complex processes such as formation of the endothelial tube network during angiogenesis. This study identifies the molecular requirements for the cross-activation between beta3 integrin and tyrosine kinase receptor 2 for vascular endothelial growth factor (VEGF) receptor (VEGFR-2) on endothelium. The relationship between VEGFR-2 and beta3 integrin appears to be synergistic, because VEGFR-2 activation induces beta3 integrin tyrosine phosphorylation, which, in turn, is crucial for VEGF-induced tyrosine phosphorylation of VEGFR-2. We demonstrate here that adhesion- and growth factor-induced beta3 integrin tyrosine phosphorylation are directly mediated by c-Src. VEGF-stimulated recruitment and activation of c-Src and subsequent beta3 integrin tyrosine phosphorylation are critical for interaction between VEGFR-2 and beta3 integrin. Moreover, c-Src mediates growth factor-induced beta3 integrin activation, ligand binding, beta3 integrin-dependent cell adhesion, directional migration of endothelial cells, and initiation of angiogenic programming in endothelial cells. Thus, the present study determines the molecular mechanisms and consequences of the synergism between 2 cell surface receptor systems, growth factor receptor and integrins, and opens new avenues for the development of pro- and antiangiogenic strategies.

  17. Activation of Toll-like receptors nucleates assembly of the MyDDosome signaling hub.

    Science.gov (United States)

    Latty, Sarah Louise; Sakai, Jiro; Hopkins, Lee; Verstak, Brett; Paramo, Teresa; Berglund, Nils A; Cammorota, Eugenia; Cicuta, Pietro; Gay, Nicholas J; Bond, Peter J; Klenerman, David; Bryant, Clare E

    2018-01-24

    Infection and tissue damage induces assembly of supramolecular organizing centres (SMOCs)), such as the Toll-like receptor (TLR) MyDDosome, to co-ordinate inflammatory signaling. SMOC assembly is thought to drive digital all-or-none responses, yet TLR activation by diverse microbes induces anything from mild to severe inflammation. Using single-molecule imaging of TLR4-MyDDosome signaling in living macrophages, we find that MyDDosomes assemble within minutes of TLR4 stimulation. TLR4/MD2 activation leads only to formation of TLR4/MD2 heterotetramers, but not oligomers, suggesting a stoichiometric mismatch between activated receptors and MyDDosomes. The strength of TLR4 signalling depends not only on the number and size of MyDDosomes formed but also how quickly these structures assemble. Activated TLR4, therefore, acts transiently nucleating assembly of MyDDosomes, a process that is uncoupled from receptor activation. These data explain how the oncogenic mutation of MyD88 (L265P) assembles MyDDosomes in the absence of receptor activation to cause constitutive activation of pro-survival NF-κB signalling. © 2018, Latty et al.

  18. Communication over the network of binary switches regulates the activation of A2A adenosine receptor.

    Directory of Open Access Journals (Sweden)

    Yoonji Lee

    2015-02-01

    Full Text Available Dynamics and functions of G-protein coupled receptors (GPCRs are accurately regulated by the type of ligands that bind to the orthosteric or allosteric binding sites. To glean the structural and dynamical origin of ligand-dependent modulation of GPCR activity, we performed total ~ 5 μsec molecular dynamics simulations of A2A adenosine receptor (A2AAR in its apo, antagonist-bound, and agonist-bound forms in an explicit water and membrane environment, and examined the corresponding dynamics and correlation between the 10 key structural motifs that serve as the allosteric hotspots in intramolecular signaling network. We dubbed these 10 structural motifs "binary switches" as they display molecular interactions that switch between two distinct states. By projecting the receptor dynamics on these binary switches that yield 2(10 microstates, we show that (i the receptors in apo, antagonist-bound, and agonist-bound states explore vastly different conformational space; (ii among the three receptor states the apo state explores the broadest range of microstates; (iii in the presence of the agonist, the active conformation is maintained through coherent couplings among the binary switches; and (iv to be most specific, our analysis shows that W246, located deep inside the binding cleft, can serve as both an agonist sensor and actuator of ensuing intramolecular signaling for the receptor activation. Finally, our analysis of multiple trajectories generated by inserting an agonist to the apo state underscores that the transition of the receptor from inactive to active form requires the disruption of ionic-lock in the DRY motif.

  19. Endothelin receptors and activity differ in human, dog, and rabbit lung.

    Science.gov (United States)

    McKay, K O; Armour, C L; Black, J L

    1996-01-01

    In this study, we have examined dog and rabbit airways as potential models for human airways in regard to the activity of endothelin. The receptors involved in the response to endothelin-1 (ET-1) in airway tissue from human, rabbit, and dog lung were investigated, as was the mechanism responsible for the contraction to ET-1 in tissue from the three species. By using specific endothelin receptor agonists and antagonists, we have demonstrated that ETB receptors predominate in rabbit and human airways and ETA receptors in dog airways. The contraction to ET-1 is not dependent on cyclooxygenase products of arachidonic acid, as indomethacin had no effect on the response to ET-1. Extracellular calcium influx via voltage-dependent channels is necessary for contraction to ET-1 in rabbit and dog airways. These results are in contrast to our previously reported results in human airways, in which neither removal of extracellular calcium nor verapamil affected the ET-1 response. The sustained phase of the contraction to ET-1 in all three species may be mediated in part by activation of protein kinase C (PKC), as the inhibitor staurosporine significantly altered the time course of the response to endothelin. We therefore conclude that in rabbit airways ET-1 activates ETB receptors, triggers the influx of extracellular calcium through voltage-dependent channels, and induces a contractile response that is, in part, dependent upon stimulation of PKC. The same mechanism is triggered in dog bronchus; however, the receptors involved in this species are of the ETA type. Finally, in human airways, the contractile response to ET-1, while independent of extracellular calcium influx, is dependent upon PKC activation after binding of the peptide to ETB receptors.

  20. Structure of the Nanobody-Stabilized Active State of the Kappa Opioid Receptor.

    Science.gov (United States)

    Che, Tao; Majumdar, Susruta; Zaidi, Saheem A; Ondachi, Pauline; McCorvy, John D; Wang, Sheng; Mosier, Philip D; Uprety, Rajendra; Vardy, Eyal; Krumm, Brian E; Han, Gye Won; Lee, Ming-Yue; Pardon, Els; Steyaert, Jan; Huang, Xi-Ping; Strachan, Ryan T; Tribo, Alexandra R; Pasternak, Gavril W; Carroll, F Ivy; Stevens, Raymond C; Cherezov, Vadim; Katritch, Vsevolod; Wacker, Daniel; Roth, Bryan L

    2018-01-11

    The κ-opioid receptor (KOP) mediates the actions of opioids with hallucinogenic, dysphoric, and analgesic activities. The design of KOP analgesics devoid of hallucinatory and dysphoric effects has been hindered by an incomplete structural and mechanistic understanding of KOP agonist actions. Here, we provide a crystal structure of human KOP in complex with the potent epoxymorphinan opioid agonist MP1104 and an active-state-stabilizing nanobody. Comparisons between inactive- and active-state opioid receptor structures reveal substantial conformational changes in the binding pocket and intracellular and extracellular regions. Extensive structural analysis and experimental validation illuminate key residues that propagate larger-scale structural rearrangements and transducer binding that, collectively, elucidate the structural determinants of KOP pharmacology, function, and biased signaling. These molecular insights promise to accelerate the structure-guided design of safer and more effective κ-opioid receptor therapeutics. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Increased amphetamine-induced locomotor activity, sensitization, and accumbal dopamine release in M5 muscarinic receptor knockout mice

    DEFF Research Database (Denmark)

    Schmidt, Lene S; Miller, Anthony D; Lester, Deranda B

    2010-01-01

    showed that M(5) receptor knockout (M (5) (-/-) ) mice are less sensitive to the reinforcing properties of addictive drugs. MATERIALS AND METHODS: Here, we investigate the role of M(5) receptors in the effects of amphetamine and cocaine on locomotor activity, locomotor sensitization, and dopamine release......-induced hyperactivity and dopamine release as well as amphetamine sensitization are enhanced in mice lacking the M(5) receptor. These results support the concept that the M(5) receptor modulates effects of addictive drugs....

  2. Study on development of active-passive rehabilitation system for upper limbs: Hybrid-PLEMO

    International Nuclear Information System (INIS)

    Kikuchi, T; Jin, Y; Fukushima, K; Akai, H; Furusho, J

    2009-01-01

    In recent years, many researchers have studied the potential of using robotics technology to assist and quantify the motor functions for neuron-rehabilitation. Some kinds of haptic devices have been developed and evaluated its efficiency with clinical tests, for example, upper limb training for patients with spasticity after stroke. Active-type (motor-driven) haptic devices can realize a lot of varieties of haptics. But they basically require high-cost safety system. On the other hand, passive-type (brake-based) haptic devices have inherent safety. However, the passive robot system has strong limitation on varieties of haptics. There are not sufficient evidences to clarify how the passive/active haptics effect to the rehabilitation of motor skills. In this paper, we developed an active-passive-switchable rehabilitation system with ER clutch/brake device named 'Hybrid-PLEMO' in order to address these problems. In this paper, basic structures and haptic control methods of the Hybrid-PLEMO are described.

  3. Study on development of active-passive rehabilitation system for upper limbs: Hybrid-PLEMO

    Energy Technology Data Exchange (ETDEWEB)

    Kikuchi, T; Jin, Y; Fukushima, K; Akai, H; Furusho, J [Department of Mechanical Engineering, Graduate School of Engineering, Osaka University, Osaka (Japan)], E-mail: kikuchi@mech.eng.osaka-u.ac.jp

    2009-02-01

    In recent years, many researchers have studied the potential of using robotics technology to assist and quantify the motor functions for neuron-rehabilitation. Some kinds of haptic devices have been developed and evaluated its efficiency with clinical tests, for example, upper limb training for patients with spasticity after stroke. Active-type (motor-driven) haptic devices can realize a lot of varieties of haptics. But they basically require high-cost safety system. On the other hand, passive-type (brake-based) haptic devices have inherent safety. However, the passive robot system has strong limitation on varieties of haptics. There are not sufficient evidences to clarify how the passive/active haptics effect to the rehabilitation of motor skills. In this paper, we developed an active-passive-switchable rehabilitation system with ER clutch/brake device named 'Hybrid-PLEMO' in order to address these problems. In this paper, basic structures and haptic control methods of the Hybrid-PLEMO are described.

  4. Activation of the Ca2+-sensing receptors increases currents through inward rectifier K+ channels via activation of phosphatidylinositol 4-kinase

    OpenAIRE

    Liu, Chung-Hung; Chang, Hsueh-Kai; Lee, Sue-Ping; Shieh, Ru-Chi

    2016-01-01

    Inward rectifier K+ channels are important for maintaining normal electrical function in many cell types. The proper function of these channels requires the presence of membrane phosphoinositide 4,5-bisphosphate (PIP2). Stimulation of the Ca2+-sensing receptor CaR, a pleiotropic G protein-coupled receptor, activates both Gq/11, which decreases PIP2, and phosphatidylinositol 4-kinase (PI-4-K), which, conversely, increases PIP2. How membrane PIP2 levels are regulated by CaR activation and wheth...

