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Sample records for agonist ave8134 attenuates

  1. The peroxisome proliferator-activated receptor-α(PPAR-α) agonist,AVE8134,attenuates the progression of heart failure and increases survival in rats

    Institute of Scientific and Technical Information of China (English)

    Wolfgang LINZ; Paulus WOHLFART; Manuel BAADER; Kristin BREITSCHOPF; Eugen FALK; Hans-Ludwig SCH(A)FER; Martin GERL; Wemer KRAMER; Hartmut R(U)TTEN

    2009-01-01

    Aim:To investigate the efficacy of the peroxisome proliferator-aotivated receptor-α (PPARα) agonist,AVE8134,in cellular and experimental models of cardiac dysfunction and heart failure.Methods:In Sprague Dawley rats with permanent ligation of the left coronary artery (post-MI),AVE8134 was compared to the PPARy agonist rosiglitazone and in a second study to the ACE inhibitor ramipril.In DOCA-salt sensitive rats,efficacy of AVE8134 on cardiac hypertrophy and fibrosis was investigated.Finally,AVE8134 was administered to old spontaneously hypertensive rats (SHR) at a nonblood pressure lowering dose with survival as endpoint.In cellular models,we studied AVE8134 on hypertrophy in rat cardiomyocytes,nitric oxide signaling in human endothelial cells (HUVEC) and LDL-uptake in human MonoMac-6 cells.Results:In post-MI rats,AVE8134 dose-dependently improved cardiac output,myocardial contractility and relaxation and reduced lung and left ventdcular weight and fibrosis.In contrast,rosiglitazone exacerbated cardiac dysfunction.Treatment at AVE8134 decreased plasma proBNP and arginine and increased plasma citrulline and urinary NOx/creatinine ratio.In DOCA rats,AVE8134 prevented development of high blood pressure,myocardial hypertrophy and cardiac fibrosis,and ameliorated endothelial dysfunction.Compound treatment increased cardiac protein expression and phosphorylation of eNOS.In old SHR,treatment with a low dose of AVE8134 improved cardiac and vascular function and increased life expectancy without lowering blood pressure.AVE8134 reduced phenylephrine-induced hypertrophy in adult rat cardiomyocytes.In HUVEC,Ser-1177-eNOS phosphorylation but not eNOS expression was increased.In monocytes,AVE8134 increased the expression of CD36 and the macrophage scavenger receptor 1,resulting in enhanced uptake of oxidized LDL.Conclusion:The PPARα agonist AVES134 prevents post-MI myocardial hypertrophy,fibrosis and cardiac dysfunction.AVES134 has beneficial effects against hypertension

  2. Neurotensin Agonist Attenuates Nicotine Potentiation to Cocaine Sensitization

    Directory of Open Access Journals (Sweden)

    Paul Fredrickson

    2014-01-01

    Full Text Available Tobacco usage typically precedes illicit drug use in adolescent and young adult populations. Several animal studies suggest nicotine increases the risk for subsequent cocaine abuse, and may be a negative prognostic factor for treatment of cocaine addiction; i.e., a “gateway drug”. Neurotensin (NT is a 13-amino acid neuropeptide that modulates dopamine, acetylcholine, glutamate, and GABA neurotransmission in brain reward pathways. NT69L, a NT(8-13 analog, blocks behavioral sensitization (an animal model for psychostimulant addiction to nicotine, and nicotine self-administration in rats. The present study tested the effect of NT69L on the potentiating effects of nicotine on cocaine-induced locomotor sensitization. Male Wistar rats were injected daily for seven days with nicotine or saline (control followed by four daily injections of cocaine. NT69L was administered 30 min prior to the last cocaine injection. Behavior was recorded with the use of activity chambers. Subchronic administration of nicotine enhanced cocaine-induced behavioral sensitization in Wistar rats, consistent with an hypothesized gateway effect. These behavioral effects of cocaine were attenuated by pretreatment with NT69L. The effect of the neurotensin agonist on cocaine sensitization in the nicotine treated group indicated a possible therapeutic effect for cocaine addiction, even in the presence of enhanced behavioral sensitization induced by nicotine.

  3. Intracerebroventricular injections of dronabinol, a cannabinoid receptor agonist, does not attenuate serotonin-induced apnea in Sprague-Dawley rats

    OpenAIRE

    Calik, Michael W.; Carley, David W

    2016-01-01

    Background Evidence suggests that vagal nerve activity may play a role in sleep apnea induction. In anesthetized rats, dronabinol, a cannabinoid (CB) receptor agonist, injected into the nodose ganglia attenuates reflex apnea and increases genioglossus activity, and reflex apnea attenuation is blocked by systemic pre-treatment with cannabinoid type 1 and/or type 2 receptor antagonists. However, it is unclear whether dronabinol has similar effects in the central nervous system; CB receptors are...

  4. Preventing or attenuating amphotericin B nephrotoxicity with dopamine receptor agonists: a literature review

    Directory of Open Access Journals (Sweden)

    Iman Karimzadeh

    2016-09-01

    Full Text Available Nephrotoxicity is generally considered as the most clinically significant and dose-limiting adverse reaction of amphotericin B. Currently, only the clinical effectiveness of salt loading and administering lipid formulations of amphotericin B have been clearly demonstrated to prevent its nephrotoxicity. In this review, we collected the published data related to dopamine receptor agonists in preventing amphotericin B nephrotoxicity. A literature search was conducted by the relevant keywords like ‘‘amphotericin B”, “nephrotoxicity’’, and ‘‘dopamine’’in databases such as Scopus, Medline, Embase and ISI Web of Knowledge. Four relevant articles were considered. Results of all the 3 experimental studies demonstrated that co-administration of dopamine (0.5-10 μg/kg/min as continuous intravenous infusion, SK&F R-105058, a prodrug of fenoldopam (10 mg/kg twice daily, orally or fenoldopam, a relatively selective dopamine receptor type 1 agonist, (0.5 or 1 μg/kg/min as continuous intravenous infusion can at least significantly mitigate the decrease in creatinine clearance caused by amphotericin B. Furthermore, fenoldopam and SK&F R-105058 can also protect against or delay amphotericin B-induced tubular damage. In contrast, the only clinical trial published until now found that simultaneous continuous intravenous infusion of low dose dopamine (3 μg/kg/min had no beneficial effect on the incidence, severity and time onset of developing amphotericin B-induced nephrotoxicity in autologous bone marrow transplant and leukemia patients. Considering the lack of beneficial effects in different settings such as acute kidney injury of any cause, negative results of the only clinical trial, and risk of significant adverse reactions, continuous intravenous infusion of low dose dopamine (1-3 μg/kg/min or selective dopamine receptor type 1 agonists (e.g., fenoldopam currently appears to have no promising clinical role in preventing or attenuating

  5. Serotonin3 receptor agonists attenuate glutamate-induced firing in rat hippocampal CA1 pyramidal cells.

    Science.gov (United States)

    Zhang, J Y; Zeise, M L; Wang, R Y

    1994-01-01

    The techniques of extracellular single cell recording and microiontophoresis were used to study the effect of 5-HT3 receptor agonists on glutamate-activated firing of CA1 hippocampal pyramidal cells. Iontophoretic application of 5-HT3 receptor agonists 2-methyl-5-HT and SR 57227A produced a current (dose)-dependent suppression of the firing of CA1 pyramidal cells; SR 57227A was more effective than 2-methyl-5-HT. The suppressant action of 2-methyl-5-HT and SR 57227A had a slow onset and showed little or no desensitization. This effect was markedly attenuated or completely blocked by the 5-HT3 receptor antagonist BRL 46470A but not by the nonspecific 5-HT1 and 5-HT2 receptor antagonist metergoline or by the 5-HT1A antagonist WAY 100478. Intravenous administration of SR 57227A was effective in reducing the firing rate of CA1 pyramidal cells and this effect was prevented by BRL 46470A administered either i.v. or iontophoretically. Iontophoresis of 2-methyl-5-HT also diminished CA1 postsynaptic field potentials evoked by electrical stimulation of the Schaffer collaterals. Again, BRL 46470A but not metergoline prevented the suppressant action of 2-methyl-5-HT. Taken together, our results indicate that activation of 5-HT3-like receptors in the hippocampal CA1 region effectively reduces the efficacy of glutamatergic neurotransmission. PMID:7984287

  6. Obeticholic acid, a synthetic bile acid agonist of the farnesoid X receptor, attenuates experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Ho, Peggy P; Steinman, Lawrence

    2016-02-01

    Bile acids are ligands for the nuclear hormone receptor, farnesoid X receptor (FXR). The bile acid-FXR interaction regulates bile acid synthesis, transport, and cholesterol metabolism. Recently, bile acid-FXR regulation has been reported to play an integral role in both hepatic and intestinal inflammation, and in atherosclerosis. In this study, we found that FXR knockout mice had more disease severity in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Obeticholic acid (6α-ethyl-chenodeoxycholic acid, 6-ECDCA), a synthetic FXR agonist, is an orally available drug that is currently in clinical trials for the treatment of inflammatory diseases such as alcoholic hepatitis, nonalcoholic steatohepatitis, and primary biliary cirrhosis. When we treated mice exhibiting established EAE with 6-ECDCA, or the natural FXR ligand chenodeoxycholic acid (CDCA), clinical disease was ameliorated by (i) suppressing lymphocyte activation and proinflammatory cytokine production; (ii) reducing CD4(+) T cells and CD19(+) B cell populations and their expression of negative checkpoint regulators programmed cell death protein 1 (PD1), programmed death-ligand 1 (PD-L1), and B and T lymphocyte attenuator (BTLA); (iii) increasing CD8(+) T cells and PD1, PDl-1, and BTLA expression; and (iv) reducing VLA-4 expression in both the T- and B-cell populations. Moreover, adoptive transfer of 6-ECDCA- or CDCA-treated donor cells failed to transfer disease in naive recipients. Thus, we show that FXR functions as a negative regulator in neuroinflammation and we highlight that FXR agonists represent a potential previously unidentified therapy for MS. PMID:26811456

  7. Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone attenuates postincisional pain by regulating macrophage polarization

    Energy Technology Data Exchange (ETDEWEB)

    Hasegawa-Moriyama, Maiko, E-mail: hase-mai@m3.kufm.kagoshima-u.ac.jp [Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Ohnou, Tetsuya; Godai, Kohei; Kurimoto, Tae; Nakama, Mayo; Kanmura, Yuichi [Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan)

    2012-09-14

    Highlights: Black-Right-Pointing-Pointer Rosiglitazone attenuated postincisional pain. Black-Right-Pointing-Pointer Rosiglitazone alters macrophage polarization to F4/80{sup +}CD206{sup +} M2 macrophages at the incisional sites. Black-Right-Pointing-Pointer Transplantation of rosiglitazone-treated macrophages produced analgesic effects. -- Abstract: Acute inflammation triggered by macrophage infiltration to injured tissue promotes wound repair and may induce pain hypersensitivity. Peroxisome proliferator-activated receptor {gamma} (PPAR){gamma} signaling is known to regulate heterogeneity of macrophages, which are often referred to as classically activated (M1) and alternatively activated (M2) macrophages. M1 macrophages have considerable antimicrobial activity and produce a wide variety of proinflammatory cytokines. In contrast, M2 macrophages are involved in anti-inflammatory and homeostatic functions linked to wound healing and tissue repair. Although it has been suggested that PPAR{gamma} agonists attenuate pain hypersensitivity, the molecular mechanism of macrophage-mediated effects of PPAR{gamma} signaling on pain development has not been explored. In this study, we investigated the link between the phenotype switching of macrophage polarization induced by PPAR{gamma} signaling and the development of acute pain hypersensitivity. Local administration of rosiglitazone significantly ameliorated hypersensitivity to heat and mechanical stimuli, and paw swelling. Consistent with the down-regulation of nuclear factor {kappa}B (NF{kappa}B) phosphorylation by rosiglitazone at the incisional sites, the number of F4/80{sup +}iNOS{sup +} M1 macrophages was decreased whereas numbers of F4/80{sup +}CD206{sup +} M2 macrophages were increased in rosiglitazone-treated incisional sites 24 h after the procedure. In addition, gene induction of anti-inflammatory M2-macrophage-associated markers such as arginase1, FIZZ1 and interleukin (IL)-10 were significantly increased, whereas