  5. A study of nitroxide polyradical/activated carbon composite as the positive electrode material for electrochemical hybrid capacitor

    Energy Technology Data Exchange (ETDEWEB)

    Li, Hui-qiao; Zou, Ying; Xia, Yong-yao [Chemistry Department and Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Fudan University, Shanghai 200433 (China)

    2007-01-01

    We present a new concept of the hybrid electrochemical capacitor technology in which a poly(2,2,6,6-tetramethylpiperidinyloxy methacrylate) nitroxide polyradical/activated carbon composite (PTMA-AC) is used as the positive electrode material and activated carbon is used as the negative electrode material. On the positive electrode, both reversible reduction and oxidation of nitroxide polyradical and non-faradic ion sorption/de-sorption of activated carbon are involved during charge and discharge process. The capacity of the composite electrode is 30% larger than that of the pure activated carbon electrode. A hybrid capacitor fabricated by the PTMA-AC composite positive electrode and the activated carbon negative electrode shows a good cycling life, it can be charged/discharged for over 1000 cycles with slight capacity loss. The hybrid capacitor also has a good rate capability, it maintains 80% of the initial capacity even at the high discharge current of up to 20C. (author)

  6. Pancreatic acini possess endothelin receptors whose internalization is regulated by PLC-activating agents.

    Science.gov (United States)

    Hildebrand, P; Mrozinski, J E; Mantey, S A; Patto, R J; Jensen, R T

    1993-05-01

    Endothelin-1 (ET-1) and ET-3 mRNA have been found in the pancreas. We investigated the ability of ET-1, ET-2, and ET-3 to interact with and alter dispersed rat pancreatic acinar cell function. Radiolabeled ETs bound in a time- and temperature-dependent fashion, which was specific and saturable. Analysis demonstrated two classes of receptors, one class (ETA receptor) had a high affinity for ET-1 but a low affinity for ET-3, and the other class (ETB receptor) had equally high affinities for ET-1 and ET-3. No specific receptor for ET-2 was identified. Pancreatic secretagogues that activate phospholipase C (PLC) inhibited binding of 125I-labeled ET-1 (125I-ET-1) or 125I-ET-3, whereas agents that act through adenosine 3',5'-cyclic monophosphate (cAMP) did not. A23187 had no effect on 125I-ET-1 or 125I-ET-3 binding, whereas the phorbol ester 12-O-tetradecanoylphorbol 13-acetate reduced binding. The effect of cholecystokinin octapeptide (CCK-8) was mediated through its own receptor. Stripping of surface bound ligand studies demonstrated that both 125I-labeled ET-1 and 125I-labeled ET-3 were rapidly internalized. CCK-8 decreased the internalization but did not change the amount of surface bound ligand. Endothelins neither stimulate nor alter changes in enzyme secretion, intracellular calcium, cAMP, or [3H]inositol trisphosphate (IP3). This study demonstrates the presence of ETA and ETB receptors on rat pancreatic acini; occupation of both receptors resulted in rapid internalization, which is regulated by PLC-activating secretagogues. Occupation of either ET receptor did not alter intracellular calcium, cAMP, IP3, or stimulate amylase release.

  7. Activated prostaglandin D2 receptors on macrophages enhance neutrophil recruitment into the lung

    Science.gov (United States)

    Jandl, Katharina; Stacher, Elvira; Bálint, Zoltán; Sturm, Eva Maria; Maric, Jovana; Peinhaupt, Miriam; Luschnig, Petra; Aringer, Ida; Fauland, Alexander; Konya, Viktoria; Dahlen, Sven-Erik; Wheelock, Craig E.; Kratky, Dagmar; Olschewski, Andrea; Marsche, Gunther; Schuligoi, Rufina; Heinemann, Akos

    2016-01-01

    Background Prostaglandin (PG) D2 is an early-phase mediator in inflammation, but its action and the roles of the 2 D-type prostanoid receptors (DPs) DP1 and DP2 (also called chemoattractant receptor–homologous molecule expressed on TH2 cells) in regulating macrophages have not been elucidated to date. Objective We investigated the role of PGD2 receptors on primary human macrophages, as well as primary murine lung macrophages, and their ability to influence neutrophil action in vitro and in vivo. Methods In vitro studies, including migration, Ca2+ flux, and cytokine secretion, were conducted with primary human monocyte-derived macrophages and neutrophils and freshly isolated murine alveolar and pulmonary interstitial macrophages. In vivo pulmonary inflammation was assessed in male BALB/c mice. Results Activation of DP1, DP2, or both receptors on human macrophages induced strong intracellular Ca2+ flux, cytokine release, and migration of macrophages. In a murine model of LPS-induced pulmonary inflammation, activation of each PGD2 receptor resulted in aggravated airway neutrophilia, tissue myeloperoxidase activity, cytokine contents, and decreased lung compliance. Selective depletion of alveolar macrophages abolished the PGD2-enhanced inflammatory response. Activation of PGD2 receptors on human macrophages enhanced the migratory capacity and prolonged the survival of neutrophils in vitro. In human lung tissue specimens both DP1 and DP2 receptors were located on alveolar macrophages along with hematopoietic PGD synthase, the rate-limiting enzyme of PGD2 synthesis. Conclusion For the first time, our results show that PGD2 markedly augments disease activity through its ability to enhance the proinflammatory actions of macrophages and subsequent neutrophil activation. PMID:26792210

  8. Reliability of chromogenic in situ hybridization for epidermal growth factor receptor gene copy number detection in non-small-cell lung carcinomas: a comparison with fluorescence in situ hybridization study.

    Science.gov (United States)

    Yoo, Seol Bong; Lee, Hyun Ju; Park, Jung Ok; Choe, Gheeyoung; Chung, Doo Hyun; Seo, Jeong-Wook; Chung, Jin-Haeng

    2010-03-01

    Fluorescence in situ hybridization (FISH) has been known to be the most representative and standardized test for assessing gene amplification. However, FISH requires a fluorescence microscope, the signals are labile and rapidly fade over time. Recently, chromogenic in situ hybridization (CISH) has emerged as a potential alternative to FISH. The aim of this study is to test the reliability of CISH technique for the detection of epidermal growth factor receptor (EGFR) gene amplification in non-small-cell lung carcinomas (NSCLC), to compare CISH results with FISH. A total of 277 formalin-fixed and paraffin embedded NSCLC tissue samples were retrieved from the surgical pathology archives at Seoul National University Bundang Hospital. CISH and FISH examinations were performed to test EGFR gene amplification status. There was high concordance in the assessment of EGFR gene copy number between CISH and FISH tests (Kappa coefficient=0.83). Excellent concordance was shown between two observers on the interpretation of the CISH results (Kappa coefficient=0.90). In conclusion, CISH result is highly reproducible, accurate and practical method to determine EGFR gene amplification in NSCLC. In addition, CISH allows a concurrent analysis of histological features of the tumors and gene copy numbers.

  9. Potentiated antibodies to mu-opiate receptors: effect on integrative activity of the brain.

    Science.gov (United States)

    Geiko, V V; Vorob'eva, T M; Berchenko, O G; Epstein, O I

    2003-01-01

    The effect of homeopathically potentiated antibodies to mu-receptors (10(-100) wt %) on integrative activity of rat brain was studied using the models of self-stimulation of the lateral hypothalamus and convulsions produced by electric current. Electric current was delivered through electrodes implanted into the ventromedial hypothalamus. Single treatment with potentiated antibodies to mu-receptors increased the rate of self-stimulation and decreased the threshold of convulsive seizures. Administration of these antibodies for 7 days led to further activation of the positive reinforcement system and decrease in seizure thresholds. Distilled water did not change the rate of self-stimulation and seizure threshold.

  10. Discoidin domain receptor 1 is activated independently of beta(1) integrin

    DEFF Research Database (Denmark)

    Vogel, W; Brakebusch, C; Fässler, R

    2000-01-01

    independent of the epidermal growth factor (EGF) receptor. In cells that endogenously express both DDR1 and the EGF receptor, stimulation with EGF does not induce DDR activation. Third, we detected full DDR1 activation after collagen stimulation in cells that have been treated with blocking antibodies...... for alpha(2)beta(1) integrin or in cells with a targeted deletion of the beta(1) integrin gene. Finally, we show that overexpression of dominant negative DDR1 in the myoblast cell line C2C12 blocks cellular differentiation and the formation of myofibers....

  11. Diatomite-immobilized BiOI hybrid photocatalyst: Facile deposition synthesis and enhanced photocatalytic activity

    International Nuclear Information System (INIS)

    Li, Baoying; Huang, Hongwei; Guo, Yuxi; Zhang, Yihe

    2015-01-01

    Graphical abstract: - Highlights: • A novel diatomite-immobilized BiOI hybrid photocatalyst has been prepared by a facile one-step deposition process for the first time. • The diatomite-immobilized BiOI hybrid photocatalyst exhibits much better photocatalytic performance. • This enhancement should be attributed to that diatomite can play as an excellent carrier platform to increase the reactive sites and promote the separation of photogenerated electron–hole pairs. • This work shed new light on facile fabrication of novel composite photocatalyst based on natural mineral. - Abstract: A novel diatomite-immobilized BiOI hybrid photocatalyst has been prepared by a facile one-step deposition process for the first time. The structure, morphology and optical property of the products were characterized by X-ray powder diffraction (XRD), scanning electron microscopy (SEM) and UV–vis diffuse reflectance spectroscopy (DRS). The photocatalytic performance of the as-prepared BiOI/diatomite photocatalysts was studied by photodegradation of Rhodamine B (RhB) and methylene blue (MB) and monitoring photocurrent generation under visible light (λ > 420 nm). The results revealed that BiOI/diatomite composites exhibit enhanced photocatalytic activity compared to the pristine BiOI sample. This enhancement should be attributed to that diatomite can play as an excellent carrier platform to increase the reactive sites and promote the separation of photogenerated electron–hole pairs. In addition, the corresponding photocatalytic mechanism was proposed based on the active species trapping experiments. This work shed new light on facile fabrication of novel composite photocatalyst based on natural mineral.

  12. Diatomite-immobilized BiOI hybrid photocatalyst: Facile deposition synthesis and enhanced photocatalytic activity

    Energy Technology Data Exchange (ETDEWEB)

    Li, Baoying; Huang, Hongwei, E-mail: hhw@cugb.edu.cn; Guo, Yuxi; Zhang, Yihe, E-mail: zyh@cugb.edu.cn

    2015-10-30

    Graphical abstract: - Highlights: • A novel diatomite-immobilized BiOI hybrid photocatalyst has been prepared by a facile one-step deposition process for the first time. • The diatomite-immobilized BiOI hybrid photocatalyst exhibits much better photocatalytic performance. • This enhancement should be attributed to that diatomite can play as an excellent carrier platform to increase the reactive sites and promote the separation of photogenerated electron–hole pairs. • This work shed new light on facile fabrication of novel composite photocatalyst based on natural mineral. - Abstract: A novel diatomite-immobilized BiOI hybrid photocatalyst has been prepared by a facile one-step deposition process for the first time. The structure, morphology and optical property of the products were characterized by X-ray powder diffraction (XRD), scanning electron microscopy (SEM) and UV–vis diffuse reflectance spectroscopy (DRS). The photocatalytic performance of the as-prepared BiOI/diatomite photocatalysts was studied by photodegradation of Rhodamine B (RhB) and methylene blue (MB) and monitoring photocurrent generation under visible light (λ > 420 nm). The results revealed that BiOI/diatomite composites exhibit enhanced photocatalytic activity compared to the pristine BiOI sample. This enhancement should be attributed to that diatomite can play as an excellent carrier platform to increase the reactive sites and promote the separation of photogenerated electron–hole pairs. In addition, the corresponding photocatalytic mechanism was proposed based on the active species trapping experiments. This work shed new light on facile fabrication of novel composite photocatalyst based on natural mineral.

  13. Similar activation of signal transduction pathways by the herpesvirus-encoded chemokine receptors US28 and ORF74

    DEFF Research Database (Denmark)

    McLean, Katherine A; Holst, Peter J; Martini, Lene

    2004-01-01

    The virally encoded chemokine receptors US28 from human cytomegalovirus and ORF74 from human herpesvirus 8 are both constitutively active. We show that both receptors constitutively activate the transcription factors nuclear factor of activated T cells (NFAT) and cAMP response element binding...