  8. The 5-HT1A agonists 8-OH-DPAT, buspirone and ipsapirone attenuate stress-induced anorexia in rats.

    Science.gov (United States)

    Dourish, C T; Kennett, G A; Curzon, G

    1987-01-01

    The effects of 5-HT agonists and antagonists, benzodiazepine anxiolytics and tricyclic antidepressants on restraint stress-induced anorexia in rats were examined. The selective 5-HT(1A) agonists 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT), buspirone and ipsapirone, when injected 2 h after the termination of stress, attenuated stress-induced anor exia and body weight loss. The effects of 8-OH-DPAT on stress-induced anorexia were blocked by the 5-HT(1A) antagonist spiperone but not by the 5-HT(2) antagonist ketanserin. The preferential 5-HT(1B) agonists RU-24969 and quipazine induced anorexia in unstressed rats and tended to supplement the anorectic effects of stress. The benzodiazepines chlordiazepoxide and diazepam and the 5-HT antagonist cyproheptadine had no effect on stress-induced anorexia, when given (like the 5-HT(1A) agonists) 2 h after the stress. Similarly, daily injection for 2 weeks of the tricyclic antidepressants desipramine and sertraline had no beneficial effect. The data suggest that 8-OH-DPAT, buspirone and ipsapirone attenuate stress-induced anorexia in rodents by a hyperphagic action on 5-HT(1A) receptors. PMID:22158750

  9. A novel natural Nrf2 activator with PPARγ-agonist (monascin) attenuates the toxicity of methylglyoxal and hyperglycemia

    Energy Technology Data Exchange (ETDEWEB)

    Hsu, Wei-Hsuan; Lee, Bao-Hong; Chang, Yu-Ying [Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 10617, Taiwan (China); Hsu, Ya-Wen [SunWay Biotechnology Company, Taipei, Taiwan (China); Pan, Tzu-Ming, E-mail: tmpan@ntu.edu.tw [Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 10617, Taiwan (China)

    2013-11-01

    Methylglyoxal (MG) is a toxic-glucose metabolite and a major precursor of advanced glycation endproducts (AGEs). MG has been reported to result in inflammation by activating receptor for AGEs (RAGE). We recently found that Monascus-fermented metabolite monascin acts as a novel natural peroxisome proliferator-activated receptor-γ (PPARγ) agonist that improves insulin sensitivity. We investigated the metabolic, biochemical, and molecular abnormalities characteristic of type 2 diabetes in MG-treated Wistar rats treated with oral administration of monascin or rosiglitazone. Monascin (a novel PPARγ agonist) activated nuclear factor-erythroid 2-related factor 2 (Nrf2) and down-regulated hyperinsulinmia in oral glucose tolerance test (OGTT). Monascin was able to elevate glyoxalase-1 expression via activation of hepatic Nrf2, hence, resulting in MG metabolism to D-lactic acid and protected from AGEs production in MG-treated rats. Rosiglitazone did not activate Nrf2 nor glyoxalase expression to lower serum and hepatic AGEs levels. Monascin acts as a novel natural Nrf2 activator with PPARγ-agonist activity were confirmed by Nrf2 and PPARγ reporter assays in Hep G2 cells. These findings suggest that monascin acts as an anti-diabetic and anti-oxidative stress agent to a greater degree than rosiglitazone and thus may have therapeutic potential for the prevention of diabetes. - Highlights: • Monascin acts as a PPARgamma agonist. • Monascin activates Nrf2 and AMPK. • Monascin promotes MG metabolism into D-lactic acid. • Monascin attenuates inflammation and diabetes in vivo.

  10. Farnesoid X receptor agonists attenuate colonic epithelial secretory function and prevent experimental diarrhoea in vivo.

    OpenAIRE

    FALLON, PADRAIC

    2014-01-01

    OBJECTIVE: Bile acids are important regulators of intestinal physiology, and the nuclear bile acid receptor, farnesoid X receptor (FXR), is emerging as a promising therapeutic target for several intestinal disorders. Here, we investigated a role for FXR in regulating intestinal fluid and electrolyte transport and the potential for FXR agonists in treating diarrhoeal diseases. DESIGN: Electrogenic ion transport was measured as changes in short-circuit current across voltage-clamped ...

  11. Preventing or attenuating amphotericin B nephrotoxicity with dopamine receptor agonists: a literature review

    OpenAIRE

    Iman Karimzadeh; Hossein Khalili; Mohammad Mahdi Sagheb

    2016-01-01

    Nephrotoxicity is generally considered as the most clinically significant and dose-limiting adverse reaction of amphotericin B. Currently, only the clinical effectiveness of salt loading and administering lipid formulations of amphotericin B have been clearly demonstrated to prevent its nephrotoxicity. In this review, we collected the published data related to dopamine receptor agonists in preventing amphotericin B nephrotoxicity. A literature search was conducted by the relevant keywords lik...

  12. VTX-1463, a novel TLR-8 agonist, attenuates nasal congestion after ragweed challenge in sensitized beagle dogs.

    Science.gov (United States)

    Royer, Christopher M; Rudolph, Karin; Dietsch, Gregory N; Hershberg, Robert M; Barrett, Edward G

    2016-03-01

    VTX-1463 is a selective toll-like receptor (TLR) 8 agonist that activates a subset of innate immune cells to produce a unique cytokine profile. Delivery of VTX-1463 via nasal spray may modulate the nasal response in allergic rhinitis. The aim of this study was to determine the effects of VTX-1463 on the nasal response in a dog model of allergic rhinitis. Ragweed (RW)-sensitized dogs were pretreated with increasing doses of VTX-1463 1 day prior to RW challenge or with two doses (4 or 8 days and 1 day prior to RW). Changes in nasal cavity volume (NV) were determined by acoustic rhinometry and nasal lavage fluid was assessed for histamine, lipid mediators, and cellular infiltrates at sequential times following RW challenge. VTX-1463 pretreatment significantly preserved NV during the acute response to RW challenge for all doses tested. The area under the curve (AUC) for NV over the 1.5 h assessment period in RW challenged vehicle controls averaged 51.5% (SEM: ±2.12%) of the baseline NV over all studies. A single 100 µg dose of VTX-1463 given 1 day prior to RW yielded an AUC for NV of 69.3% (±6.59%) of baseline, while a 1000 µg dose administered twice (8 days and 1 day prior to RW) resulted in an AUC for NV of 85.4% (±4.74%, P histamine, PGE2, PGD2, and cysteinyl LTs, were significantly reduced relative to the vehicle control. The selective TLR8 agonist, VTX-1463, preserved NV in a dose-dependent manner in the acute phase of a nasal allergic response. The therapeutic effect appears to result from attenuated mast cell mediator release. Modulating the local cytokine response via TLR8 agonism appears to have a therapeutic effect on the acute allergic nasal response. PMID:27042301

  13. Rosiglitazone, a peroxisome proliferator-activated receptor-γ agonist, attenuates acrolein-induced airway mucus hypersecretion in rats

    International Nuclear Information System (INIS)

    Background: Peroxisome proliferator-activated receptor-γ (PPAR-γ), a member of the ligand-activated nuclear receptor superfamily, has been shown to be implicated in anti-inflammatory and immunomodulatory responses, but its role in airway mucus hypersecretion remains not clear. Objective: To investigate the role of PPAR-γ in airway mucus hypersecretion, we used an acrolein-exposed rat model treated with rosiglitazone, a peroxisome proliferator-activated receptor-γ agonist. Methods: Rats were exposed to acrolein (3.0 ppm, 6 h/day, 7 days/week) and orally administered with rosiglitazone (2, 4, 8 mg/kg) once daily for up to 2 weeks. The expressions of Muc5ac protein and mRNA, and infiltration of inflammatory cells and levels of inflammatory cytokines (interleukin (IL)-1β, IL-8 and tumor necrosis factor (TNF)-α) in bronchoalveolar lavage fluid (BALF) were detected with real-time PCR, Western blot, cell counting and ELISA. In addition, the role of nuclear factor (NF)-κB pathway in this process was also explored. Results: Acrolein exposure significantly induced goblet cell hyperplasia in bronchial epithelium and Muc5ac mRNA and protein expressions in rat lungs, as well as the associated airway inflammation evidenced by the increased numbers of inflammatory cells and levels of inflammatory cytokines in BALF, which were attenuated with rosiglitazone treatment in a dose-dependent manner (P < 0.05). Simultaneously, the increased expression of NF-κB and decreased expression of cytoplasmic IκB in acrolein-exposed lungs were reversed by rosiglitazone treatment. Conclusions: These findings suggest that PPAR-γ activation by its ligands can attenuate acrolein-induced airway mucus hypersecretion in rats, which may be involved in inhibition of NF-κB pathway.

  14. Cannabinoid Receptor Type 2 Agonist Attenuates Apoptosis by Activation of Phosphorylated CREB-Bcl-2 Pathway After Subarachnoid Hemorrhage in Rats

    OpenAIRE

    Fujii, Mutsumi; Sherchan, Prativa; Soejima, Yoshiteru; Hasegawa, Yu; Flores, Jerry; Doycheva, Desislava; Zhang, John H.

    2014-01-01

    Early brain injury (EBI) which comprises of vasogenic edema and apoptotic cell death is an important component of subarachnoid hemorrhage (SAH) pathophysiology. This study evaluated whether Cannabinoid receptor type 2 (CB2R) agonist, JWH133, attenuates EBI after SAH and whether CB2R stimulation reduces pro-apoptotic caspase-3 via up-regulation of cAMP response element-binding protein (CREB)-Bcl-2 signaling pathway. Male Sprague Dawley rats (n=123) were subjected to SAH by endovascular perfora...

  15. Atrial natriuretic peptide attenuates agonist-induced pulmonary edema in mice with targeted disruption of the gene for natriuretic peptide receptor-A.

    Science.gov (United States)

    Klinger, James R; Tsai, Shu-Whei; Green, Sabrina; Grinnell, Katie L; Machan, Jason T; Harrington, Elizabeth O

    2013-02-01

    Atrial natriuretic peptide (ANP) inhibits agonist-induced pulmonary edema formation, but the signaling pathway responsible is not well defined. To investigate the role of the particulate guanylate cyclase-linked receptor, natriuretic peptide receptor-A (NPR-A), we measured acute lung injury responses in intact mice and pulmonary microvascular endothelial cells (PMVEC) with normal and disrupted expression of NPR-A. NPR-A wild-type (NPR-A+/+), heterozygous (NPR-A+/-), and knockout (NPR-A-/-) mice were anesthetized and treated with thrombin receptor agonist peptide (TRAP) or lipopolysaccharide (LPS). Lung injury was assessed by lung wet-to-dry (W/D) weight and by protein and cell concentration of bronchoalveolar lavage (BAL) fluid. No difference in pulmonary edema formation was seen between NPR-A genotypes under baseline conditions. TRAP and LPS increased lung W/D weight and BAL fluid cell counts more in NPR-A-/- mice than in NPR-A+/- or NPR-A+/+ mice, but no genotype-related differences were seen in TRAP-induced increases in bloodless lung W/D weight or LPS-induced increases in BAL protein concentration. Pretreatment with ANP infusion completely blocked TRAP-induced increases in lung W/D weight and blunted LPS-induced increases in BAL cell counts and protein concentration in both NPR-A-/- and NPR-A+/+ mice. Thrombin decreased transmembrane electrical resistance in monolayers of PMVECs in vitro, and this effect was attenuated by ANP in PMVECs isolated from both genotypes. Administration of the NPR-C-specific ligand, cANF, also blocked TRAP-induced increases in lung W/D weight and LPS-induced increases in BAL cell count and protein concentration in NPR-A+/+ and NPR-A-/- mice. We conclude that ANP is capable of attenuating agonist-induced lung edema in the absence of NPR-A. The protective effect of ANP on agonist-induced lung injury and pulmonary barrier function may be mediated by NPR-C. PMID:23195629

  16. Nicotinic Acetylcholine Receptor Agonists Attenuate Septic Acute Kidney Injury in Mice by Suppressing Inflammation and Proteasome Activity

    OpenAIRE

    Chatterjee, Prodyot K.; Yeboah, Michael M.; Oonagh Dowling; Xiangying Xue; Powell, Saul R.; Yousef Al-Abed; Metz, Christine N

    2012-01-01

    Sepsis is one of the leading causes of acute kidney injury (AKI). Septic patients who develop acute kidney injury (AKI) are at increased risk of death. To date there is no effective treatment for AKI or septic AKI. Based on their anti-inflammatory properties, we examined the effects of nicotinic acetylcholine receptor agonists on renal damage using a mouse model of lipopolysaccharide (LPS)-induced AKI where localized LPS promotes inflammation-mediated kidney damage. Administration of nicotine...