  14. Activation of G-proteins by receptor-stimulated nucleoside diphosphate kinase in Dictyostelium.

    Science.gov (United States)

    Bominaar, A A; Molijn, A C; Pestel, M; Veron, M; Van Haastert, P J

    1993-01-01

    Recently, interest in the enzyme nucleoside diphosphate kinase (EC2.7.4.6) has increased as a result of its possible involvement in cell proliferation and development. Since NDP kinase is one of the major sources of GTP in cells, it has been suggested that the effects of an altered NDP kinase activity on cellular processes might be the result of altered transmembrane signal transduction via guanine nucleotide-binding proteins (G-proteins). In the cellular slime mould Dictyostelium discoideum, extracellular cAMP induces an increase of phospholipase C activity via a surface cAMP receptor and G-proteins. In this paper it is demonstrated that part of the cellular NDP kinase is associated with the membrane and stimulated by cell surface cAMP receptors. The GTP produced by the action of NDP kinase is capable of activating G-proteins as monitored by altered G-protein-receptor interaction and the activation of the effector enzyme phospholipase C. Furthermore, specific monoclonal antibodies inhibit the effect of NDP kinase on G-protein activation. These results suggest that receptor-stimulated NDP kinase contributes to the mediation of hormone action by producing GTP for the activation of GTP-binding proteins. Images PMID:8389692

  15. Therapeutic actions of an insulin receptor activator and a novel peroxisome proliferator-activated receptor gamma agonist in the spontaneously hypertensive obese rat model of metabolic syndrome X.

    Science.gov (United States)

    Velliquette, Rodney A; Friedman, Jacob E; Shao, J; Zhang, Bei B; Ernsberger, Paul

    2005-07-01

    Insulin resistance clusters with hyperlipidemia, impaired glucose tolerance, and hypertension as metabolic syndrome X. We tested a low molecular weight insulin receptor activator, demethylasterriquinone B-1 (DMAQ-B1), and a novel indole peroxisome proliferator-activated receptor gamma agonist, 2-(2-(4-phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid (PPEIA), in spontaneously hypertensive obese rats (SHROB), a genetic model of syndrome X. Agents were given orally for 19 days. SHROB showed fasting normoglycemia but impaired glucose tolerance after an oral load, as shown by increased glucose area under the curve (AUC) [20,700 mg x min/ml versus 8100 in lean spontaneously hypertensive rats (SHR)]. Insulin resistance was indicated by 20-fold excess fasting insulin and increased insulin AUC (6300 ng x min/ml versus 990 in SHR). DMAQ-B1 did not affect glucose tolerance (glucose AUC = 21,300) but reduced fasting insulin 2-fold and insulin AUC (insulin AUC = 4300). PPEIA normalized glucose tolerance (glucose AUC = 9100) and reduced insulin AUC (to 3180) without affecting fasting insulin. PPEIA also increased food intake, fat mass, and body weight gain (81 +/- 12 versus 45 +/- 8 g in untreated controls), whereas DMAQ-B1 had no effect on body weight but reduced subscapular fat mass. PPEIA but not DMAQ-B1 reduced blood pressure. In skeletal muscle, insulin-stimulated phosphorylation of the insulin receptor and insulin receptor substrate protein 1-associated phosphatidylinositol 3-kinase activity were decreased by 40 to 55% in SHROB relative to lean SHR. PPEIA, but not DMAQ-B1, enhanced both insulin actions. SHROB also showed severe hypertriglyceridemia (355 +/- 42 mg/dl versus 65 +/- 3 in SHR) attenuated by both agents (DMAQ-B1, 228 +/- 18; PPEIA, 79 +/- 3). Both these novel antidiabetic agents attenuate insulin resistance and hypertriglyceridemia associated with metabolic syndrome but via distinct mechanisms.

  16. Phasic dopamine release drives rapid activation of striatal D2-receptors

    Science.gov (United States)

    Marcott, Pamela F; Mamaligas, Aphroditi A; Ford, Christopher P

    2014-01-01

    Summary Striatal dopamine transmission underlies numerous goal-directed behaviors. Medium spiny neurons (MSNs) are a major target of dopamine in the striatum. However, as dopamine does not directly evoke a synaptic event in MSNs, the time course of dopamine signaling in these cells remains unclear. To examine how dopamine release activates D2-receptors on MSNs, G-protein activated inwardly rectifying potassium (GIRK2; Kir 3.2) channels were virally overexpressed in the striatum and the resulting outward currents were used as a sensor of D2-receptor activation. Electrical and optogenetic stimulation of dopamine terminals evoked robust D2-receptor inhibitory post-synaptic currents (IPSCs) in GIRK2-expressing MSNs that occurred in under a second. Evoked D2-IPSCs could be driven by repetitive stimulation and were not occluded by background dopamine tone. Together, the results indicate that D2-receptors on MSNs exhibit functional low affinity and suggest that striatal D2-receptors can encode both tonic and phasic dopamine signals. PMID:25242218

  17. Activation of neurotensin receptors and purinoceptors in human colonic adenocarcinoma cells detected with the microphysiometer.

    Science.gov (United States)

    Richards, M; van Giersbergen, P; Zimmermann, A; Lesur, B; Hoflack, J

    1997-10-01

    Activation of endogenous neurotensin (NT) receptors and P2-purinoceptors expressed by human colonic adenocarcinoma HT-29 cells increased extracellular acidification rates that were detected in the microphysiometer. NT (pGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu), NT[8-13] (Arg-Arg-Pro-Tyr-Ile-Leu), NT[9-13] (Arg-Pro-Tyr-Ile-Leu), and NT1 (N alpha methyl-Arg-Lys-Pro-Trp-Tle-Leu [Tle = tert-leucine]) were full agonists, whereas XL 775 (N-[N-[2-[3-[[6-amino-1-oxo-2-[[(phenylmethoxy)carbonyl]-amino]hex yl]amino]phenyl]-3-(4-hydroxyphenyl)-1-oxo-2-propenyl]-L-isoleucyl]-L-le ucine) was a partial agonist for activating NT receptors expressed by HT-29 cells. Desensitization induced by NT was rapid and monophasic with 85% of the initial response lost by a 30-s exposure. Once initiated, the rate and extent of desensitization were similar for different concentrations of a given agonist, for agonists of different potencies, and for agonists of different efficacies, which suggests that desensitization may be independent of receptor occupancy or agonist efficacy. Resensitization was a much slower process, requiring 60 min before the full agonist response to NT was recovered. ATP, via P2-purinoceptors, also activated cellular acidification rates in a concentration-dependent manner. ATP induced a biphasic desensitization of purinoceptors with a loss of ca. 50% of the initial stimulation detectable between 30 and 90 s of exposure to the agonist. Desensitization of NT receptors did not influence the activation of P2-purinoceptors by ATP, suggesting there was no heterologous desensitization between the two types of receptors. Superfusion with NT receptor agonists for 15 min at concentrations that did not elicit changes in extracellular acidification rates blocked, in a concentration-dependent manner, the agonist response induced by 100 nM NT. This may reflect sequestration of the receptor. These results suggest that the high agonist affinity state of NT receptors may

  18. GABAA receptors in visual and auditory cortex and neural activity changes during basic visual stimulation

    Directory of Open Access Journals (Sweden)

    Pengmin eQin

    2012-12-01

    Full Text Available Recent imaging studies have demonstrated that levels of resting GABA in the visual cortex predict the degree of stimulus-induced activity in the same region. These studies have used the presentation of discrete visual stimulus; the change from closed eyes to open also represents a simple visual stimulus, however, and has been shown to induce changes in local brain activity and in functional connectivity between regions. We thus aimed to investigate the role of the GABA system, specifically GABAA receptors, in the changes in brain activity between the eyes closed (EC and eyes open (EO state in order to provide detail at the receptor level to complement previous studies of GABA concentrations. We conducted an fMRI study involving two different modes of the change from EC to EO: An EO and EC block design, allowing the modelling of the haemodynamic response, followed by longer periods of EC and EO to allow the measuring of functional connectivity. The same subjects also underwent [18F]Flumazenil PET measure GABAA receptor binding potentials. It was demonstrated that the local-to-global ratio of GABAA receptor binding potential in the visual cortex predicted the degree of changes in neural activity from EC to EO. This same relationship was also shown in the auditory cortex. Furthermore, the local-to-global ratio of GABAA receptor binding potential in the visual cortex also predicts the change of functional connectivity between visual and auditory cortex from EC to EO. These findings contribute to our understanding of the role of GABAA receptors in stimulus-induced neural activity in local regions and in inter-regional functional connectivity.

  19. Accessibility of receptor-bound urokinase to type-1 plasminogen activator inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Cubellis, M.V.; Andreasen, P.; Ragno, P.; Mayer, M.; Dano, K.; Blasi, F. (Univ. of Copenhagen (Denmark))

    1989-07-01

    Urokinase plasminogen activator (uPA) interacts with a surface receptor and with specific inhibitors, such as plasminogen activator inhibitor type 1 (PAI-1). These interactions are mediated by two functionally independent domains of the molecule: the catalytic domain (at the carboxyl terminus) and the growth factor domain (at the amino terminus). The authors have now investigated whether PAI-1 can bind and inhibit receptor-bound uPA. Binding of {sup 125}I-labeled ATF (amino-terminal fragment of uPA) to human U937 monocyte-like cells can be competed for by uPA-PAI-1 complexes, but not by PAI-1 alone. Preformed {sup 125}I-labeled uPA-PAI-1 complexes can bind to uPA receptor with the same binding specificity as uPA. PAI-1 also binds to, and inhibits the activity of, receptor-bound uPA in U937 cells, as shown in U937 cells by a caseinolytic plaque assay. Plasminogen activator activity of these cells is dependent on exogenous uPA, is competed for by receptor-binding diisopropyl fluorophosphate-treated uPA, and is inhibited by the addition of PAI-1. In conclusion, in U937 cells the binding to the receptor does not shield uPA from the action of PAI-1. The possibility that in adherent cells a different localization of PAI-1 and uPA leads to protection of uPA from PAI-1 is to be considered.

  20. Activation-Dependent Rapid Postsynaptic Clustering of Glycine Receptors in Mature Spinal Cord Neurons

    Science.gov (United States)

    Eto, Kei; Murakoshi, Hideji; Watanabe, Miho; Hirata, Hiromi; Moorhouse, Andrew J.; Ishibashi, Hitoshi

    2017-01-01

    Abstract Inhibitory synapses are established during development but continue to be generated and modulated in strength in the mature nervous system. In the spinal cord and brainstem, presynaptically released inhibitory neurotransmitter dominantly switches from GABA to glycine during normal development in vivo. While presynaptic mechanisms of the shift of inhibitory neurotransmission are well investigated, the contribution of postsynaptic neurotransmitter receptors to this shift is not fully elucidated. Synaptic clustering of glycine receptors (GlyRs) is regulated by activation-dependent depolarization in early development. However, GlyR activation induces hyperpolarization after the first postnatal week, and little is known whether and how presynaptically released glycine regulates postsynaptic receptors in a depolarization-independent manner in mature developmental stage. Here we developed spinal cord neuronal culture of rodents using chronic strychnine application to investigate whether initial activation of GlyRs in mature stage could change postsynaptic localization of GlyRs. Immunocytochemical analyses demonstrate that chronic blockade of GlyR activation until mature developmental stage resulted in smaller clusters of postsynaptic GlyRs that could be enlarged upon receptor activation for 1 h in the mature stage. Furthermore, live cell-imaging techniques show that GlyR activation decreases its lateral diffusion at synapses, and this phenomenon is dependent on PKC, but neither Ca2+ nor CaMKII activity. These results suggest that the GlyR activation can regulate receptor diffusion and cluster size at inhibitory synapses in mature stage, providing not only new insights into the postsynaptic mechanism of shifting inhibitory neurotransmission but also the inhibitory synaptic plasticity in mature nervous system. PMID:28197549

  1. Modulation of the constitutive activity of the ghrelin receptor by use of pharmacological tools and mutagenesis.

    Science.gov (United States)

    Mokrosiński, Jacek; Holst, Birgitte

    2010-01-01

    Ghrelin and its receptor are important regulators of metabolic functions, including appetite, energy expenditure, fat accumulation, and growth hormone (GH) secretion. The ghrelin receptor is characterized by an ability to signal even without any ligand present with approximately 50% of the maximally ghrelin-induced efficacy-a feature that may have important physiological implications. The high basal signaling can be modulated either by administration of specific ligands or by engineering of mutations in the receptor structure. [D-Arg(1), D-Phe(5), D-Trp(7,9), Leu(11)]-substance P was the first inverse agonist to be identified for the ghrelin receptor, and this peptide has been used as a starting point for identification of the structural requirements for inverse agonist properties in the ligand. The receptor binding core motif was identified as D-Trp-Phe-D-Trp-Leu-Leu, and elongation of this peptide in the amino-terminal end determined the efficacy. Attachment of a positively charged amino acid was responsible for full inverse agonism, whereas an alanin converted the peptide into a partial agonist. Importantly, by use of mutational mapping of the residues critical for the modified D-Trp-Phe-D-Trp-Leu-Leu peptides, it was found that space-generating mutations in the deeper part of the receptor improved inverse agonism, whereas similar mutations located in the more extracellular part improved agonism. Modulation of the basal signaling by mutations in the receptor structure is primarily obtained by substitutions in an aromatic cluster that keep TMs VI and VII in close proximity to TM III and thus stabilize the active conformation. Also, substitution of a Phe in TM V is crucial for the high basal activity of the receptor as this residue serves as a partner for Trp VI:13 in the active conformation. It is suggested that inverse agonist and antagonist against the ghrelin receptor provide an interesting possibility in the development of drugs for treatment of obesity and

  2. An Angiotensin II type 1 receptor activation switch patch revealed through Evolutionary Trace analysis

    DEFF Research Database (Denmark)

    Bonde, Marie Mi; Yao, Rong; Ma, Jian-Nong

    2010-01-01

    to be completely resolved. Evolutionary Trace (ET) analysis is a computational method, which identifies clusters of functionally important residues by integrating information on evolutionary important residue variations with receptor structure. Combined with known mutational data, ET predicted a patch of residues......) displayed phenotypes associated with changed activation state, such as increased agonist affinity or basal activity, promiscuous activation, or constitutive internalization highlighting the importance of testing different signaling pathways. We conclude that this evolutionary important patch mediates...

  3. Anatomic and Pathologic Variability During Radiotherapy for a Hybrid Active Breath-Hold Gating Technique

    International Nuclear Information System (INIS)

    Glide-Hurst, Carri K.; Gopan, Ellen; Hugo, Geoffrey D.

    2010-01-01

    Purpose: To evaluate intra- and interfraction variability of tumor and lung volume and position using a hybrid active breath-hold gating technique. Methods and Materials: A total of 159 repeat normal inspiration active breath-hold CTs were acquired weekly during radiotherapy for 9 lung cancer patients (12-21 scans per patient). A physician delineated the gross tumor volume (GTV), lungs, and spinal cord on the first breath-hold CT, and contours were propagated semiautomatically. Intra- and interfraction variability of tumor and lung position and volume were evaluated. Tumor centroid and border variability were quantified. Results: On average, intrafraction variability of lung and GTV centroid position was 0.1). Increases in free-breathing tidal volume were associated with increases in breath-hold ipsilateral lung volume (p < 0.05). Conclusions: The breath-hold technique was reproducible within 2 mm during each fraction. Interfraction variability of GTV position and shape was substantial because of tumor volume and breath-hold lung volume change during therapy. These results support the feasibility of a hybrid breath-hold gating technique and suggest that online image guidance would be beneficial.

  4. SERS-active ZnO/Ag hybrid WGM microcavity for ultrasensitive dopamine detection

    Science.gov (United States)

    Lu, Junfeng; Xu, Chunxiang; Nan, Haiyan; Zhu, Qiuxiang; Qin, Feifei; Manohari, A. Gowri; Wei, Ming; Zhu, Zhu; Shi, Zengliang; Ni, Zhenhua

    2016-08-01

    Dopamine (DA) is a potential neuro modulator in the brain which influences a variety of motivated behaviors and plays a key role in life science. A hybrid ZnO/Ag microcavity based on Whispering Gallery Mode (WGM) effect has been developed for ultrasensitive detection of dopamine. Utilizing this effect of structural cavity mode, a Raman signal of R6G (5 × 10-3 M) detected by this designed surface-enhanced Raman spectroscopy (SERS)-active substrate was enhanced more than 10-fold compared with that of ZnO film/Ag substrate. Also, this hybrid microcavity substrate manifests high SERS sensitivity to rhodamine 6 G and detection limit as low as 10-12 M to DA. The Localized Surface Plasmons of Ag nanoparticles and WGM-enhanced light-matter interaction mainly contribute to the high SERS sensitivity and help to achieve a lower detection limit. This designed SERS-active substrate based on the WGM effect has the potential for detecting neurotransmitters in life science.

  5. Multi-objective decoupling algorithm for active distance control of intelligent hybrid electric vehicle

    Science.gov (United States)

    Luo, Yugong; Chen, Tao; Li, Keqiang

    2015-12-01

    The paper presents a novel active distance control strategy for intelligent hybrid electric vehicles (IHEV) with the purpose of guaranteeing an optimal performance in view of the driving functions, optimum safety, fuel economy and ride comfort. Considering the complexity of driving situations, the objects of safety and ride comfort are decoupled from that of fuel economy, and a hierarchical control architecture is adopted to improve the real-time performance and the adaptability. The hierarchical control structure consists of four layers: active distance control object determination, comprehensive driving and braking torque calculation, comprehensive torque distribution and torque coordination. The safety distance control and the emergency stop algorithms are designed to achieve the safety and ride comfort goals. The optimal rule-based energy management algorithm of the hybrid electric system is developed to improve the fuel economy. The torque coordination control strategy is proposed to regulate engine torque, motor torque and hydraulic braking torque to improve the ride comfort. This strategy is verified by simulation and experiment using a forward simulation platform and a prototype vehicle. The results show that the novel control strategy can achieve the integrated and coordinated control of its multiple subsystems, which guarantees top performance of the driving functions and optimum safety, fuel economy and ride comfort.

  6. Antioxidant activity and bioactive compound contents before and after in vitro digestion of new tomato hybrids.

    Science.gov (United States)

    Tommonaro, Giuseppina; Speranza, Giovanna; De Prisco, Rocco; Iodice, Carmine; Crudele, Egle; Abbamondi, Gennaro Roberto; Nicolaus, Barbara

    2017-12-01

    The antioxidant properties and bioactive compound contents of fresh new tomato hybrids before and after in vitro digestion were investigated. To this aim, the antioxidant activities of lipophilic, hydrophilic and polyphenolic extracts of tomato hybrids were determined by ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)), DMPD (N,N-dimethyl-p-phenylenediamine dihydrochloride) and DPPH (2,2-diphenyl-1-picrylhydrazyl) methods respectively, while the bioactive compound contents were estimated via Folin-Ciocalteu (polyphenols), pH differential (anthocyanins) and high-performance liquid chromatography (lycopene and β-carotene) methods. After the digestion process, a marked loss (ranging from 37 to 77%) of antioxidant capacity linked to the hydrophilic fraction was observed. In contrast, the lipophilic and methanolic fractions showed an increase in antioxidant activity (ranging from 9 to 40%) after gastric digestion, and a rapid decrease was observed after total digestion. Moreover, the presence of anthocyanins and carotenoids after simulated digestion was a notable result. The bioavailability of bioactive metabolites from nutraceutical food and their healthful properties in humans are strictly dependent on the digestion process. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

  7. Active-passive hybrid piezoelectric actuators for high-precision hard disk drive servo systems

    Science.gov (United States)

    Chan, Kwong Wah; Liao, Wei-Hsin

    2006-03-01

    Positioning precision is crucial to today's increasingly high-speed, high-capacity, high data density, and miniaturized hard disk drives (HDDs). The demand for higher bandwidth servo systems that can quickly and precisely position the read/write head on a high track density becomes more pressing. Recently, the idea of applying dual-stage actuators to track servo systems has been studied. The push-pull piezoelectric actuated devices have been developed as micro actuators for fine and fast positioning, while the voice coil motor functions as a large but coarse seeking. However, the current dual-stage actuator design uses piezoelectric patches only without passive damping. In this paper, we propose a dual-stage servo system using enhanced active-passive hybrid piezoelectric actuators. The proposed actuators will improve the existing dual-stage actuators for higher precision and shock resistance, due to the incorporation of passive damping in the design. We aim to develop this hybrid servo system not only to increase speed of track seeking but also to improve precision of track following servos in HDDs. New piezoelectrically actuated suspensions with passive damping have been designed and fabricated. In order to evaluate positioning and track following performances for the dual-stage track servo systems, experimental efforts are carried out to implement the synthesized active-passive suspension structure with enhanced piezoelectric actuators using a composite nonlinear feedback controller.

  8. Excessive D1 Dopamine Receptor Activation in the Dorsal Striatum Promotes Autistic-Like Behaviors.

    Science.gov (United States)

    Lee, Yunjin; Kim, Hannah; Kim, Ji-Eun; Park, Jin-Young; Choi, Juli; Lee, Jung-Eun; Lee, Eun-Hwa; Han, Pyung-Lim

    2018-07-01

    The dopamine system has been characterized in motor function, goal-directed behaviors, and rewards. Recent studies recognize various dopamine system genes as being associated with autism spectrum disorder (ASD). However, how dopamine system dysfunction induces ASD pathophysiology remains unknown. In the present study, we demonstrated that mice with increased dopamine functions in the dorsal striatum via the suppression of dopamine transporter expression in substantia nigra neurons or the optogenetic stimulation of the nigro-striatal circuitry exhibited sociability deficits and repetitive behaviors relevant to ASD pathology in animal models, while these behavioral changes were blocked by a D1 receptor antagonist. Pharmacological activation of D1 dopamine receptors in normal mice or the genetic knockout (KO) of D2 dopamine receptors also produced typical autistic-like behaviors. Moreover, the siRNA-mediated inhibition of D2 dopamine receptors in the dorsal striatum was sufficient to replicate autistic-like phenotypes in D2 KO mice. Intervention of D1 dopamine receptor functions or the signaling pathways-related D1 receptors in D2 KO mice produced anti-autistic effects. Together, our results indicate that increased dopamine function in the dorsal striatum promotes autistic-like behaviors and that the dorsal striatum is the neural correlate of ASD core symptoms.

  9. Internalization mechanisms of the epidermal growth factor receptor after activation with different ligands.

    Directory of Open Access Journals (Sweden)

    Lasse Henriksen

    Full Text Available The epidermal growth factor receptor (EGFR regulates normal growth and differentiation, but dysregulation of the receptor or one of the EGFR ligands is involved in the pathogenesis of many cancers. There are eight ligands for EGFR, however most of the research into trafficking of the receptor after ligand activation focuses on the effect of epidermal growth factor (EGF and transforming growth factor-α (TGF-α. For a long time it was believed that clathrin-mediated endocytosis was the major pathway for internalization of the receptor, but recent work suggests that different pathways exist. Here we show that clathrin ablation completely inhibits internalization of EGF- and TGF-α-stimulated receptor, however the inhibition of receptor internalization in cells treated with heparin-binding EGF-like growth factor (HB-EGF or betacellulin (BTC was only partial. In contrast, clathrin knockdown fully inhibits EGFR degradation after all ligands tested. Furthermore, inhibition of dynamin function blocked EGFR internalization after stimulation with all ligands. Knocking out a number of clathrin-independent dynamin-dependent pathways of internalization had no effect on the ligand-induced endocytosis of the EGFR. We suggest that EGF and TGF-α lead to EGFR endocytosis mainly via the clathrin-mediated pathway. Furthermore, we suggest that HB-EGF and BTC also lead to EGFR endocytosis via a clathrin-mediated pathway, but can additionally use an unidentified internalization pathway or better recruit the small amount of clathrin remaining after clathrin knockdown.