  17. The glucagon-like peptide 1 receptor agonist liraglutide attenuates the reinforcing properties of alcohol in rodents.

    Science.gov (United States)

    Vallöf, Daniel; Maccioni, Paola; Colombo, Giancarlo; Mandrapa, Minja; Jörnulf, Julia Winsa; Egecioglu, Emil; Engel, Jörgen A; Jerlhag, Elisabet

    2016-03-01

    The incretin hormone, glucagon-like peptide 1 (GLP-1), regulates gastric emptying, glucose-dependent stimulation of insulin secretion and glucagon release, and GLP-1 analogs are therefore approved for treatment of type II diabetes. GLP-1 receptors are expressed in reward-related areas such as the ventral tegmental area and nucleus accumbens, and GLP-1 was recently shown to regulate several alcohol-mediated behaviors as well as amphetamine-induced, cocaine-induced and nicotine-induced reward. The present series of experiments were undertaken to investigate the effect of the GLP-1 receptor agonist, liraglutide, on several alcohol-related behaviors in rats that model different aspects of alcohol use disorder in humans. Acute liraglutide treatment suppressed the well-documented effects of alcohol on the mesolimbic dopamine system, namely alcohol-induced accumbal dopamine release and conditioned place preference in mice. In addition, acute administration of liraglutide prevented the alcohol deprivation effect and reduced alcohol intake in outbred rats, while repeated treatment of liraglutide decreased alcohol intake in outbred rats as well as reduced operant self-administration of alcohol in selectively bred Sardinian alcohol-preferring rats. Collectively, these data suggest that GLP-1 receptor agonists could be tested for treatment of alcohol dependence in humans. PMID:26303264

  18. Constitutive androstane receptor agonist, TCPOBOP, attenuates steatohepatitis in the methionine choline-deficient diet-fed mouse

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To ascertain whether constitutive androstane receptor (CAR) activation by 1,4-bis-[2-(3,5,dichloropyridyloxy)] benzene (TCPOBOP) modulates steatohepatitis in the methionine choline-deficient (MCD) diet-fed animal. METHODS: C57/BL6 wild-type mice were fed the MCD or standard diet for 2 wk and were treated with either the CAR agonist, TCPOBOP, or the CAR inverse agonist, androstanol. RESULTS: Expression of CYP2B10 and CYP3A11, known CAR target genes, increased 30-fold and 45-fold, respectively, in TCPOBOP-treated mice fed the MCD diet. TCPOBOP treatment reduced hepatic steatosis (44.6 ± 5.4% vs 30.4 ± 4.5%, P < 0.05) and serum triglyceride levels (48 ± 8 vs 20 ± 1 mg/Dl, P < 0.05) in MCD dietfed mice as compared with the standard diet-fed mice. This reduction in hepatic steatosis was accompanied by an increase in enzymes involved in fatty acid microsomal ω-oxidation and peroxisomal β-oxidation, namely CYP4A10, LPBE, and 3-ketoacyl-CoA thiolase. The reduction in steatosis was also accompanied by a reduction in liver cell apoptosis and inflammation. In contrast, androstanol was without effect on any of the above parameters. CONCLUSION: CAR activation stimulates induction of genes involved in fatty acid oxidation, and ameliorates hepatic steatosis, apoptosis and inflammation.

  19. A PXR-mediated negative feedback loop attenuates the expression of CYP3A in response to the PXR agonist pregnenalone-16α-carbonitrile.

    Directory of Open Access Journals (Sweden)

    Ian Bailey

    Full Text Available The nuclear receptor superfamily of ligand-activated transcription factors plays a central role in the regulation of cellular responses to chemical challenge. Nuclear receptors are activated by a wide range of both endogenous and exogenous chemicals, and their target genes include those involved in the metabolism and transport of the activating chemical. Such target gene activation, thus, acts to remove the stimulating xenobiotic or to maintain homeostatic levels of endogenous chemicals. Given the dual nature of this system it is important to understand how these two roles are balanced, such that xenobiotics are efficiently removed while not impacting negatively on homeostasis of endogenous chemicals. Using DNA microarray technology we have examined the transcriptome response of primary rat hepatocytes to two nuclear receptor ligands: Pregnenalone-16α-carbonitrile (PCN, a xenobiotic PXR agonist, and lithocholic acid, an endogenous mixed PXR/VDR/FXR agonist. We demonstrate that despite differences in the profile of activated nuclear receptors, transcriptome responses for these two ligands are broadly similar at lower concentrations, indicating a conserved general response. However, as concentrations of stimulating ligand rises, the transcriptome responses diverge, reflecting a need for specific responses to the two stimulating chemicals. Finally, we demonstrate a novel feed-back loop for PXR, whereby ligand-activation of PXR suppresses transcription of the PXR gene, acting to attenuate PXR protein expression levels at higher ligand concentrations. Through in silico simulation we demonstrate that this feed-back loop is an important factor to prevent hyperexpression of PXR target genes such as CYP3A and confirm these findings in vitro. This novel insight into the regulation of the PXR-mediated regulatory signal networks provides a potential mechanistic rationale for the robustness in steroid homeostasis within the cell.

  20. Retinoic acid receptor agonist Am80 inhibits CXCL2 production from microglial BV-2 cells via attenuation of NF-κB signaling.

    Science.gov (United States)

    Takaoka, Yuichiro; Takahashi, Moeka; Kurauchi, Yuki; Hisatsune, Akinori; Seki, Takahiro; Shudo, Koichi; Katsuki, Hiroshi

    2016-09-01

    Accumulating lines of evidence suggest that retinoic acid receptor agonists such as Am80 exerts anti-inflammatory actions in the central nervous system, although detailed mechanisms of the action remain largely unknown. Our previous findings suggest that Am80 provides therapeutic effect on intracerebral hemorrhage in mice via suppression of expression of chemokine (C-X-C motif) ligand 2 (CXCL2). Here we investigated the mechanisms of inhibitory action of Am80 on expression of CXCL2 and other pro-inflammatory factors in microglial BV-2 cells. Pretreatment with Am80 markedly suppressed lipopolysaccharide (LPS)-induced expression of CXCL2 mRNA and release of CXCL2 protein. Am80 had no effect on LPS-induced activation of p38 mitogen-activated protein kinase and extracellular signal-regulated kinase. On the other hand, Am80 prevented LPS-induced nuclear translocation of p65 subunit of NF-κB complex. In addition, total expression levels of p65 and IκBα proteins, as well as of mRNAs encoding p65 and IκBα, were lowered by Am80. Dependence of CXCL2 expression on NF-κB was confirmed by the effect of an NF-κB inhibitor caffeic acid phenethyl ester that abolished LPS-induced CXCL2 expression. Caffeic acid phenethyl ester also abolished LPS-induced expression of inducible nitric oxide synthase, interleukin-1β and tumor necrosis factor α, which may be relevant to the inhibitory effect of Am80 on expression of these pro-inflammatory factors. We additionally found that Am80 attenuated LPS-induced up-regulation of CD14, a co-receptor for Toll-like receptor 4 (TLR4). These results suggest that inhibitory effect on TLR4 signaling mediated by NF-κB pathway underlies the anti-inflammatory action of retinoic acid receptor agonists in microglia. PMID:27351827

  1. Hyperactivity induced by the dopamine D2/D3 receptor agonist quinpirole is attenuated by inhibitors of endocannabinoid degradation in mice.

    Science.gov (United States)

    Luque-Rojas, María Jesús; Galeano, Pablo; Suárez, Juan; Araos, Pedro; Santín, Luis J; de Fonseca, Fernando Rodríguez; Calvo, Eduardo Blanco

    2013-04-01

    The present study was designed to investigate the effect of pharmacological inhibition of endocannabinoid degradation on behavioural actions of the dopamine D2/D3 receptor agonist quinpirole in male C57Bl/6J mice. In addition, we studied the effects of endocannabinoid degradation inhibition on both cocaine-induced psychomotor activation and behavioural sensitization. We analysed the effects of inhibition of the two main endocannabinoid degradation enzymes: fatty acid amide hydrolase (FAAH), using inhibitor URB597 (1 mg/kg); monoacylglycerol lipase (MAGL), using inhibitor URB602 (10 mg/kg). Administration of quinpirole (1 mg/kg) caused a temporal biphasic response characterized by a first phase of immobility (0-50 min), followed by enhanced locomotion (next 70 min) that was associated with the introduction of stereotyped behaviours (stereotyped jumping and rearing). Pretreatment with both endocannabinoid degradation inhibitors did not affect the hypoactivity actions of quinpirole. However, this pretreatment resulted in a marked decrease in quinpirole-induced locomotion and stereotyped behaviours. Administration of FAAH or MAGL inhibitors did not attenuate the acute effects of cocaine. Furthermore, these inhibitors did not impair the acquisition of cocaine-induced behavioural sensitization or the expression of cocaine-induced conditioned locomotion. Only MAGL inhibition attenuated the expression of an already acquired cocaine-induced behavioural sensitization. These results suggest that pharmacological inhibition of endocannabinoid degradation might exert a negative feedback on D2/D3 receptor-mediated hyperactivity. This finding might be relevant for therapeutic approaches for either psychomotor disorders (dyskinesia, corea) or disorganized behaviours associated with dopamine-mediated hyperactivity. PMID:22647577

  2. D-serine deficiency attenuates the behavioral and cellular effects induced by the hallucinogenic 5-HT(2A) receptor agonist DOI

    DEFF Research Database (Denmark)

    Santini, Martin A; Balu, Darrick T; Puhl, Matthew D;

    2014-01-01

    , the serine racemase knockout (SRKO) mouse, to explore the role of glutamatergic transmission in regulating 5-HT2AR-mediated cellular and behavioral responses. SRKO mice treated with the 5-HT2AR agonist (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) showed a clearly diminished HTR and lower induction of c-fos m...

  3. Attenuation by a sigma1 (σ1) receptor agonist of the learning and memory deficits induced by a prenatal restraint stress in juvenile rats

    OpenAIRE

    Meunier, Johann; Gué, Michèle; Récasens, Max; Maurice, Tangui

    2004-01-01

    Stress during pregnancy results in complex neurochemical and behavioral alterations throughout the offspring lifetime. We here examined the impact of prenatal stress (PS) on memory functions in male and female offspring and report the efficacy of a selective sigma1 (σ1) receptor agonist, igmesine, in alleviating the observed deficits.Dams received an unpredictable 90-min duration restraint stress from gestational day E17 to E20. Learning was examined in offspring between day P24 and P36 using...

  4. The ghrelin receptor agonist HM01 mimics the neuronal effects of ghrelin in the arcuate nucleus and attenuates anorexia-cachexia syndrome in tumor-bearing rats.

    Science.gov (United States)

    Borner, Tito; Loi, Laura; Pietra, Claudio; Giuliano, Claudio; Lutz, Thomas A; Riediger, Thomas

    2016-07-01

    The gastric hormone ghrelin positively affects energy balance by increasing food intake and reducing energy expenditure. Ghrelin mimetics are a possible treatment against cancer anorexia-cachexia syndrome (CACS). This study aimed to characterize the action of the nonpeptidergic ghrelin receptor agonist HM01 on neuronal function, energy homeostasis and muscle mass in healthy rats and to evaluate its possible usefulness for the treatment of CACS in a rat tumor model. Using extracellular single-unit recordings, we tested whether HM01 mimics the effects of ghrelin on neuronal activity in the arcuate nucleus (Arc). Furthermore, we assessed the effect of chronic HM01 treatment on food intake (FI), body weight (BW), lean and fat volumes, and muscle mass in healthy rats. Using a hepatoma model, we investigated the possible beneficial effects of HM01 on tumor-induced anorexia, BW loss, muscle wasting, and metabolic rate. HM01 (10(-7)-10(-6) M) mimicked the effect of ghrelin (10(-8) M) by increasing the firing rate in 76% of Arc neurons. HM01 delivered chronically for 12 days via osmotic minipumps (50 μg/h) increased FI in healthy rats by 24%, paralleled by increased BW, higher fat and lean volumes, and higher muscle mass. Tumor-bearing rats treated with HM01 had 30% higher FI than tumor-bearing controls and were protected against BW loss. HM01 treatment resulted in higher muscle mass and fat mass. Moreover, tumor-bearing rats reduced their metabolic rate following HM01 treatment. Our studies substantiate the possible therapeutic usefulness of ghrelin receptor agonists like HM01 for the treatment of CACS and possibly other forms of disease-related anorexia and cachexia. PMID:27147616

  5. Acute administration of non-classical estrogen receptor agonists attenuates ischemia-induced hippocampal neuron loss in middle-aged female rats.