  10. Internalization Mechanisms of the Epidermal Growth Factor Receptor after Activation with Different Ligands

    Science.gov (United States)

    Henriksen, Lasse; Grandal, Michael Vibo; Knudsen, Stine Louise Jeppe; van Deurs, Bo; Grøvdal, Lene Melsæther

    2013-01-01

    The epidermal growth factor receptor (EGFR) regulates normal growth and differentiation, but dysregulation of the receptor or one of the EGFR ligands is involved in the pathogenesis of many cancers. There are eight ligands for EGFR, however most of the research into trafficking of the receptor after ligand activation focuses on the effect of epidermal growth factor (EGF) and transforming growth factor-α (TGF-α). For a long time it was believed that clathrin-mediated endocytosis was the major pathway for internalization of the receptor, but recent work suggests that different pathways exist. Here we show that clathrin ablation completely inhibits internalization of EGF- and TGF-α-stimulated receptor, however the inhibition of receptor internalization in cells treated with heparin-binding EGF-like growth factor (HB-EGF) or betacellulin (BTC) was only partial. In contrast, clathrin knockdown fully inhibits EGFR degradation after all ligands tested. Furthermore, inhibition of dynamin function blocked EGFR internalization after stimulation with all ligands. Knocking out a number of clathrin-independent dynamin-dependent pathways of internalization had no effect on the ligand-induced endocytosis of the EGFR. We suggest that EGF and TGF-α lead to EGFR endocytosis mainly via the clathrin-mediated pathway. Furthermore, we suggest that HB-EGF and BTC also lead to EGFR endocytosis via a clathrin-mediated pathway, but can additionally use an unidentified internalization pathway or better recruit the small amount of clathrin remaining after clathrin knockdown. PMID:23472148

  11. Activation of GABAB receptors inhibits protein kinase B /Glycogen Synthase Kinase 3 signaling

    Directory of Open Access Journals (Sweden)

    Lu Frances Fangjia

    2012-11-01

    Full Text Available Abstract Accumulated evidence has suggested that potentiation of cortical GABAergic inhibitory neurotransmission may be a key mechanism in the treatment of schizophrenia. However, the downstream molecular mechanisms related to GABA potentiation remain unexplored. Recent studies have suggested that dopamine D2 receptor antagonists, which are used in the clinical treatment of schizophrenia, modulate protein kinase B (Akt/glycogen synthase kinase (GSK-3 signaling. Here we report that activation of GABAB receptors significantly inhibits Akt/GSK-3 signaling in a β-arrestin-dependent pathway. Agonist stimulation of GABAB receptors enhances the phosphorylation of Akt (Thr-308 and enhances the phosphorylation of GSK-3α (Ser-21/β (Ser-9 in both HEK-293T cells expressing GABAB receptors and rat hippocampal slices. Furthermore, knocking down the expression of β-arrestin2 using siRNA abolishes the GABAB receptor-mediated modulation of GSK-3 signaling. Our data may help to identify potentially novel targets through which GABAB receptor agents may exert therapeutic effects in the treatment of schizophrenia.

  12. Direct activation of Transient Receptor Potential Vanilloid 1(TRPV1 by Diacylglycerol (DAG

    Directory of Open Access Journals (Sweden)

    Oh Seog

    2008-10-01

    Full Text Available Abstract The capsaicin receptor, known as transient receptor potential channel vanilloid subtype 1 (TRPV1, is activated by a wide range of noxious stimulants and putative ligands such as capsaicin, heat, pH, anandamide, and phosphorylation by protein kinase C (PKC. However, the identity of endogenous activators for TRPV1 under physiological condition is still debated. Here, we report that diacylglycerol (DAG directly activates TRPV1 channel in a membrane-delimited manner in rat dorsal root ganglion (DRG neurons. 1-oleoyl-2-acetyl-sn-glycerol (OAG, a membrane-permeable DAG analog, elicited intracellular Ca2+ transients, cationic currents and cobalt uptake that were blocked by TRPV1-selective antagonists, but not by inhibitors of PKC and DAG lipase in rat DRG neurons or HEK 293 cells heterologously expressing TRPV1. OAG induced responses were about one fifth of capsaicin induced signals, suggesting that OAG displays partial agonism. We also found that endogenously produced DAG can activate rat TRPV1 channels. Mutagenesis of rat TRPV1 revealed that DAG-binding site is at Y511, the same site for capsaicin binding, and PtdIns(4,5P2binding site may not be critical for the activation of rat TRPV1 by DAG in heterologous system. We propose that DAG serves as an endogenous ligand for rat TRPV1, acting as an integrator of Gq/11-coupled receptors and receptor tyrosine kinases that are linked to phospholipase C.

  13. Role of tissue factor and protease-activated receptors in a mouse model of endotoxemia.

    Science.gov (United States)

    Pawlinski, Rafal; Pedersen, Brian; Schabbauer, Gernot; Tencati, Michael; Holscher, Todd; Boisvert, William; Andrade-Gordon, Patricia; Frank, Rolf Dario; Mackman, Nigel

    2004-02-15

    Sepsis is associated with a systemic activation of coagulation and an excessive inflammatory response. Anticoagulants have been shown to inhibit both coagulation and inflammation in sepsis. In this study, we used both genetic and pharmacologic approaches to analyze the role of tissue factor and protease-activated receptors in coagulation and inflammation in a mouse endotoxemia model. We used mice expressing low levels of the procoagulant molecule, tissue factor (TF), to analyze the effects of TF deficiency either in all tissues or selectively in hematopoietic cells. Low TF mice had reduced coagulation, inflammation, and mortality compared with control mice. Similarly, a deficiency of TF expression by hematopoietic cells reduced lipopolysaccharide (LPS)-induced coagulation, inflammation, and mortality. Inhibition of the down-stream coagulation protease, thrombin, reduced fibrin deposition and prolonged survival without affecting inflammation. Deficiency of either protease activated receptor-1 (PAR-1) or protease activated receptor-2 (PAR-2) alone did not affect inflammation or survival. However, a combination of thrombin inhibition and PAR-2 deficiency reduced inflammation and mortality. These data demonstrate that hematopoietic cells are the major pathologic site of TF expression during endotoxemia and suggest that multiple protease-activated receptors mediate crosstalk between coagulation and inflammation.

  14. Peroxisome Proliferator-Activated Receptor Ligands and Their Role in Chronic Myeloid Leukemia: Therapeutic Strategies.

    Science.gov (United States)

    Yousefi, Bahman; Samadi, Nasser; Baradaran, Behzad; Shafiei-Irannejad, Vahid; Zarghami, Nosratollah

    2016-07-01

    Imatinib therapy remains the gold standard for treatment of chronic myeloid leukemia; however, the acquired resistance to this therapeutic agent in patients has urged the scientists to devise modalities for overcoming this chemoresistance. For this purpose, initially therapeutic agents with higher tyrosine kinase activity were introduced, which had the potential for inhibiting even mutant forms of Bcr-Abl. Furthermore, coupling imatinib with peroxisome proliferator-activated receptor ligands also showed beneficial effects in chronic myeloid leukemia cell proliferation. These combination protocols inhibited cell growth and induced apoptosis as well as differentiation in chronic myeloid leukemia cell lines. In addition, peroxisome proliferator-activated receptors ligands increased imatinib uptake by upregulating the expression of human organic cation transporter 1. Taken together, peroxisome proliferator-activated receptors ligands are currently being considered as novel promising therapeutic candidates for chronic myeloid leukemia treatment, because they can synergistically enhance the efficacy of imatinib. In this article, we reviewed the potential of peroxisome proliferator-activated receptors ligands for use in chronic myeloid leukemia treatment. The mechanism of action of these therapeutics modalities are also presented in detail. © 2016 John Wiley & Sons A/S.

  15. Anti-tumor Activity of Toll-Like Receptor 7 Agonists

    Directory of Open Access Journals (Sweden)

    Huju Chi

    2017-05-01

    Full Text Available Toll-like receptors (TLRs are a class of pattern recognition receptors that play a bridging role in innate immunity and adaptive immunity. The activated TLRs not only induce inflammatory responses, but also elicit the development of antigen specific immunity. TLR7, a member of TLR family, is an intracellular receptor expressed on the membrane of endosomes. TLR7 can be triggered not only by ssRNA during viral infections, but also by immune modifiers that share a similar structure to nucleosides. Its powerful immune stimulatory action can be potentially used in the anti-tumor therapy. This article reviewed the anti-tumor activity and mechanism of TLR7 agonists that are frequently applied in preclinical and clinical investigations, and mainly focused on small synthetic molecules, including imiquimod, resiquimod, gardiquimod, and 852A, etc.

  16. Synthetic ligands of the elastin receptor induce elastogenesis in human dermal fibroblasts via activation of their IGF-1 receptors.

    Science.gov (United States)

    Qa'aty, Nour; Vincent, Matthew; Wang, Yanting; Wang, Andrew; Mitts, Thomas F; Hinek, Aleksander

    2015-12-01

    We have previously reported that a mixture of peptides obtained after chemical or enzymatic degradation of bovine elastin, induced new elastogenesis in human skin. Now, we investigated the elastogenic potential of synthetic peptides mimicking the elastin-derived, VGVAPG sequence, IGVAPG sequence that we found in the rice bran, and a similar peptide, VGVTAG that we identified in the IGF-1-binding protein-1 (IGFBP-1). We now demonstrate that treatment with each of these xGVxxG peptides (recognizable by the anti-elastin antibody), up-regulated the levels of elastin-encoding mRNA, tropoelastin protein, and the deposition of new elastic fibers in cultures of human dermal fibroblasts and in cultured explants of human skin. Importantly, we found that such induction of new elastogenesis may involve two parallel signaling pathways triggered after activation of IGF-1 receptor. In the first one, the xGVxxG peptides interact with the cell surface elastin receptor, thereby causing the downstream activation of the c-Src kinase and a consequent cross-activation of the adjacent IGF-1R, even in the absence of its principal ligand. In the second pathway their hydrophobic association with the N-terminal domain (VGVTAG) of the serum-derived IGFBP-1 induces conformational changes of this IGF-1 chaperone allowing for the release of its cargo and a consequent ligand-specific phosphorylation of IGF-1R. We present a novel, clinically relevant mechanism in which products of partial degradation of dermal elastin may stimulate production of new elastic fibers by dermal fibroblasts. Our findings particularly encourage the use of biologically safe synthetic xGVxxG peptides for regeneration of the injured or aged human skin. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  17. Protease-Activated Receptor 4 Variant p.Tyr157Cys Reduces Platelet Functional Responses and Alters Receptor Trafficking.