    Directory of Open Access Journals (Sweden)

    Diane Lebesgue

    Full Text Available BACKGROUND: Pretreatment with 17beta-estradiol (E2 is profoundly neuroprotective in young animals subjected to focal and global ischemia. However, whether E2 retains its neuroprotective efficacy in aging animals, especially when administered after brain insult, is largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: We examined the neuroprotective effects of E2 and two agonists that bind to non-classical estrogen receptors, G1 and STX, when administered after ischemia in middle-aged rats after prolonged ovarian hormone withdrawal. Eight weeks after ovariectomy, middle-aged female rats underwent 10 minutes of global ischemia by four vessel occlusion. Immediately after reperfusion, animals received a single infusion of either E2 (2.25 microg, G1 (50 microg or STX (50 microg into the lateral ventricle (ICV or a single systemic injection of E2 (100 microg/kg. Surviving pyramidal neurons in the hippocampal CA1 were quantified 1 week later. E2 and both agonists that target non-classical estrogen receptors (G1 and STX administered ICV at the time of reperfusion provided significant levels of neuroprotection, with 55-60% of CA1 neurons surviving vs 15% survival in controls. A single systemic injection of a pharmacological dose of E2 also rescued approximately 50% of CA1 pyramidal neurons destined to die. To determine if E2 and G1 have similar mechanisms of action in hippocampal neurons, we compared the ability of E2 and G1 to modify CA1 pyramidal neuron responses to excitatory inputs from the Schaffer collaterals recorded in hippocampal slices derived from female rats not subjected to global ischemia. E2 and G1 (10 nM significantly potentiated pyramidal neuron responses to excitatory inputs when applied to hippocampal slices. CONCLUSIONS/SIGNIFICANCE: These findings suggest (1 that middle-aged female rats retain their responsiveness to E2 even after a long period of hormone withdrawal, (2 that non-classical estrogen receptors may mediate the neuroprotective

  6. Ginsenoside Rb1 Attenuates Agonist-Induced Contractile Response via Inhibition of Store-Operated Calcium Entry in Pulmonary Arteries of Normal and Pulmonary Hypertensive Rats

    Directory of Open Access Journals (Sweden)

    Rui-Xing Wang

    2015-03-01

    Full Text Available Background: Pulmonary hypertension (PH is characterized by sustained vasoconstriction, enhanced vasoreactivity and vascular remodeling, which leads to right heart failure and death. Despite several treatments are available, many forms of PH are still incurable. Ginsenoside Rb1, a principle active ingredient of Panax ginseng, exhibits multiple pharmacological effects on cardiovascular system, and suppresses monocrotaline (MCT-induced right heart hypertrophy. However, its effect on the pulmonary vascular functions related to PH is unknown. Methods: We examined the vasorelaxing effects of ginsenoside Rb1 on endothelin-1 (ET-1 induced contraction of pulmonary arteries (PAs and store-operated Ca2+ entry (SOCE in pulmonary arterial smooth muscle cells (PASMCs from chronic hypoxia (CH and MCT-induced PH. Results: Ginsenoside Rb1 elicited concentration-dependent relaxation of ET-1-induced PA contraction. The vasorelaxing effect was unaffected by nifedipine, but abolished by the SOCE blocker Gd3+. Ginsenoside Rb1 suppressed cyclopiazonic acid (CPA-induced PA contraction, and CPA-activated cation entry and Ca2+ transient in PASMCs. ET-1 and CPA-induced contraction, and CPA-activated cation entry and Ca2+ transients were enhanced in PA and PASMCs of CH and MCT-treated rats; the enhanced responses were abolished by ginsenoside Rb1. Conclusion: Ginsenoside Rb1 attenuates ET-1-induced contractile response via inhibition of SOCE, and it can effectively antagonize the enhanced pulmonary vasoreactivity in PH.

  7. Dopaminergic agonists for hepatic encephalopathy

    DEFF Research Database (Denmark)

    Als-Nielsen, B; Gluud, L L; Gluud, C

    2004-01-01

    Hepatic encephalopathy may be associated with an impairment of the dopaminergic neurotransmission. Dopaminergic agonists may therefore have a beneficial effect on patients with hepatic encephalopathy.......Hepatic encephalopathy may be associated with an impairment of the dopaminergic neurotransmission. Dopaminergic agonists may therefore have a beneficial effect on patients with hepatic encephalopathy....

  8. Emerging GLP-1 receptor agonists

    DEFF Research Database (Denmark)

    Lund, Asger; Knop, Filip K; Vilsbøll, Tina

    2011-01-01

    Introduction: Recently, glucagon-like peptide-1 receptor (GLP-1R) agonists have become available for the treatment of type 2 diabetes. These agents exploit the physiological effects of GLP-1, which is able to address several of the pathophysiological features of type 2 diabetes. GLP-1R agonists...... presently available are administered once or twice daily, but several once-weekly GLP-1R agonists are in late clinical development. Areas covered: The present review aims to give an overview of the clinical data on the currently available GLP-1R agonists used for treatment of type 2 diabetes, exenatide and...... liraglutide, as well as the emerging GLP-1R agonists including the long-acting compounds. Expert opinion: An emerging therapeutic trend toward initial or early combination therapy with metformin- and incretin-based therapy is anticipated for patients with type 2 diabetes. GLP-1-based therapy has so far proven...

  9. Self-medication of a cannabinoid CB2 agonist in an animal model of neuropathic pain

    OpenAIRE

    Gutierrez, Tannia; Crystal, Jonathon D.; Zvonok, Alexander M.; Makriyannis, Alexandros; Hohmann, Andrea G.

    2011-01-01

    Drug self-administration methods were used to test the hypothesis that rats would self-medicate with a cannabinoid CB2 agonist to attenuate a neuropathic pain state. Self-medication of the CB2 agonist (R,S)-AM1241, but not vehicle, attenuated mechanical hypersensitivity produced by spared nerve injury. Switching rats from (R,S)-AM1241 to vehicle self-administration also decreased lever responding in an extinction paradigm. (R,S)-AM1241 self-administration did not alter paw withdrawal threshol...

  10. Emerging GLP-1 receptor agonists

    DEFF Research Database (Denmark)

    Lund, Asger; Knop, Filip K; Vilsbøll, Tina

    2011-01-01

    presently available are administered once or twice daily, but several once-weekly GLP-1R agonists are in late clinical development. Areas covered: The present review aims to give an overview of the clinical data on the currently available GLP-1R agonists used for treatment of type 2 diabetes, exenatide and...... liraglutide, as well as the emerging GLP-1R agonists including the long-acting compounds. Expert opinion: An emerging therapeutic trend toward initial or early combination therapy with metformin- and incretin-based therapy is anticipated for patients with type 2 diabetes. GLP-1-based therapy has so far proven...

  11. AGONISTIC BEHAVIOR OF LABORATORY MICE

    OpenAIRE

    D. Cinghiţă; D. Stănescu

    2005-01-01

    In this work we study agonistic behavior of laboratory white mice when they are kept in captivity. For all this experimental work we used direct observation of mice, in small lists, because we need a reduced space to emphasize characteristics of agonistic behavior. Relations between members of the same species that live in organized groups are based in most cases on hierarchical structure. Relations between leader and subservient, decided by fighting, involve a thorough observation between i...

  12. Proteasome involvement in agonist-induced down-regulation of mu and delta opioid receptors.

    Science.gov (United States)

    Chaturvedi, K; Bandari, P; Chinen, N; Howells, R D

    2001-04-13

    This study investigated the mechanism of agonist-induced opioid receptor down-regulation. Incubation of HEK 293 cells expressing FLAG-tagged delta and mu receptors with agonists caused a time-dependent decrease in opioid receptor levels assayed by immunoblotting. Pulse-chase experiments using [(35)S]methionine metabolic labeling indicated that the turnover rate of delta receptors was accelerated 5-fold following agonist stimulation. Inactivation of functional G(i) and G(o) proteins by pertussis toxin-attenuated down-regulation of the mu opioid receptor, while down-regulation of the delta opioid receptor was unaffected. Pretreatment of cells with inhibitors of lysosomal proteases, calpain, and caspases had little effect on mu and delta opioid receptor down-regulation. In marked contrast, pretreatment with proteasome inhibitors attenuated agonist-induced mu and delta receptor down-regulation. In addition, incubation of cells with proteasome inhibitors in the absence of agonists increased steady-state mu and delta opioid receptor levels. Immunoprecipitation of mu and delta opioid receptors followed by immunoblotting with ubiquitin antibodies suggested that preincubation with proteasome inhibitors promoted accumulation of polyubiquitinated receptors. These data provide evidence that the ubiquitin/proteasome pathway plays a role in agonist-induced down-regulation and basal turnover of opioid receptors. PMID:11152677

  13. AT2R Agonist, Compound 21, Is Reno-Protective Against Type 1 Diabetic Nephropathy

    DEFF Research Database (Denmark)

    Koulis, Christine; Chow, Bryna S M; McKelvey, Maria; Steckelings, Ulrike Muscha; Unger, Thomas; Thallas-Bonke, Vicki; Thomas, Merlin C; Cooper, Mark E; Jandeleit-Dahm, Karin A; Allen, Terri J

    2015-01-01

    . Activation of the angiotensin II type 2 receptors has been postulated to oppose angiotensin II type 1 receptor-mediated actions and thus attenuate fibrosis. This study aimed to elucidate the reno-protective role of the novel selective angiotensin II type 2 receptor agonist, Compound 21, in an experimental...

  14. Dissociated sterol-based liver X receptor agonists as therapeutics for chronic inflammatory diseases.

    Science.gov (United States)

    Yu, Shan; Li, Sijia; Henke, Adam; Muse, Evan D; Cheng, Bo; Welzel, Gustav; Chatterjee, Arnab K; Wang, Danling; Roland, Jason; Glass, Christopher K; Tremblay, Matthew

    2016-07-01

    Liver X receptor (LXR), a nuclear hormone receptor, is an essential regulator of immune responses. Activation of LXR-mediated transcription by synthetic agonists, such as T0901317 and GW3965, attenuates progression of inflammatory disease in animal models. However, the adverse effects of these conventional LXR agonists in elevating liver lipids have impeded exploitation of this intriguing mechanism for chronic therapy. Here, we explore the ability of a series of sterol-based LXR agonists to alleviate inflammatory conditions in mice without hepatotoxicity. We show that oral treatment with sterol-based LXR agonists in mice significantly reduces dextran sulfate sodium colitis-induced body weight loss, which is accompanied by reduced expression of inflammatory markers in the large intestine. The anti-inflammatory property of these agonists is recapitulated in vitro in mouse lamina propria mononuclear cells, human colonic epithelial cells, and human peripheral blood mononuclear cells. In addition, treatment with LXR agonists dramatically suppresses inflammatory cytokine expression in a model of traumatic brain injury. Importantly, in both disease models, the sterol-based agonists do not affect the liver, and the conventional agonist T0901317 results in significant liver lipid accumulation and injury. Overall, these results provide evidence for the development of sterol-based LXR agonists as novel therapeutics for chronic inflammatory diseases.-Yu, S., Li, S., Henke, A., Muse, E. D., Cheng, B., Welzel, G., Chatterjee, A. K., Wang, D., Roland, J., Glass, C. K., Tremblay, M. Dissociated sterol-based liver X receptor agonists as therapeutics for chronic inflammatory diseases. PMID:27025962

  15. Rotary antenna attenuator

    Science.gov (United States)

    Dickinson, R. M.; Hardy, J. C.

    1969-01-01

    Radio frequency attenuator, having negligible insertion loss at minimum attenuation, can be used for making precise antenna gain measurements. It is small in size compared to a rotary-vane attenuator.

  16. GnRH agonist triggering

    DEFF Research Database (Denmark)

    Kol, Shahar; Humaidan, Peter; Al Humaidan, Peter Samir Heskjær

    2013-01-01

    The concept that a bolus of gonadotrophin-releasing hormone agonist (GnRHa) can replace human chorionic gonadotrophin (HCG) as a trigger of final oocyte maturation was introduced several years ago. Recent developments in the area strengthen this premise. GnRHa trigger offers important advantages...... triggering concept should be challenged and that the GnRHa trigger is the way to move forward with thoughtful consideration of the needs, safety and comfort of our patients. Routinely, human chorionic gonadotrophin (HCG) is used to induce ovulation in fertility treatments. This approach deviates...... significantly from physiology and often results in insufficient hormonal support in early pregnancy and in ovarian hyperstimulation syndrome (OHSS). An alternative approach is to use a gonadotrophin-releasing hormone (GnRH) agonist which allows a more physiological trigger of ovulation and, most importantly...

  17. β-Agonist-mediated Relaxation of Airway Smooth Muscle Is Protein Kinase A-dependent*

    Science.gov (United States)

    Morgan, Sarah J.; Deshpande, Deepak A.; Tiegs, Brian C.; Misior, Anna M.; Yan, Huandong; Hershfeld, Alena V.; Rich, Thomas C.; Panettieri, Reynold A.; An, Steven S.; Penn, Raymond B.

    2014-01-01

    Inhaled β-agonists are effective at reversing bronchoconstriction in asthma, but the mechanism by which they exert this effect is unclear and controversial. PKA is the historically accepted effector, although this assumption is made on the basis of associative and not direct evidence. Recent studies have asserted that exchange protein activated by cAMP (Epac), not PKA, mediates the relaxation of airway smooth muscle (ASM) observed with β-agonist treatment. This study aims to clarify the role of PKA in the prorelaxant effects of β-agonists on ASM. Inhibition of PKA activity via expression of the PKI and RevAB peptides results in increased β-agonist-mediated cAMP release, abolishes the inhibitory effect of isoproterenol on histamine-induced intracellular calcium flux, and significantly attenuates histamine-stimulated MLC-20 phosphorylation. Analyses of ASM cell and tissue contraction demonstrate that PKA inhibition eliminates most, if not all, β-agonist-mediated relaxation of contracted smooth muscle. Conversely, Epac knockdown had no effect on the regulation of contraction or procontractile signaling by isoproterenol. These findings suggest that PKA, not Epac, is the predominant and physiologically relevant effector through which β-agonists exert their relaxant effects. PMID:24973219

  18. β-Agonist-mediated relaxation of airway smooth muscle is protein kinase A-dependent.

    Science.gov (United States)

    Morgan, Sarah J; Deshpande, Deepak A; Tiegs, Brian C; Misior, Anna M; Yan, Huandong; Hershfeld, Alena V; Rich, Thomas C; Panettieri, Reynold A; An, Steven S; Penn, Raymond B

    2014-08-15

    Inhaled β-agonists are effective at reversing bronchoconstriction in asthma, but the mechanism by which they exert this effect is unclear and controversial. PKA is the historically accepted effector, although this assumption is made on the basis of associative and not direct evidence. Recent studies have asserted that exchange protein activated by cAMP (Epac), not PKA, mediates the relaxation of airway smooth muscle (ASM) observed with β-agonist treatment. This study aims to clarify the role of PKA in the prorelaxant effects of β-agonists on ASM. Inhibition of PKA activity via expression of the PKI and RevAB peptides results in increased β-agonist-mediated cAMP release, abolishes the inhibitory effect of isoproterenol on histamine-induced intracellular calcium flux, and significantly attenuates histamine-stimulated MLC-20 phosphorylation. Analyses of ASM cell and tissue contraction demonstrate that PKA inhibition eliminates most, if not all, β-agonist-mediated relaxation of contracted smooth muscle. Conversely, Epac knockdown had no effect on the regulation of contraction or procontractile signaling by isoproterenol. These findings suggest that PKA, not Epac, is the predominant and physiologically relevant effector through which β-agonists exert their relaxant effects. PMID:24973219

  19. PPARα-Independent Arterial Smooth Muscle Relaxant Effects of PPARα Agonists

    Directory of Open Access Journals (Sweden)

    Neerupma Silswal

    2012-01-01

    Full Text Available We sought to determine direct vascular effects of peroxisome proliferator-activated receptor alpha (PPARα agonists using isolated mouse aortas and middle cerebral arteries (MCAs. The PPARα agonists GW7647, WY14643, and gemfibrozil acutely relaxed aortas held under isometric tension and dilated pressurized MCAs with the following order of potency: GW7647≫WY14643>gemfibrozil. Responses were endothelium-independent, and the use of PPARα deficient mice demonstrated that responses were also PPARα-independent. Pretreating arteries with high extracellular K+ attenuated PPARα agonist-mediated relaxations in the aorta, but not in the MCA. In the aorta, the ATP sensitive potassium (KATP channel blocker glibenclamide also impaired relaxations whereas the other K+ channel inhibitors, 4-aminopyridine and Iberiotoxin, had no effect. In aortas, GW7647 and WY14643 elevated cGMP levels by stimulating soluble guanylyl cyclase (sGC, and inhibition of sGC with ODQ blunted relaxations to PPARα agonists. In the MCA, dilations were inhibited by the protein kinase C (PKC activator, phorbol 12,13-dibutyrate, and also by ODQ. Our results demonstrated acute, nonreceptor-mediated relaxant effects of PPARα agonists on smooth muscle of mouse arteries. Responses to PPARα agonists in the aorta involved KATP channels and sGC, whereas in the MCA the PKC and sGC pathways also appeared to contribute to the response.

  20. DC attenuation meter

    Science.gov (United States)

    Hargrove, Douglas L.

    2004-09-14

    A portable, hand-held meter used to measure direct current (DC) attenuation in low impedance electrical signal cables and signal attenuators. A DC voltage is applied to the signal input of the cable and feedback to the control circuit through the signal cable and attenuators. The control circuit adjusts the applied voltage to the cable until the feedback voltage equals the reference voltage. The "units" of applied voltage required at the cable input is the system attenuation value of the cable and attenuators, which makes this meter unique. The meter may be used to calibrate data signal cables, attenuators, and cable-attenuator assemblies.

  1. PPARγ Agonist Beyond Glucose Lowering Effect

    OpenAIRE

    Sugawara, Akira; Uruno, Akira; Kudo, Masataka; Matsuda, Ken; Yang, Chul Woo; Ito, Sadayoshi

    2011-01-01

    The nuclear hormone receptor PPARγ is activated by several agonists, including members of the thiazolidinedione group of insulin sensitizers. Pleiotropic beneficial effects of these agonists, independent of their blood glucose-lowering effects, have recently been demonstrated in the vasculature. PPARγ agonists have been shown to lower blood pressure in animals and humans, perhaps by suppressing the renin-angiotensin (Ang)-aldosterone system (RAAS), including the inhibition of Ang II type 1 re...

  2. Anti-Inflammatory Effects of β2-Receptor Agonists Salbutamol and Terbutaline Are Mediated by MKP-1.

    Science.gov (United States)

    Keränen, Tiina; Hömmö, Tuija; Hämäläinen, Mari; Moilanen, Eeva; Korhonen, Riku

    2016-01-01

    Mitogen-activated protein kinase phosphatase 1 (MKP-1) expression is induced by inflammatory factors, and it is an endogenous suppressor of inflammatory response. MKP-1 expression is increased by PDE4 inhibitor rolipram suggesting that it is regulated by cAMP-enhancing compounds. Therefore, we investigated the effect of β2-receptor agonists on MKP-1 expression and inflammatory response. We found that β2-receptor agonists salbutamol and terbutaline, as well as 8-Br-cAMP, increased MKP-1 expression. Salbutamol and terbutaline also inhibited p38 MAPK phosphorylation and TNF production in J774 mouse macrophages. Interestingly, salbutamol suppressed carrageenan-induced paw inflammation in wild-type mice, but the effect was attenuated in MKP-1(-/-) mice. In conclusion, these data show that β2-receptor agonists increase MKP-1 expression, which seems to mediate, at least partly, the observed anti-inflammatory effects of β2-receptor agonists. PMID:26849227

  3. Pressure surge attenuator

    Science.gov (United States)

    Christie, Alan M.; Snyder, Kurt I.

    1985-01-01

    A pressure surge attenuation system for pipes having a fluted region opposite crushable metal foam. As adapted for nuclear reactor vessels and heads, crushable metal foam is disposed to attenuate pressure surges.

  4. Beta-agonists and animal welfare

    Science.gov (United States)

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

  5. Photonic Crystal Fiber Attenuator

    Institute of Scientific and Technical Information of China (English)

    Joo Beom Eom; Hokyung Kim; Jinchae Kim; Un-Chul Paek; Byeong Ha Lee

    2003-01-01

    We propose a novel fiber attenuator based on photonic crystal fibers. The difference in the modal field diameters of a conventional single mode fiber and a photonic crystal fiber was used. A variable optical attenuator was also achieved by applying macro-bending on the PCF part of the proposed attenuator

  6. [Adrenergic beta-agonist intoxication].

    Science.gov (United States)

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

    2003-01-01

    The authors describe two clinical cases (father and daughter), observed in the Hospital Urgency with distal tremors, anxiety, palpitations, nausea, headaches and dizziness, two hours after ingestión of cow liver. They also had leucocytosis (with neutrophylia), hypokalemia and hyperglycaemia. After treatment with potassium i.v. and propranolol, the symptoms disappeared. The symptoms recurred at home because the patients didn't take the prescribed medication and persisted for five days, with spontaneous disappearance. The serum of both patients revealed the presence of clenbuterol (65 hg/ml - father and 58 hg/ml - daughter). The animal's liver had a concentration of 1,42 mg/kg. Clenbuterol is a ß-adrenergic agonist with low specificity, with some veterinary indications. However, this substance has been illegally used as a growth's promotor. We intend to alert doctors for this problem, particularly those that work in the Urgency. PMID:22226216

  7. β2-agonist therapy in lung disease.

    Science.gov (United States)

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

    2013-04-01

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

  8. Peroxisome proliferator-activated receptor-gamma agonists suppress tissue factor overexpression in rat balloon injury model with paclitaxel infusion.

    Directory of Open Access Journals (Sweden)

    Jun-Bean Park

    Full Text Available The role and underlying mechanisms of rosiglitazone, a peroxisome proliferator-activated receptor-gamma (PPAR-γ agonist, on myocardial infarction are poorly understood. We investigated the effects of this PPAR-γ agonist on the expression of tissue factor (TF, a primary molecule for thrombosis, and elucidated its underlying mechanisms. The PPAR-γ agonist inhibited TF expression in response to TNF-α in human umbilical vein endothelial cells, human monocytic leukemia cell line, and human umbilical arterial smooth muscle cells. The overexpression of TF was mediated by increased phosphorylation of mitogen-activated protein kinase (MAPK, which was blocked by the PPAR-γ agonist. The effective MAPK differed depending on each cell type. Luciferase and ChIP assays showed that transcription factor, activator protein-1 (AP-1, was a pivotal target of the PPAR-γ agonist to lower TF transcription. Intriguingly, two main drugs for drug-eluting stent, paclitaxel or rapamycin, significantly exaggerated thrombin-induced TF expression, which was also effectively blocked by the PPAR-γ agonist in all cell types. This PPAR-γ agonist did not impair TF pathway inhibitor (TFPI in three cell types. In rat balloon injury model (Sprague-Dawley rats, n = 10/group with continuous paclitaxel infusion, the PPAR-γ agonist attenuated TF expression by 70±5% (n = 4; P<0.0001 in injured vasculature. Taken together, rosiglitazone reduced TF expression in three critical cell types involved in vascular thrombus formation via MAPK and AP-1 inhibitions. Also, this PPAR-γ agonist reversed the paclitaxel-induced aggravation of TF expression, which suggests a possibility that the benefits might outweigh its risks in a group of patients with paclitaxel-eluting stent implanted.