    Science.gov (United States)

    Norman, Jane E; Cunningham, Margaret R; Jones, Matthew L; Walker, Mary E; Westbury, Sarah K; Sessions, Richard B; Mundell, Stuart J; Mumford, Andrew D

    2016-05-01

    Protease-activated receptor 4 (PAR4) is a key regulator of platelet reactivity and is encoded by F2RL3, which has abundant rare missense variants. We aimed to provide proof of principle that rare F2LR3 variants potentially affect platelet reactivity and responsiveness to PAR1 antagonist drugs and to explore underlying molecular mechanisms. We identified 6 rare F2RL3 missense variants in 236 cardiac patients, of which the variant causing a tyrosine 157 to cysteine substitution (Y157C) was predicted computationally to have the greatest effect on PAR4 structure. Y157C platelets from 3 cases showed reduced responses to PAR4-activating peptide and to α-thrombin compared with controls, but no reduction in responses to PAR1-activating peptide. Pretreatment with the PAR1 antagonist vorapaxar caused lower residual α-thrombin responses in Y157C platelets than in controls, indicating greater platelet inhibition. HEK293 cells transfected with a PAR4 Y157C expression construct had reduced PAR4 functional responses, unchanged total PAR4 expression but reduced surface expression. PAR4 Y157C was partially retained in the endoplasmic reticulum and displayed an expression pattern consistent with defective N-glycosylation. Mutagenesis of Y322, which is the putative hydrogen bond partner of Y157, also reduced PAR4 surface expression in HEK293 cells. Reduced PAR4 responses associated with Y157C result from aberrant anterograde surface receptor trafficking, in part, because of disrupted intramolecular hydrogen bonding. Characterization of PAR4 Y157C establishes that rare F2RL3 variants have the potential to markedly alter platelet PAR4 reactivity particularly after exposure to therapeutic PAR1 antagonists. © 2016 American Heart Association, Inc.

  18. Nifedipine inhibits advanced glycation end products (AGEs) and their receptor (RAGE) interaction-mediated proximal tubular cell injury via peroxisome proliferator-activated receptor-gamma activation

    International Nuclear Information System (INIS)

    Matsui, Takanori; Yamagishi, Sho-ichi; Takeuchi, Masayoshi; Ueda, Seiji; Fukami, Kei; Okuda, Seiya

    2010-01-01

    Research highlights: → Nifedipine inhibited the AGE-induced up-regulation of RAGE mRNA levels in tubular cells, which was prevented by GW9662, an inhibitor of peroxisome proliferator-activated receptor-γ. → GW9662 treatment alone increased RAGE mRNA levels in tubular cells. → Nifedipine inhibited the AGE-induced reactive oxygen species generation, NF-κB activation and increases in intercellular adhesion molecule-1 and transforming growth factor-β gene expression in tubular cells, all of which were blocked by GW9662. -- Abstract: There is a growing body of evidence that advanced glycation end products (AGEs) and their receptor (RAGE) interaction evokes oxidative stress generation and subsequently elicits inflammatory and fibrogenic reactions, thereby contributing to the development and progression of diabetic nephropathy. We have previously found that nifedipine, a calcium-channel blocker (CCB), inhibits the AGE-induced mesangial cell damage in vitro. However, effects of nifedipine on proximal tubular cell injury remain unknown. We examined here whether and how nifedipine blocked the AGE-induced tubular cell damage. Nifedipine, but not amlodipine, a control CCB, inhibited the AGE-induced up-regulation of RAGE mRNA levels in tubular cells, which was prevented by the simultaneous treatment of GW9662, an inhibitor of peroxisome proliferator-activated receptor-γ (PPARγ). GW9662 treatment alone was found to increase RAGE mRNA levels in tubular cells. Further, nifedipine inhibited the AGE-induced reactive oxygen species generation, NF-κB activation and increases in intercellular adhesion molecule-1 and transforming growth factor-beta gene expression in tubular cells, all of which were blocked by GW9662. Our present study provides a unique beneficial aspect of nifedipine on diabetic nephropathy; it could work as an anti-oxidative and anti-inflammatory agent against AGEs in tubular cells by suppressing RAGE expression via PPARγ activation.

  19. Nifedipine inhibits advanced glycation end products (AGEs) and their receptor (RAGE) interaction-mediated proximal tubular cell injury via peroxisome proliferator-activated receptor-gamma activation

    Energy Technology Data Exchange (ETDEWEB)

    Matsui, Takanori [Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume (Japan); Yamagishi, Sho-ichi, E-mail: shoichi@med.kurume-u.ac.jp [Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume (Japan); Takeuchi, Masayoshi [Department of Pathophysiological Science, Faculty of Pharmaceutical Science, Hokuriku University, Kanazawa (Japan); Ueda, Seiji; Fukami, Kei; Okuda, Seiya [Department of Medicine, Kurume University School of Medicine, Kurume (Japan)

    2010-07-23

    Research highlights: {yields} Nifedipine inhibited the AGE-induced up-regulation of RAGE mRNA levels in tubular cells, which was prevented by GW9662, an inhibitor of peroxisome proliferator-activated receptor-{gamma}. {yields} GW9662 treatment alone increased RAGE mRNA levels in tubular cells. {yields} Nifedipine inhibited the AGE-induced reactive oxygen species generation, NF-{kappa}B activation and increases in intercellular adhesion molecule-1 and transforming growth factor-{beta} gene expression in tubular cells, all of which were blocked by GW9662. -- Abstract: There is a growing body of evidence that advanced glycation end products (AGEs) and their receptor (RAGE) interaction evokes oxidative stress generation and subsequently elicits inflammatory and fibrogenic reactions, thereby contributing to the development and progression of diabetic nephropathy. We have previously found that nifedipine, a calcium-channel blocker (CCB), inhibits the AGE-induced mesangial cell damage in vitro. However, effects of nifedipine on proximal tubular cell injury remain unknown. We examined here whether and how nifedipine blocked the AGE-induced tubular cell damage. Nifedipine, but not amlodipine, a control CCB, inhibited the AGE-induced up-regulation of RAGE mRNA levels in tubular cells, which was prevented by the simultaneous treatment of GW9662, an inhibitor of peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}). GW9662 treatment alone was found to increase RAGE mRNA levels in tubular cells. Further, nifedipine inhibited the AGE-induced reactive oxygen species generation, NF-{kappa}B activation and increases in intercellular adhesion molecule-1 and transforming growth factor-beta gene expression in tubular cells, all of which were blocked by GW9662. Our present study provides a unique beneficial aspect of nifedipine on diabetic nephropathy; it could work as an anti-oxidative and anti-inflammatory agent against AGEs in tubular cells by suppressing RAGE expression

  20. Palliation of bone cancer pain by antagonists of platelet-activating factor receptors.

    Directory of Open Access Journals (Sweden)

    Katsuya Morita

    Full Text Available Bone cancer pain is the most severe among cancer pain and is often resistant to current analgesics. Thus, the development of novel analgesics effective at treating bone cancer pain are desired. Platelet-activating factor (PAF receptor antagonists were recently demonstrated to have effective pain relieving effects on neuropathic pain in several animal models. The present study examined the pain relieving effect of PAF receptor antagonists on bone cancer pain using the femur bone cancer (FBC model in mice. Animals were injected with osteolytic NCTC2472 cells into the tibia, and subsequently the effects of PAF receptor antagonists on pain behaviors were evaluated. Chemical structurally different type of antagonists, TCV-309, BN 50739 and WEB 2086 ameliorated the allodynia and improved pain behaviors such as guarding behavior and limb-use abnormalities in FBC model mice. The pain relieving effects of these antagonists were achieved with low doses and were long lasting. Blockade of spinal PAF receptors by intrathecal injection of TCV-309 and WEB 2086 or knockdown of the expression of spinal PAF receptor protein by intrathecal transfer of PAF receptor siRNA also produced a pain relieving effect. The amount of an inducible PAF synthesis enzyme, lysophosphatidylcholine acyltransferase 2 (LPCAT2 protein significantly increased in the spinal cord after transplantation of NCTC 2472 tumor cells into mouse tibia. The combination of morphine with PAF receptor antagonists develops marked enhancement of the analgesic effect against bone cancer pain without affecting morphine-induced constipation. Repeated administration of TCV-309 suppressed the appearance of pain behaviors and prolonged survival of FBC mice. The present results suggest that PAF receptor antagonists in combination with, or without, opioids may represent a new strategy for the treatment of persistent bone cancer pain and improve the quality of life of patients.

  1. Activation of temperature-sensitive TRPV1-like receptors in ARC POMC neurons reduces food intake.

    Directory of Open Access Journals (Sweden)

    Jae Hoon Jeong

    2018-04-01

    Full Text Available Proopiomelanocortin (POMC neurons in the arcuate nucleus of the hypothalamus (ARC respond to numerous hormonal and neural signals, resulting in changes in food intake. Here, we demonstrate that ARC POMC neurons express capsaicin-sensitive transient receptor potential vanilloid 1 receptor (TRPV1-like receptors. To show expression of TRPV1-like receptors in ARC POMC neurons, we use single-cell reverse transcription-polymerase chain reaction (RT-PCR, immunohistochemistry, electrophysiology, TRPV1 knock-out (KO, and TRPV1-Cre knock-in mice. A small elevation of temperature in the physiological range is enough to depolarize ARC POMC neurons. This depolarization is blocked by the TRPV1 receptor antagonist and by Trpv1 gene knockdown. Capsaicin-induced activation reduces food intake that is abolished by a melanocortin receptor antagonist. To selectively stimulate TRPV1-like receptor-expressing ARC POMC neurons in the ARC, we generate an adeno-associated virus serotype 5 (AAV5 carrying a Cre-dependent channelrhodopsin-2 (ChR2-enhanced yellow fluorescent protein (eYFP expression cassette under the control of the two neuronal POMC enhancers (nPEs. Optogenetic stimulation of TRPV1-like receptor-expressing POMC neurons decreases food intake. Hypothalamic temperature is rapidly elevated and reaches to approximately 39 °C during treadmill running. This elevation is associated with a reduction in food intake. Knockdown of the Trpv1 gene exclusively in ARC POMC neurons blocks the feeding inhibition produced by increased hypothalamic temperature. Taken together, our findings identify a melanocortinergic circuit that links acute elevations in hypothalamic temperature with acute reductions in food intake.

  2. Hyperfunctioning thyroid nodules in toxic multinodular goiter share activating thyrotropin receptor mutations with solitary toxic adenoma.

    Science.gov (United States)

    Tonacchera, M; Chiovato, L; Pinchera, A; Agretti, P; Fiore, E; Cetani, F; Rocchi, R; Viacava, P; Miccoli, P; Vitti, P

    1998-02-01

    Toxic multinodular goiter is a cause of nonautoimmune hyperthyroidism and is believed to differ in its nature and pathogenesis from toxic adenoma. Gain-of-function mutations of the TSH receptor gene have been identified as a cause of toxic adenoma. The pathogenesis at the molecular level of hyperfunctioning nodules in toxic multinodular goiter has yet not been reported. Six patients with a single hot nodule within a multinodular goiter and 11 patients with toxic thyroid adenoma were enrolled in our study. At histology five hyperfunctioning nodules in multinodular goiters showed the features of adenomas, and one was identified as a hyperplastic nodule. The entire exon 10 of the TSH receptor gene was directly sequenced after PCR amplification from genomic DNA obtained from surgical specimens. Functional studies of mutated receptors were performed in COS-7 cells. Five out of 6 (83%) hyperfunctioning nodules within toxic multinodular goiters harbored a TSH receptor mutation. A TSH receptor mutation was also evident in the hyperfunctioning nodule that at histology had the features of noncapsulated hyperplastic nodule. Among toxic adenomas, 8 out of 11 (72%) nodules harbored a TSH receptor mutation. All the mutations were heterozygotic and somatic. Nonfunctioning nodules, whether adenomas or hyperplastic nodules present in association with hyperfunctioning nodules in the same multinodular goiters, had no TSH receptor mutation. All the mutations identified had constitutive activity as assessed by cAMP production after expression in COS-7 cells. Hyperfunctioning thyroid nodules in multinodular goiters recognize the same pathogenetic event (TSH receptor mutation) as toxic adenoma. Other mechanisms are implicated in the growth of nonfunctioning thyroid nodules coexistent in the same gland.