  9. Both the antioxidant and D3 agonist actions of pramipexole mediate its neuroprotective actions in mesencephalic cultures.

    Science.gov (United States)

    Ling, Z D; Robie, H C; Tong, C W; Carvey, P M

    1999-04-01

    Pramipexole (PPX) is a full intrinsic activity, direct-acting dopamine (DA) agonist possessing 7-fold higher affinity for D3 than for D2 receptors. It also is a potent antioxidant. PPX was previously shown to be neuroprotective because it dose dependently attenuated the DA neuron loss produced by levodopa in mesencephalic cultures. Several different drugs with properties similar to PPX were studied here to better understand the mechanism or mechanisms responsible for this neuroprotective effect. The D3-preferring agonist 7-hydroxy-diphenylaminotetralin (7-OH-DPAT) and the D3 antagonist U99194, respectively, increased and decreased the neuroprotective effects of PPX in a dose-dependent fashion. Addition of the selective D2 agonist U95666 or the D2/D3 antagonists domperidone or raclopride did not affect PPX's neuroprotective effect. Interestingly, 7-OH-DPAT by itself did not attenuate the DA neuron loss produced by levodopa. However, when 7-OH-DPAT was combined with a low dose of the antioxidants U101033E or alpha-tocopherol, the toxic effects of levodopa were attenuated. Similar results were observed when the D3-preferring agonist PD128, 907 was studied. In addition, media conditioned by exposure of mesencephalic cultures incubated with all D3-preferring agonists studied was shown to enhance the growth of DA neurons in freshly harvested recipient cultures implicating a D3-mediated trophic activity in the neuroprotective effect. These data suggest that PPX's neuroprotective actions in the levodopa toxicity model are a consequence of its combined actions as a D3 receptor agonist and an antioxidant. PMID:10087005

  10. Self-medication of a cannabinoid CB2 agonist in an animal model of neuropathic pain.

    Science.gov (United States)

    Gutierrez, Tannia; Crystal, Jonathon D; Zvonok, Alexander M; Makriyannis, Alexandros; Hohmann, Andrea G

    2011-09-01

    Drug self-administration methods were used to test the hypothesis that rats would self-medicate with a cannabinoid CB(2) agonist to attenuate a neuropathic pain state. Self-medication of the CB(2) agonist (R,S)-AM1241, but not vehicle, attenuated mechanical hypersensitivity produced by spared nerve injury. Switching rats from (R,S)-AM1241 to vehicle self-administration also decreased lever responding in an extinction paradigm. (R,S)-AM1241 self-administration did not alter paw withdrawal thresholds in sham-operated or naive animals. The percentage of active lever responding was similar in naive groups self-administering vehicle or (R,S)-AM1241. The CB(2) antagonist SR144528 blocked both antiallodynic effects of (R,S)-AM1241 self-medication and the percentage of active lever responding in neuropathic (but not naive) rats. Neuropathic and sham groups exhibited similar percentages of active lever responding for (R,S)-AM1241 on a fixed ratio 1 (FR1) schedule. However, neuropathic animals worked harder than shams to obtain (R,S)-AM1241 when the schedule of reinforcement was increased (to FR6). (R,S)-AM1241 self-medication on FR1, FR3, or FR6 schedules attenuated nerve injury-induced mechanical allodynia. (R,S)-AM1241 (900μg intravenously) failed to produce motor ataxia observed after administration of the mixed CB(1)/CB(2) agonist WIN55,212-2 (0.5mg/kg intravenously). Our results suggest that cannabinoid CB(2) agonists may be exploited to treat neuropathic pain with limited drug abuse liability and central nervous system side effects. These studies validate the use of drug self-administration methods for identifying nonpsychotropic analgesics possessing limited abuse potential. These methods offer potential to elucidate novel analgesics that suppress spontaneous neuropathic pain that is not measured by traditional assessments of evoked pain. PMID:21550725

  11. Variable laser attenuator

    Science.gov (United States)

    Foltyn, Stephen R.

    1988-01-01

    The disclosure relates to low loss, high power variable attenuators comprng one or more transmissive and/or reflective multilayer dielectric filters. The attenuator is particularly suitable to use with unpolarized lasers such as excimer lasers. Beam attenuation is a function of beam polarization and the angle of incidence between the beam and the filter and is controlled by adjusting the angle of incidence the beam makes to the filter or filters. Filters are selected in accordance with beam wavelength.

  12. Negative cooperativity in binding of muscarinic receptor agonists and GDP as a measure of agonist efficacy

    OpenAIRE

    Jakubík, J; Janíčková, H; El-Fakahany, EE; Doležal, V

    2011-01-01

    BACKGROUND AND PURPOSE Conventional determination of agonist efficacy at G-protein coupled receptors is measured by stimulation of guanosine-5′-γ−thiotriphosphate (GTPγS) binding. We analysed the role of guanosine diphosphate (GDP) in the process of activation of the M2 muscarinic acetylcholine receptor and provide evidence that negative cooperativity between agonist and GDP binding is an alternative measure of agonist efficacy. EXPERIMENTAL APPROACH Filtration and scintillation proximity ass...

  13. Thrombopoietin Receptor Agonists in Primary ITP

    OpenAIRE

    Siegal, Deborah; Crowther, Mark; Cuker, Adam

    2013-01-01

    Thrombopoietin (TPO) regulates thrombopoiesis through activation of TPO receptors on the megakaryocyte cell surface, resulting in increased platelet production. The TPO receptor agonists are novel treatments for patients with chronic ITP aimed at increasing platelet production through interactions with the TPO receptor on megakaryocytes. Two TPO receptor agonists, romiplostim and eltrombopag, have received regulatory approval. In patients with chronic ITP who remain at risk of bleeding follow...

  14. PPAR Agonists and Cardiovascular Disease in Diabetes

    Directory of Open Access Journals (Sweden)

    Anna C. Calkin

    2008-01-01

    Full Text Available Peroxisome proliferators activated receptors (PPARs are ligand-activated nuclear transcription factors that play important roles in lipid and glucose homeostasis. To the extent that PPAR agonists improve diabetic dyslipidaemia and insulin resistance, these agents have been considered to reduce cardiovascular risk. However, data from murine models suggests that PPAR agonists also have independent anti-atherosclerotic actions, including the suppression of vascular inflammation, oxidative stress, and activation of the renin angiotensin system. Many of these potentially anti-atherosclerotic effects are thought to be mediated by transrepression of nuclear factor-kB, STAT, and activator protein-1 dependent pathways. In recent clinical trials, PPARα agonists have been shown to be effective in the primary prevention of cardiovascular events, while their cardiovascular benefit in patients with established cardiovascular disease remains equivocal. However, the use of PPARγ agonists, and more recently dual PPARα/γ coagonists, has been associated with an excess in cardiovascular events, possibly reflecting unrecognised fluid retention with potent agonists of the PPARγ receptor. Newer pan agonists, which retain their anti-atherosclerotic activity without weight gain, may provide one solution to this problem. However, the complex biologic effects of the PPARs may mean that only vascular targeted agents or pure transrepressors will realise the goal of preventing atherosclerotic vascular disease.

  15. Dihydrocodeine / Agonists for Alcohol Dependents

    Directory of Open Access Journals (Sweden)

    Albrecht eUlmer

    2012-03-01

    Full Text Available Objective: Alcohol addiction too often remains insufficiently treated. It shows the same profile as severe chronic diseases, but no comparable, effective basic treatment has been established up to now. Especially patients with repeated relapses, despite all therapeutic approaches, and patients who are not able to attain an essential abstinence to alcohol, need a basic medication. It seems necessary to acknowledge that parts of them need any agonistic substance, for years, possibly lifelong. For >14 years, we have prescribed such substances with own addictive character for these patients.Methods: We present a documented best possible practice, no designed study. Since 1997, we prescribed Dihydrocodeine (DHC to 102 heavily alcohol addict-ed patients, later, also Buprenorphine, Clomethiazole (>6 weeks, Baclofen and in one case Amphetamine, each on individual indication. This paper focuses on the data with DH, especially. The Clomethiazole-data has been submitted to a German journal. The number of treatments with the other substances is still low. Results: The 102 patients with the DHC-treatment had 1367 medically assisted detoxifications and specialized therapies before! The 4 years-retention rate was 26.4%, including 2.8% successfully terminated treatments. In our 12-step scale on clinical impression, we noticed a significant improvement from mean 3.7 to 8.4 after 2 years. The demand for medically assisted detoxifications in the 2 years remaining patients was reduced by 65.5%. Mean GGT improved from 206.6 U/l at baseline to 66.8 U/l after 2 years. Experiences with the other substances are similar but different in details.Conclusions: Similar to the Italian studies with GHB and Baclofen, we present a new approach, not only with new substances, but also with a new setting and much more trusting attitude. We observe a huge improvement, reaching an almost optimal, stable, long term status in around ¼ of the patients already. Many further

  16. Suppression of interleukin-6-induced C-reactive protein expression by FXR agonists

    International Nuclear Information System (INIS)

    C-reactive protein (CRP), a human acute-phase protein, is a risk factor for future cardiovascular events and exerts direct pro-inflammatory and pro-atherogenic properties. The farnesoid X receptor (FXR), a member of the nuclear hormone receptor superfamily, plays an essential role in the regulation of enterohepatic circulation and lipid homeostasis. In this study, we report that two synthetic FXR agonists, WAY-362450 and GW4064, suppressed interleukin-6-induced CRP expression in human Hep3B hepatoma cells. Knockdown of FXR by short interfering RNA attenuated the inhibitory effect of the FXR agonists and also increased the ability of interleukin-6 to induce CRP production. Furthermore, treatment of wild type C57BL/6 mice with the FXR agonist, WAY-362450, attenuated lipopolysaccharide-induced serum amyloid P component and serum amyloid A3 mRNA levels in the liver, whereas no effect was observed in FXR knockout mice. These data provide new evidence for direct anti-inflammatory properties of FXR.

  17. Inhibition of receptor tyrosine kinase signalling by small molecule agonist of T-cell protein tyrosine phosphatase

    International Nuclear Information System (INIS)

    T-cell protein tyrosine phosphatase (TCPTP/TC45) is a ubiquitously expressed intra-cellular non-receptor protein tyrosine phosphatase involved in the negative regulation of several cancer relevant cellular signalling pathways. We have previously shown that interaction between the α-cytoplasmic tail of α1β1 integrin and TCPTP activates TCPTP by disrupting an inhibitory intra-molecular bond in TCPTP. Thus, inhibition of the regulatory interaction in TCPTP is a desirable strategy for TCPTP activation and attenuation of oncogenic RTK signalling. However, this is challenging with low molecular weight compounds. We developed a high-throughput compatible assay to analyse activity of recombinant TCPTP in vitro. Using this assay we have screened 64280 small molecules to identify novel agonists for TCPTP. Dose-dependent response to TCPTP agonist was performed using the in vitro assay. Inhibition effects and specificity of TCPTP agonists were evaluated using TCPTP expressing and null mouse embryonic fibroblasts. Western blot analysis was used to evaluate attenuation of PDGFRβ and EGFR phosphorylation. Inhibition of VEGF signalling was analysed with VEGF-induced endothelial cell sprouting assays. From the screen we identified six TCPTP agonists. Two compounds competed with α1-cytoplasmic domain for binding to TCPTP, suggesting that they activate TCPTP similar to α1-cyt by disrupting the intra-molecular bond in TCPTP. Importantly, one of the compounds (spermidine) displayed specificity towards TCPTP in cells, since TCPTP -/- cells were 43-fold more resistant to the compound than TCPTP expressing cells. This compound attenuates PDGFRβ and VEGFR2 signalling in cells in a TCPTP-dependent manner and functions as a negative regulator of EGFR phosphorylation in cancer cells. In this study we showed that small molecules mimicking TCPTP-α1 interaction can be used as TCPTP agonists. These data provide the first proof-of-concept description of the use of high-throughput screening

  18. Landing gear noise attenuation

    Science.gov (United States)

    Moe, Jeffrey W. (Inventor); Whitmire, Julia (Inventor); Kwan, Hwa-Wan (Inventor); Abeysinghe, Amal (Inventor)

    2011-01-01

    A landing gear noise attenuator mitigates noise generated by airframe deployable landing gear. The noise attenuator can have a first position when the landing gear is in its deployed or down position, and a second position when the landing gear is in its up or stowed position. The noise attenuator may be an inflatable fairing that does not compromise limited space constraints associated with landing gear retraction and stowage. A truck fairing mounted under a truck beam can have a compliant edge to allow for non-destructive impingement of a deflected fire during certain conditions.

  19. RADIO FREQUENCY ATTENUATOR

    Science.gov (United States)

    Giordano, S.

    1963-11-12

    A high peak power level r-f attenuator that is readily and easily insertable along a coaxial cable having an inner conductor and an outer annular conductor without breaking the ends thereof is presented. Spaced first and second flares in the outer conductor face each other with a slidable cylindrical outer conductor portion therebetween. Dielectric means, such as water, contact the cable between the flares to attenuate the radio-frequency energy received thereby. The cylindrical outer conductor portion is slidable to adjust the voltage standing wave ratio to a low level, and one of the flares is slidable to adjust the attenuation level. An integral dielectric container is also provided. (AFC)

  20. beta2-Agonists at the Olympic Games.

    Science.gov (United States)

    Fitch, Kenneth D

    2006-01-01

    The different approaches that the International Olympic Committee (IOC) had adopted to beta2-agonists and the implications for athletes are reviewed by a former Olympic team physician who later became a member of the Medical Commission of the IOC (IOC-MC). Steadily increasing knowledge of the effects of inhaled beta2-agonists on health, is concerned with the fact that oral beta2-agonists may be anabolic, and rapid increased use of inhaled beta2-agonists by elite athletes has contributed to the changes to the IOC rules. Since 2001, the necessity for athletes to meet IOC criteria (i.e., that they have asthma and/or exercise-induced asthma [EIA]) has resulted in improved management of athletes. The prevalence of beta2-agonist use by athletes mirrors the known prevalence of asthma symptoms in each country, although athletes in endurance events have the highest prevalence. The age-of-onset of asthma/EIA in elite winter athletes may be atypical. Of the 193 athletes at the 2006 Winter Olympics who met th IOC's criteria, only 32.1% had childhood asthma and 48.7% of athletes reported onset at age 20 yr or older. These findings lead to speculation that years of intense endurance training may be a causative factor in bronchial hyperreactivity. The distinction between oral (prohibited in sports) and inhaled salbutamol is possible, but athletes must be warned that excessive use of inhaled salbutamol can lead to urinary concentrations similar to those observed after oral administration. This article provides justification that athletes should provide evidence of asthma or EIA before being permitted to use inhaled beta2-agonists. PMID:17085798

  1. Attenuator And Conditioner

    Science.gov (United States)

    Anderson, Gene R.; Armendariz, Marcelino G.; Carson, Richard F.; Bryan, Robert P.; Duckett, III, Edwin B.; Kemme, Shanalyn Adair; McCormick, Frederick B.; Peterson, David W.

    2006-04-04

    An apparatus and method of attenuating and/or conditioning optical energy for an optical transmitter, receiver or transceiver module is disclosed. An apparatus for attenuating the optical output of an optoelectronic connector including: a mounting surface; an array of optoelectronic devices having at least a first end; an array of optical elements having at least a first end; the first end of the array of optical elements optically aligned with the first end of the array of optoelectronic devices; an optical path extending from the first end of the array of optoelectronic devices and ending at a second end of the array of optical elements; and an attenuator in the optical path for attenuating the optical energy emitted from the array of optoelectronic devices. Alternatively, a conditioner may be adapted in the optical path for conditioning the optical energy emitted from the array of optoelectronic devices.

  2. Identification of Selective ERRγ Inverse Agonists

    Directory of Open Access Journals (Sweden)

    Jina Kim

    2016-01-01

    Full Text Available GSK5182 (4 is currently one of the lead compounds for the development of estrogen-related receptor gamma (ERRγ inverse agonists. Here, we report the design, synthesis, pharmacological and in vitro absorption, distribution, metabolism, excretion, toxicity (ADMET properties of a series of compounds related to 4. Starting from 4, a series of analogs were structurally modified and their ERRγ inverse agonist activity was measured. A key pharmacophore feature of this novel class of ligands is the introduction of a heterocyclic group for A-ring substitution in the core scaffold. Among the tested compounds, several of them are potent ERRγ inverse agonists as determined by binding and functional assays. The most promising compound, 15g, had excellent binding selectivity over related subtypes (IC50 = 0.44, >10, >10, and 10 μM at the ERRγ, ERRα, ERRβ, and ERα subtypes, respectively. Compound 15g also resulted in 95% transcriptional repression at a concentration of 10 μM, while still maintaining an acceptable in vitro ADMET profile. This novel class of ERRγ inverse agonists shows promise in the development of drugs targeting ERRγ-related diseases.

  3. Reciprocity of agonistic support in ravens.

    Science.gov (United States)

    Fraser, Orlaith N; Bugnyar, Thomas

    2012-01-01

    Cooperative behaviour through reciprocation or interchange of valuable services in primates has received considerable attention, especially regarding the timeframe of reciprocation and its ensuing cognitive implications. Much less, however, is known about reciprocity in other animals, particularly birds. We investigated patterns of agonistic support (defined as a third party intervening in an ongoing conflict to attack one of the conflict participants, thus supporting the other) in a group of 13 captive ravens, Corvus corax. We found support for long-term, but not short-term, reciprocation of agonistic support. Ravens were more likely to support individuals who preened them, kin and dominant group members. These results suggest that ravens do not reciprocate on a calculated tit-for-tat basis, but aid individuals from whom reciprocated support would be most useful and those with whom they share a good relationship. Additionally, dyadic levels of agonistic support and consolation (postconflict affiliation from a bystander to the victim) correlated strongly with each other, but we found no evidence to suggest that receiving agonistic support influences the victim's likelihood of receiving support (consolation) after the conflict ends. Our findings are consistent with an emotionally mediated form of reciprocity in ravens and provide additional support for convergent cognitive evolution in birds and mammals. PMID:22298910

  4. FXR agonist activity of conformationally constrained analogs of GW 4064

    Energy Technology Data Exchange (ETDEWEB)

    Akwabi-Ameyaw, Adwoa; Bass, Jonathan Y.; Caldwell, Richard D.; Caravella, Justin A.; Chen, Lihong; Creech, Katrina L.; Deaton, David N.; Madauss, Kevin P.; Marr, Harry B.; McFadyen, Robert B.; Miller, Aaron B.; Navas, III, Frank; Parks, Derek J.; Spearing, Paul K.; Todd, Dan; Williams, Shawn P.; Wisely, G. Bruce; (GSKNC)

    2010-09-27

    Two series of conformationally constrained analogs of the FXR agonist GW 4064 1 were prepared. Replacement of the metabolically labile stilbene with either benzothiophene or naphthalene rings led to the identification of potent full agonists 2a and 2g.

  5. Exploring prospects of β3-adrenoceptor agonists and inverse agonists for colon mobility control

    Directory of Open Access Journals (Sweden)

    Maria Grazia Perrone

    2013-07-01

    Full Text Available Inverse agonists are useful active ingredient of drugs clinically used to treat diseases mainly involving receptors endowed with non-endogenous agonist induced activity (constitutive or basal activity. SP-1e and SP-1g are the first two potent and highly selective β3-adrenoceptor inverse agonists [EC50=181 nM (IA=- 64% and 136 nM (IA=-73%, respectively], which their peculiar activity seems due to the absolute configurations of the two stereogenic centres present in each molecule. Rat proximal colon motility measurements allowed their further pharmacological characterization and pA2 values determination by Schild analysis (7.89 and 8.16, respectively. The purpose of our work is a further characterization of our novel β3-adrenoceptor agonists (SP-1a-d, SP-1f,1h and inverse agonists (SP-1e and SP-1g on rat proximal colon motility and a confirmation of their inverse agonist nature in a more complex system like the functional test on rat proximal colon. Male Wistar rats segment of the proximal colon were placed in organ baths containing Krebs solution. Muscle tension was recorded isotonically. Cumulative β3-AR agonists doses experiments were performed for each test compound: isoprenaline, BRL37344, SP-1a-d, SP-1f and SP-1h were dissolved in Krebs. The EC50 values of each agonists and pA2 of inverse agonists were determined. SP- 1a-d, SP-1f and SP-1h in rat colon have a muscle relaxing effect thus confirming their partial agonist activity found in CHO-K1 cell line. SP-1e and SP-1g behaved as antagonists with pA2 values of 7.89 and 8.16, respectively. In conclusion, experiments carried out by using isolated rat proximal colon allowed us to determine the pA2 values of the two β3-AR inverse agonists and add knowledge on the behavior of a novel set of compounds and their possible value as agents useful whenever is necessary to also control the colon motility.

  6. Gonadotropin releasing hormone agonists: Expanding vistas

    Directory of Open Access Journals (Sweden)

    Navneet Magon

    2011-01-01

    Full Text Available Gonadotropin-releasing hormone (GnRH agonists are derived from native GnRH by amino acid substitution which yields the agonist resistant to degradation and increases its half-life. The hypogonadotropic hypogonadal state produced by GnRH agonists has been often dubbed as "pseudomenopause" or "medical oophorectomy," which are both misnomers. GnRH analogues (GnRH-a work by temporarily "switching off" the ovaries. Ovaries can be "switched off" for the therapy and therapeutic trial of many conditions which include but are not limited to subfertility, endometriosis, adenomyosis, uterine leiomyomas, precocious puberty, premenstrual dysphoric disorder, chronic pelvic pain, or the prevention of menstrual bleeding in special clinical situations. Rapidly expanding vistas of usage of GnRH agonists encompass use in sex reassignment of male to female transsexuals, management of final height in cases of congenital adrenal hyperplasia, and preserving ovarian function in women undergoing cytotoxic chemotherapy. Hypogonadic side effects caused by the use of GnRH agonists can be tackled with use of "add-back" therapy. Goserelin, leuprolide, and nafarelin are commonly used in clinical practice. GnRH-a have provided us a powerful therapeutic approach to the treatment of numerous conditions in reproductive medicine. Recent synthesis of GnRH antagonists with a better tolerability profile may open new avenues for both research and clinical applications. All stakeholders who are partners in women′s healthcare need to join hands to spread awareness so that these drugs can be used to realize their full potential.

  7. PPARα agonist, fenofibrate, ameliorates age-related renal injury.

    Science.gov (United States)

    Kim, Eun Nim; Lim, Ji Hee; Kim, Min Young; Kim, Hyung Wook; Park, Cheol Whee; Chang, Yoon Sik; Choi, Bum Soon

    2016-08-01

    The kidney ages quickly compared with other organs. Expression of senescence markers reflects changes in the energy metabolism in the kidney. Two important issues in aging are mitochondrial dysfunction and oxidative stress. Peroxisome proliferator-activated receptor α (PPARα) is a member of the ligand-activated nuclear receptor superfamily. PPARα plays a major role as a transcription factor that regulates the expression of genes involved in various processes. In this study, 18-month-old male C57BL/6 mice were divided into two groups, the control group (n=7) and the fenofibrate-treated group (n=7) was fed the normal chow plus fenofibrate for 6months. The PPARα agonist, fenofibrate, improved renal function, proteinuria, histological change (glomerulosclerosis and tubular interstitial fibrosis), inflammation, and apoptosis in aging mice. This protective effect against age-related renal injury occurred through the activation of AMPK and SIRT1 signaling. The activation of AMPK and SIRT1 allowed for the concurrent deacetylation and phosphorylation of their target molecules and decreased the kidney's susceptibility to age-related changes. Activation of the AMPK-FOXO3a and AMPK-PGC-1α signaling pathways ameliorated oxidative stress and mitochondrial dysfunction. Our results suggest that activation of PPARα and AMPK-SIRT1 signaling may have protective effects against age-related renal injury. Pharmacological targeting of PPARα and AMPK-SIRT1 signaling molecules may prevent or attenuate age-related pathological changes in the kidney. PMID:27130813

  8. Radiofrequency attenuator and method

    Science.gov (United States)

    Warner, Benjamin P.; McCleskey, T. Mark; Burrell, Anthony K.; Agrawal, Anoop; Hall, Simon B.