  3. Receptor-G Protein Interaction Studied by Bioluminescence Resonance Energy Transfer: Lessons From Protease-Activated Receptor 1

    Directory of Open Access Journals (Sweden)

    Mohammed Akli eAYOUB

    2012-06-01

    Full Text Available Since its development, the bioluminescence resonance energy transfer (BRET approach has been extensively applied to study G protein-coupled receptors (GPCRs in real time and in live cells. One of the major aspects of GPCRs investigated in considerable details is their physical coupling to the heterotrimeric G proteins. As a result, new concepts have emerged, but few questions are still a matter of debate illustrating the complexity of GPCR-G protein interactions and coupling. Here, we summarized the recent advances on our understanding of GPCR-G protein coupling based on BRET approaches and supported by other FRET-based studies. We essentially focused on our recent studies in which we addressed the concept of preassembly versus the agonist-dependent interaction between the protease-activated receptor 1 (PAR1 and its cognate G proteins. We discussed the concept of agonist-induced conformational changes within the preassembled PAR1-G protein complexes as well as the critical question how the multiple coupling of PAR1 with two different G proteins, Gi1 and G12, but also -arrestin 1, can be regulated.

  4. Multiplicity of nuclear receptor activation by PFOA and PFOS in primary human and rodent hepatocytes

    International Nuclear Information System (INIS)

    Bjork, J.A.; Butenhoff, J.L.; Wallace, K.B.

    2011-01-01

    Perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS) are surface active fluorochemicals that, due to their exceptional stability to degradation, are persistent in the environment. Both PFOA and PFOS are eliminated slowly in humans, with geometric mean serum elimination half-lives estimated at 3.5 and 4.8 years, respectively. The biological activity of PFOA and PFOS in rodents is attributed primarily to transactivation of the nuclear receptor peroxisome proliferator activated receptor alpha (PPARA), which is an important regulator of lipid and carbohydrate metabolism. However, there are significant species-specific differences in the response to PFOA and PFOS exposure; non-rodent species, including humans, are refractory to several but not all of these effects. Many of the metabolic effects have been attributed to the activation of PPARA; however, recent studies using PPARα knockout mice demonstrate residual PPARA-independent effects, some of which may involve the activation of alternate nuclear receptors, including NR1I2 (PXR), NR1I3 (CAR), NR1H3 (LXRA), and NR1H4 (FXR). The objective of this investigation was to characterize the activation of multiple nuclear receptors and modulation of metabolic pathways associated with exposure to PFOA and PFOS, and to compare and contrast the effects between rat and human primary liver cells using quantitative reverse transcription PCR (RT-qPCR). Our results demonstrate that multiple nuclear receptors participate in the metabolic response to PFOA and PFOS exposure resulting in a substantial shift from carbohydrate metabolism to fatty acid oxidation and hepatic triglyceride accumulation in rat liver cells. This shift in intermediary metabolism was more pronounced for PFOA than PFOS. Furthermore, while there is some similarity in the activation of metabolic pathways between rat and humans, particularly in PPARA regulated responses; the changes in primary human cells were more subtle and possibly reflect an adaptive

  5. Structure-dependent binding and activation of perfluorinated compounds on human peroxisome proliferator-activated receptor γ

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Lianying [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, P.O. Box 2871, 18 Shuangqing Road, Beijing 100085 (China); College of Life Science, Dezhou University, Dezhou 253023 (China); Ren, Xiao-Min; Wan, Bin [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, P.O. Box 2871, 18 Shuangqing Road, Beijing 100085 (China); Guo, Liang-Hong, E-mail: LHGuo@rcees.ac.cn [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, P.O. Box 2871, 18 Shuangqing Road, Beijing 100085 (China)

    2014-09-15

    Perfluorinated compounds (PFCs) have been shown to disrupt lipid metabolism and even induce cancer in rodents through activation of peroxisome proliferator-activated receptors (PPARs). Lines of evidence showed that PPARα was activated by PFCs. However, the information on the binding interactions between PPARγ and PFCs and subsequent alteration of PPARγ activity is still limited and sometimes inconsistent. In the present study, in vitro binding of 16 PFCs to human PPARγ ligand binding domain (hPPARγ-LBD) and their activity on the receptor in cells were investigated. The results showed that the binding affinity was strongly dependent on their carbon number and functional group. For the eleven perfluorinated carboxylic acids (PFCAs), the binding affinity increased with their carbon number from 4 to 11, and then decreased slightly. The binding affinity of the three perfluorinated sulfonic acids (PFSAs) was stronger than their PFCA counterparts. No binding was detected for the two fluorotelomer alcohols (FTOHs). Circular dichroim spectroscopy showed that PFC binding induced distinctive structural change of the receptor. In dual luciferase reporter assays using transiently transfected Hep G2 cells, PFCs acted as hPPARγ agonists, and their potency correlated with their binding affinity with hPPARγ-LBD. Molecular docking showed that PFCs with different chain length bind with the receptor in different geometry, which may contribute to their differences in binding affinity and transcriptional activity. - Highlights: • Binding affinity between PFCs and PPARγ was evaluated for the first time. • The binding strength was dependent on fluorinated carbon chain and functional group. • PFC binding induced distinctive structural change of the receptor. • PFCs could act as hPPARγ agonists in Hep G2 cells.

  6. Medium chain fatty acids are selective peroxisome proliferator activated receptor (PPAR) γ activators and pan-PPAR partial agonists

    NARCIS (Netherlands)

    Liberato, Marcelo Vizoná; Nascimento, Alessandro S; Ayers, Steven D; Lin, Jean Z; Cvoro, Aleksandra; Silveira, Rodrigo L; Martínez, Leandro; Souza, Paulo C T; Saidemberg, Daniel; Deng, Tuo; Amato, Angela Angelica; Togashi, Marie; Hsueh, Willa A; Phillips, Kevin; Palma, Mário Sérgio; Neves, Francisco A R; Skaf, Munir S; Webb, Paul; Polikarpov, Igor

    2012-01-01

    Thiazolidinediones (TZDs) act through peroxisome proliferator activated receptor (PPAR) γ to increase insulin sensitivity in type 2 diabetes (T2DM), but deleterious effects of these ligands mean that selective modulators with improved clinical profiles are needed. We obtained a crystal structure of

  7. Constitutive Activity among Orphan Class-A G Protein Coupled Receptors.

    Directory of Open Access Journals (Sweden)

    Adam L Martin

    Full Text Available The purpose of this study was to evaluate the extent of constitutive activity among orphan class-A G protein coupled receptors within the cAMP signaling pathway. Constitutive signaling was revealed by changes in gene expression under control of the cAMP response element. Gene expression was measured in Chinese hamster ovary cells transiently co-transfected with plasmids containing a luciferase reporter and orphan receptor. Criteria adopted for defining constitutive activation were: 1 200% elevation over baseline reporter gene expression; 2 40% inhibition of baseline expression; and 3 40% inhibition of expression stimulated by 3 μM forskolin. Five patterns of activity were noted: 1 inhibition under both baseline and forskolin stimulated expression (GPR15, GPR17, GPR18, GPR20, GPR25, GPR27, GPR31, GPR32, GPR45, GPR57, GPR68, GPR83, GPR84, GPR132, GPR150, GPR176; 2 no effect on baseline expression, but inhibition of forskolin stimulated expression (GPR4, GPR26, GPR61, GPR62, GPR78, GPR101, GPR119; 3 elevation of baseline signaling coupled with inhibition of forskolin stimulated expression (GPR6, GPR12; 4 elevation of baseline signaling without inhibition of forskolin stimulated expression (GPR3, GPR21, GPR52, GPR65; and 5 no effect on expression (GPR1, GPR19, GPR22, GPR34, GPR35, GPR39, GPR63, GPR82, GPR85, GPR87. Constitutive activity was observed in 75% of the orphan class-A receptors examined (30 of 40. This constitutive signaling cannot be explained by simple overexpression of the receptor. Inhibition of cAMP mediated expression was far more common (65% than stimulation of expression (15%. Orphan receptors that were closely related based on amino acid homology tended to have similar effects on gene expression. These results suggest that identification of inverse agonists may be a fruitful approach for categorizing these orphan receptors and targeting them for pharmacological intervention.

  8. Constitutive Activity among Orphan Class-A G Protein Coupled Receptors.

    Science.gov (United States)

    Martin, Adam L; Steurer, Michael A; Aronstam, Robert S

    2015-01-01

    The purpose of this study was to evaluate the extent of constitutive activity among orphan class-A G protein coupled receptors within the cAMP signaling pathway. Constitutive signaling was revealed by changes in gene expression under control of the cAMP response element. Gene expression was measured in Chinese hamster ovary cells transiently co-transfected with plasmids containing a luciferase reporter and orphan receptor. Criteria adopted for defining constitutive activation were: 1) 200% elevation over baseline reporter gene expression; 2) 40% inhibition of baseline expression; and 3) 40% inhibition of expression stimulated by 3 μM forskolin. Five patterns of activity were noted: 1) inhibition under both baseline and forskolin stimulated expression (GPR15, GPR17, GPR18, GPR20, GPR25, GPR27, GPR31, GPR32, GPR45, GPR57, GPR68, GPR83, GPR84, GPR132, GPR150, GPR176); 2) no effect on baseline expression, but inhibition of forskolin stimulated expression (GPR4, GPR26, GPR61, GPR62, GPR78, GPR101, GPR119); 3) elevation of baseline signaling coupled with inhibition of forskolin stimulated expression (GPR6, GPR12); 4) elevation of baseline signaling without inhibition of forskolin stimulated expression (GPR3, GPR21, GPR52, GPR65); and 5) no effect on expression (GPR1, GPR19, GPR22, GPR34, GPR35, GPR39, GPR63, GPR82, GPR85, GPR87). Constitutive activity was observed in 75% of the orphan class-A receptors examined (30 of 40). This constitutive signaling cannot be explained by simple overexpression of the receptor. Inhibition of cAMP mediated expression was far more common (65%) than stimulation of expression (15%). Orphan receptors that were closely related based on amino acid homology tended to have similar effects on gene expression. These results suggest that identification of inverse agonists may be a fruitful approach for categorizing these orphan receptors and targeting them for pharmacological intervention.

  9. SH2-Balpha is an insulin-receptor adapter protein and substrate that interacts with the activation loop of the insulin-receptor kinase.

    OpenAIRE

    Kotani, K; Wilden, P; Pillay, T S

    1998-01-01

    We identified SH2-Balpha as an insulin-receptor-binding protein based on interaction screening in yeast hybrid systems and co-precipitation in cells. SH2-Balpha contains pleckstrin-homology ('PH') and Src homology 2 (SH2) domains and is closely related to APS (adapter protein with a PH domain and an SH2 domain) and lnk, adapter proteins first identified in lymphocytes. SH2-Balpha is ubiquitously expressed and is present in rat epididymal adipose tissue, liver and skeletal muscle, physiologica...

  10. Retinoids induce integrin-independent lymphocyte adhesion through RAR-α nuclear receptor activity

    Energy Technology Data Exchange (ETDEWEB)

    Whelan, Jarrett T.; Wang, Lei; Chen, Jianming; Metts, Meagan E.; Nasser, Taj A.; McGoldrick, Liam J. [Department of Biochemistry and Molecular Biology, The Brody School of Medicine at East Carolina University, Greenville, NC 27834 (United States); Bridges, Lance C., E-mail: bridgesl@ecu.edu [Department of Biochemistry and Molecular Biology, The Brody School of Medicine at East Carolina University, Greenville, NC 27834 (United States); East Carolina Diabetes and Obesity Institute, The Brody School of Medicine at East Carolina University, Greenville, NC 27834 (United States)

    2014-11-28

    Highlights: • Transcription and translation are required for retinoid-induced lymphocyte adhesion. • RAR activation is sufficient to induced lymphocyte cell adhesion. • Vitamin D derivatives inhibit RAR-prompted lymphocyte adhesion. • Adhesion occurs through a novel binding site within ADAM disintegrin domains. • RARα is a key nuclear receptor for retinoid-dependent lymphocyte cell adhesion. - Abstract: Oxidative metabolites of vitamin A, in particular all-trans-retinoic acid (atRA), have emerged as key factors in immunity by specifying the localization of immune cells to the gut. Although it is appreciated that isomers of retinoic acid activate the retinoic acid receptor (RAR) and retinoid X receptor (RXR) family of nuclear receptors to elicit cellular changes, the molecular details of retinoic acid action remain poorly defined in immune processes. Here we employ a battery of agonists and antagonists to delineate the specific nuclear receptors utilized by retinoids to evoke lymphocyte cell adhesion to ADAM (adisintegrin and metalloprotease) protein family members. We report that RAR agonism is sufficient to promote immune cell adhesion in both immortal and primary immune cells. Interestingly, adhesion occurs independent of integrin function, and mutant studies demonstrate that atRA-induced adhesion to ADAM members required a distinct binding interface(s) as compared to integrin recognition. Anti-inflammatory corticosteroids as well as 1,25-(OH){sub 2}D{sub 3}, a vitamin D metabolite that prompts immune cell trafficking to the skin, potently inhibited the observed adhesion. Finally, our data establish that induced adhesion was specifically attributable to the RAR-α receptor isotype. The current study provides novel molecular resolution as to which nuclear receptors transduce retinoid exposure into immune cell adhesion.

  11. Retinoids induce integrin-independent lymphocyte adhesion through RAR-α nuclear receptor activity

    International Nuclear Information System (INIS)

    Whelan, Jarrett T.; Wang, Lei; Chen, Jianming; Metts, Meagan E.; Nasser, Taj A.; McGoldrick, Liam J.; Bridges, Lance C.

    2014-01-01

    Highlights: • Transcription and translation are required for retinoid-induced lymphocyte adhesion. • RAR activation is sufficient to induced lymphocyte cell adhesion. • Vitamin D derivatives inhibit RAR-prompted lymphocyte adhesion. • Adhesion occurs through a novel binding site within ADAM disintegrin domains. • RARα is a key nuclear receptor for retinoid-dependent lymphocyte cell adhesion. - Abstract: Oxidative metabolites of vitamin A, in particular all-trans-retinoic acid (atRA), have emerged as key factors in immunity by specifying the localization of immune cells to the gut. Although it is appreciated that isomers of retinoic acid activate the retinoic acid receptor (RAR) and retinoid X receptor (RXR) family of nuclear receptors to elicit cellular changes, the molecular details of retinoic acid action remain poorly defined in immune processes. Here we employ a battery of agonists and antagonists to delineate the specific nuclear receptors utilized by retinoids to evoke lymphocyte cell adhesion to ADAM (adisintegrin and metalloprotease) protein family members. We report that RAR agonism is sufficient to promote immune cell adhesion in both immortal and primary immune cells. Interestingly, adhesion occurs independent of integrin function, and mutant studies demonstrate that atRA-induced adhesion to ADAM members required a distinct binding interface(s) as compared to integrin recognition. Anti-inflammatory corticosteroids as well as 1,25-(OH) 2 D 3 , a vitamin D metabolite that prompts immune cell trafficking to the skin, potently inhibited the observed adhesion. Finally, our data establish that induced adhesion was specifically attributable to the RAR-α receptor isotype. The current study provides novel molecular resolution as to which nuclear receptors transduce retinoid exposure into immune cell adhesion

  12. GABAB-receptor activation alters the firing pattern of dopamine neurons in the rat substantia nigra.

    Science.gov (United States)

    Engberg, G; Kling-Petersen, T; Nissbrandt, H

    1993-11-01

    Previous electrophysiological experiments have emphasized the importance of the firing pattern for the functioning of midbrain dopamine (DA) neurons. In this regard, excitatory amino acid receptors appear to constitute an important modulatory control mechanism. In the present study, extracellular recording techniques were used to investigate the significance of GABAB-receptor activation for the firing properties of DA neurons in the substantia nigra (SN) in the rat. Intravenous administration of the GABAB-receptor agonist baclofen (1-16 mg/kg) was associated with a dose-dependent regularization of the firing pattern, concomitant with a reduction in burst firing. At higher doses (16-32 mg/kg), the firing rate of the DA neurons was dose-dependently decreased. Also, microiontophoretic application of baclofen regularized the firing pattern of nigral DA neurons, including a reduction of burst firing. Both the regularization of the firing pattern and inhibition of firing rate produced by systemic baclofen administration was antagonized by the GABAB-receptor antagonist CGP 35348 (200 mg/kg, i.v.). The GABAA-receptor agonist muscimol produced effects on the firing properties of DA neurons that were opposite to those observed following baclofen, i.e., an increase in firing rate accompanied by a decreased regularity. The NMDA receptor antagonist MK 801 (0.4-3.2 mg/kg, i.v.) produced a moderate, dose-dependent increase in the firing rate of the nigral DA neurons as well as a slightly regularized firing pattern. Pretreatment with MK 801 (3.2 mg/kg, i.v., 3-10 min) did neither promote nor prevent the regularization of the firing pattern or inhibition of firing rate on the nigral DA neurons produced by baclofen. The present results clearly show that GABAB-receptors can alter the firing pattern of nigral DA neurons, hereby counterbalancing the previously described ability of glutamate to induce burst firing activity on these neurons.

  13. Activation of muscarinic acetylcholine receptors elicits pigment granule dispersion in retinal pigment epithelium isolated from bluegill.

    Science.gov (United States)

    González, Alfredo; Crittenden, Elizabeth L; García, Dana M

    2004-07-13

    In fish, melanin pigment granules in the retinal pigment epithelium disperse into apical projections as part of the suite of responses the eye makes to bright light conditions. This pigment granule dispersion serves to reduce photobleaching and occurs in response to neurochemicals secreted by the retina. Previous work has shown that acetylcholine may be involved in inducing light-adaptive pigment dispersion. Acetylcholine receptors are of two main types, nicotinic and muscarinic. Muscarinic receptors are in the G-protein coupled receptor superfamily, and five different muscarinic receptors have been molecularly cloned in human. These receptors are coupled to adenylyl cyclase, calcium mobilization and ion channel activation. To determine the receptor pathway involved in eliciting pigment granule migration, we isolated retinal pigment epithelium from bluegill and subjected it to a battery of cholinergic agents. The general cholinergic agonist carbachol induces pigment granule dispersion in isolated retinal pigment epithelium. Carbachol-induced pigment granule dispersion is blocked by the muscarinic antagonist atropine, by the M1 antagonist pirenzepine, and by the M3 antagonist 4-DAMP. Pigment granule dispersion was also induced by the M1 agonist 4-[N-(4-chlorophenyl) carbamoyloxy]-4-pent-2-ammonium iodide. In contrast the M2 antagonist AF-DX 116 and the M4 antagonist tropicamide failed to block carbachol-induced dispersion, and the M2 agonist arecaidine but-2-ynyl ester tosylate failed to elicit dispersion. Our results suggest that carbachol-mediated pigment granule dispersion occurs through the activation of Modd muscarinic receptors, which in other systems couple to phosphoinositide hydrolysis and elevation of intracellular calcium. This conclusion must be corroborated by molecular studies, but suggests Ca2+-dependent pathways may be involved in light-adaptive pigment dispersion.

  14. Activation of muscarinic acetylcholine receptors elicits pigment granule dispersion in retinal pigment epithelium isolated from bluegill

    Directory of Open Access Journals (Sweden)

    Crittenden Elizabeth L

    2004-07-01

    Full Text Available Abstract Background In fish, melanin pigment granules in the retinal pigment epithelium disperse into apical projections as part of the suite of responses the eye makes to bright light conditions. This pigment granule dispersion serves to reduce photobleaching and occurs in response to neurochemicals secreted by the retina. Previous work has shown that acetylcholine may be involved in inducing light-adaptive pigment dispersion. Acetylcholine receptors are of two main types, nicotinic and muscarinic. Muscarinic receptors are in the G-protein coupled receptor superfamily, and five different muscarinic receptors have been molecularly cloned in human. These receptors are coupled to adenylyl cyclase, calcium mobilization and ion channel activation. To determine the receptor pathway involved in eliciting pigment granule migration, we isolated retinal pigment epithelium from bluegill and subjected it to a battery of cholinergic agents. Results The general cholinergic agonist carbachol induces pigment granule dispersion in isolated retinal pigment epithelium. Carbachol-induced pigment granule dispersion is blocked by the muscarinic antagonist atropine, by the M1 antagonist pirenzepine, and by the M3 antagonist 4-DAMP. Pigment granule dispersion was also induced by the M1 agonist 4-[N-(4-chlorophenyl carbamoyloxy]-4-pent-2-ammonium iodide. In contrast the M2 antagonist AF-DX 116 and the M4 antagonist tropicamide failed to block carbachol-induced dispersion, and the M2 agonist arecaidine but-2-ynyl ester tosylate failed to elicit dispersion. Conclusions Our results suggest that carbachol-mediated pigment granule dispersion occurs through the activation of Modd muscarinic receptors, which in other systems couple to phosphoinositide hydrolysis and elevation of intracellular calcium. This conclusion must be corroborated by molecular studies, but suggests Ca2+-dependent pathways may be involved in light-adaptive pigment dispersion.

  15. Activation of neurokinin-1 receptors during ozone inhalation contributes to epithelial injury and repair.

    Science.gov (United States)

    Oslund, Karen L; Hyde, Dallas M; Putney, Leialoha F; Alfaro, Mario F; Walby, William F; Tyler, Nancy K; Schelegle, Edward S

    2008-09-01

    We investigated the importance of neurokinin (NK)-1 receptors in epithelial injury and repair and neutrophil function. Conscious Wistar rats were exposed to 1 ppm ozone or filtered air for 8 hours, followed by an 8-hour postexposure period. Before exposure, we administered either the NK-1 receptor antagonist, SR140333, or saline as a control. Ethidium homodimer was instilled into lungs as a marker of necrotic airway epithelial cells. After fixation, whole mounts of airway dissected lung lobes were immunostained for 5-bromo-2'-deoxyuridine, a marker of epithelial proliferation. Both ethidium homodimer and 5-bromo-2'-deoxyuridine-positive epithelial cells were quantified in specific airway generations. Rats treated with the NK-1 receptor antagonist had significantly reduced epithelial injury and epithelial proliferation compared with control rats. Sections of terminal bronchioles showed no significant difference in the number of neutrophils in airways between groups. In addition, staining ozone-exposed lung sections for active caspase 3 showed no apoptotic cells, but ethidium-positive cells colocalized with the orphan nuclear receptor, Nur77, a marker of nonapoptotic, programmed cell death mediated by the NK-1 receptor. An immortalized human airway epithelial cell line, human bronchial epithelial-1, showed no significant difference in the number of oxidant stress-positive cells during exposure to hydrogen peroxide and a range of SR140333 doses, demonstrating no antioxidant effect of the receptor antagonist. We conclude that activation of the NK-1 receptor during acute ozone inhalation contributes to epithelial injury and subsequent epithelial proliferation, a critical component of repair, but does not influence neutrophil emigration into airways.

  16. Antiplasmodial activity of novel keto-enamine chalcone-chloroquine based hybrid pharmacophores.

    Science.gov (United States)

    Sashidhara, Koneni V; Kumar, Manoj; Modukuri, Ram K; Srivastava, Rajeev Kumar; Soni, Awakash; Srivastava, Kumkum; Singh, Shiv Vardan; Saxena, J K; Gauniyal, Harsh M; Puri, Sunil K

    2012-05-01

    A series of novel keto-enamine chalcone-chloroquine based hybrids were synthesized following new methodology developed in our laboratory. The synthesized compounds were screened against chloroquine sensitive strain (3D7) of Plasmodium falciparum in an in vitro model. Some of the compounds were showing comparable antimalarial activity at par with chloroquine. Compounds with significant