    2009-11-10

    Radiofrequency attenuator and method. The attenuator includes a pair of transparent windows. A chamber between the windows is filled with molten salt. Preferred molten salts include quarternary ammonium cations and fluorine-containing anions such as tetrafluoroborate (BF.sub.4.sup.-), hexafluorophosphate (PF.sub.6.sup.-), hexafluoroarsenate (AsF.sub.6.sup.-), trifluoromethylsulfonate (CF.sub.3SO.sub.3.sup.-), bis(trifluoromethylsulfonyl)imide ((CF.sub.3SO.sub.2).sub.2N.sup.-), bis(perfluoroethylsulfonyl)imide ((CF.sub.3CF.sub.2SO.sub.2).sub.2N.sup.-) and tris(trifluoromethylsulfonyl)methide ((CF.sub.3SO.sub.2).sub.3 C.sup.-). Radicals or radical cations may be added to or electrochemically generated in the molten salt to enhance the RF attenuation.

  9. Pressure surge attenuator

    International Nuclear Information System (INIS)

    A pressure surge attenuation arrangement comprises crushable metal foam disposed adjacent regions adapted to be expanded by a pressure surge. In a pipe system such region consists of a thin walled inner pipe surrounded by a housing with crushable metal foam disposed in the space between the housing and the inner pipe. (author)

  10. Tritium Attenuation by Distillation

    International Nuclear Information System (INIS)

    The objective of this study was to determine how a 100 Area distillation system could be used to reduce to a satisfactory low value the tritium content of the dilute moderator produced in the 100 Area stills, and whether such a tritium attenuator would have sufficient capacity to process all this material before it is sent to the 400 Area for reprocessing

  11. Natural attenuation of herbicides

    DEFF Research Database (Denmark)

    Tuxen, Nina; Højberg, Anker Lajer; Broholm, Mette Martina;

    2002-01-01

    A field injection experiment in a sandy, aerobic aquifer showed that two phenoxy acids MCPP (mecoprop) and dichlorprop were degraded within I in downgradient of the injection wells after an apparent lag period. The plume development and microbial measurements indicated that microbial growth gover...... observations may be important for application of natural attenuation as a remedy in field scale systems....

  12. GLP-1 agonists for type 2 diabetes

    DEFF Research Database (Denmark)

    Jespersen, Maria J; Knop, Filip K; Christensen, Mikkel

    2013-01-01

    Within recent years, glucagon-like peptide 1 receptor agonists (GLP-1-RA) have emerged as a new treatment option for type 2 diabetes. The GLP-1-RA are administered subcutaneously and differ substantially in pharmacokinetic profiles. AREAS COVERED: This review describes the pharmacokinetics and...... safety aspects of the currently available GLP-1 receptor agonists, liraglutide (based on the structure of native GLP-1), exenatide twice daily and exenatide once weekly (based on exendin-4) in relation to the kinetics and toxicology of native GLP-1. The review is based on electronic literature searches...... and legal documents in the form of assessment reports from the European Medicines Agency and the United States Food and Drug Administration. EXPERT OPINION: GLP-1-based therapy combines several unique mechanisms of action and have the potential to gain widespread use in the fight against diabetes and...

  13. Perspectives for design of selective muscarinic agonists

    Czech Academy of Sciences Publication Activity Database

    Jakubík, Jan; Doležal, Vladimír; El-Fakahany, E. E.; Janíčková, Helena; Randáková, Alena; Šantrůčková, Eva

    Vol. 1. Martin: Jessenius Faculty of Medicine, 2011 - (Babušiková, E.; Dobrota, D.; Lehotský, J.), s. 154-168 ISBN 978-80-88866-99-2 R&D Projects: GA ČR(CZ) GA305/09/0681; GA AV ČR(CZ) IAA500110703; GA MŠk(CZ) LC554 Institutional research plan: CEZ:AV0Z50110509 Keywords : muscarinic acetylcholine receptor agonists * Alzheimer's disease * schizophrenia Subject RIV: FH - Neurology

  14. Response of Macroprolactinemia to Dopamine Agonists

    Directory of Open Access Journals (Sweden)

    Gonca Tamer

    2008-01-01

    Full Text Available Macroprolactinemia, defined as hyperprolactinemia with a predominance of the big big prolactin (macroprolactin isoform, is considered idiopathic and poorly symptomatic. Although macroprolactinemia has been considered to be a cause of apparent resistance to antiprolactinemic drugs, prolactin (PRL normalization with dopaminergic treatment cannot exclude macroprolactinemia.We report three cases with macroprolactinemia, whose PRL and macroprolactin levels were decreased and hyperprolactinemic symptoms were improved with dopamine agonists. Turk Jem 2008; 12: 83-5

  15. Signal Use by Octopuses in Agonistic Interactions.

    Science.gov (United States)

    Scheel, David; Godfrey-Smith, Peter; Lawrence, Matthew

    2016-02-01

    Cephalopods show behavioral parallels to birds and mammals despite considerable evolutionary distance [1, 2]. Many cephalopods produce complex body patterns and visual signals, documented especially in cuttlefish and squid, where they are used both in camouflage and a range of interspecific interactions [1, 3-5]. Octopuses, in contrast, are usually seen as solitary and asocial [6, 7]; their body patterns and color changes have primarily been interpreted as camouflage and anti-predator tactics [8-12], though the familiar view of the solitary octopus faces a growing list of exceptions. Here, we show by field observation that in a shallow-water octopus, Octopus tetricus, a range of visible displays are produced during agonistic interactions, and these displays correlate with the outcome of those interactions. Interactions in which dark body color by an approaching octopus was matched by similar color in the reacting octopus were more likely to escalate to grappling. Darkness in an approaching octopus met by paler color in the reacting octopus accompanied retreat of the paler octopus. Octopuses also displayed on high ground and stood with spread web and elevated mantle, often producing these behaviors in combinations. This study is the first to document the systematic use of signals during agonistic interactions among octopuses. We show prima facie conformity of our results to an influential model of agonistic signaling [13]. These results suggest that interactions have a greater influence on octopus evolution than has been recognized and show the importance of convergent evolution in behavioral traits. PMID:26832440

  16. Obeticholic acid, a synthetic bile acid agonist of the farnesoid X receptor, attenuates experimental autoimmune encephalomyelitis

    OpenAIRE

    Peggy P. Ho; Steinman, Lawrence

    2016-01-01

    Bile acids bind to the nuclear hormone receptor, farnesoid X receptor (FXR). This bile acid–FXR interaction regulates bile acid synthesis, transport, and cholesterol metabolism. Recently, drugs targeting FXR activation have been reported to treat both liver and intestinal inflammatory diseases in both animal models and human clinical trials. Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease of the central nervous system and serves as an animal model for ...

  17. A compact rotary vane attenuator

    Science.gov (United States)

    Nixon, D. L.; Otosh, T. Y.; Stelzried, C. T.

    1969-01-01

    Rotary vane attenuator, when used as a front end attenuator, introduces an insertion loss that is proportional to the angle of rotation. New technique allows the construction of a shortened compact unit suitable for most installations.

  18. Photon attenuation by intensifying screens

    International Nuclear Information System (INIS)

    The photon attenuation by intensifying screens of different chemical composition has been determined. The attenuation of photons between 20 keV and 120 keV was measured by use of a multi-channel analyzer and a broad bremsstrahlung distribution. The attenuation by the intensifying screens was hereby determined simultaneously at many different monoenergetic photon energies. Experimentally determined attenuations were found to agree well with attenuation calculated from mass attenuation coefficients. The attenuation by the screens was also determined at various bremsstrahlung distributions, simulating those occurring behind the patient in various diagnostic X-ray examinations. The high attenuation in some of the intensifying screens form the basis for an analysis of the construction of asymmetric screen pairs. Single screen systems are suggested as a favourable alternative to thick screen pair systems. (Author)

  19. Collybolide is a novel biased agonist of κ-opioid receptors with potent antipruritic activity.

    Science.gov (United States)

    Gupta, Achla; Gomes, Ivone; Bobeck, Erin N; Fakira, Amanda K; Massaro, Nicholas P; Sharma, Indrajeet; Cavé, Adrien; Hamm, Heidi E; Parello, Joseph; Devi, Lakshmi A

    2016-05-24

    Among the opioid receptors, the κ-opioid receptor (κOR) has been gaining considerable attention as a potential therapeutic target for the treatment of complex CNS disorders including depression, visceral pain, and cocaine addiction. With an interest in discovering novel ligands targeting κOR, we searched natural products for unusual scaffolds and identified collybolide (Colly), a nonnitrogenous sesquiterpene from the mushroom Collybia maculata. This compound has a furyl-δ-lactone core similar to that of Salvinorin A (Sal A), another natural product from the plant Salvia divinorum Characterization of the molecular pharmacological properties reveals that Colly, like Sal A, is a highly potent and selective κOR agonist. However, the two compounds differ in certain signaling and behavioral properties. Colly exhibits 10- to 50-fold higher potency in activating the mitogen-activated protein kinase pathway compared with Sal A. Taken with the fact that the two compounds are equipotent for inhibiting adenylyl cyclase activity, these results suggest that Colly behaves as a biased agonist of κOR. Behavioral studies also support the biased agonistic activity of Colly in that it exhibits ∼10-fold higher potency in blocking non-histamine-mediated itch compared with Sal A, and this difference is not seen in pain attenuation by these two compounds. These results represent a rare example of functional selectivity by two natural products that act on the same receptor. The biased agonistic activity, along with an easily modifiable structure compared with Sal A, makes Colly an ideal candidate for the development of novel therapeutics targeting κOR with reduced side effects. PMID:27162327

  20. Pyrvinium attenuates Hedgehog signaling downstream of smoothened.

    Science.gov (United States)

    Li, Bin; Fei, Dennis Liang; Flaveny, Colin A; Dahmane, Nadia; Baubet, Valérie; Wang, Zhiqiang; Bai, Feng; Pei, Xin-Hai; Rodriguez-Blanco, Jezabel; Hang, Brian; Orton, Darren; Han, Lu; Wang, Baolin; Capobianco, Anthony J; Lee, Ethan; Robbins, David J

    2014-09-01

    The Hedgehog (HH) signaling pathway represents an important class of emerging developmental signaling pathways that play critical roles in the genesis of a large number of human cancers. The pharmaceutical industry is currently focused on developing small molecules targeting Smoothened (Smo), a key signaling effector of the HH pathway that regulates the levels and activity of the Gli family of transcription factors. Although one of these compounds, vismodegib, is now FDA-approved for patients with advanced basal cell carcinoma, acquired mutations in Smo can result in rapid relapse. Furthermore, many cancers also exhibit a Smo-independent activation of Gli proteins, an observation that may underlie the limited efficacy of Smo inhibitors in clinical trials against other types of cancer. Thus, there remains a critical need for HH inhibitors with different mechanisms of action, particularly those that act downstream of Smo. Recently, we identified the FDA-approved anti-pinworm compound pyrvinium as a novel, potent (IC50, 10 nmol/L) casein kinase-1α (CK1α) agonist. We show here that pyrvinium is a potent inhibitor of HH signaling, which acts by reducing the stability of the Gli family of transcription factors. Consistent with CK1α agonists acting on these most distal components of the HH signaling pathway, pyrvinium is able to inhibit the activity of a clinically relevant, vismodegib -resistant Smo mutant, as well as the Gli activity resulting from loss of the negative regulator suppressor of fused. We go on to demonstrate the utility of this small molecule in vivo, against the HH-dependent cancer medulloblastoma, attenuating its growth and reducing the expression of HH biomarkers. PMID:24994715

  1. Menthol attenuates respiratory irritation responses to multiple cigarette smoke irritants.

    Science.gov (United States)

    Willis, Daniel N; Liu, Boyi; Ha, Michael A; Jordt, Sven-Eric; Morris, John B

    2011-12-01

    Menthol, the cooling agent in peppermint, is added to almost all commercially available cigarettes. Menthol stimulates olfactory sensations, and interacts with transient receptor potential melastatin 8 (TRPM8) ion channels in cold-sensitive sensory neurons, and transient receptor potential ankyrin 1 (TRPA1), an irritant-sensing channel. It is highly controversial whether menthol in cigarette smoke exerts pharmacological actions affecting smoking behavior. Using plethysmography, we investigated the effects of menthol on the respiratory sensory irritation response in mice elicited by smoke irritants (acrolein, acetic acid, and cyclohexanone). Menthol, at a concentration (16 ppm) lower than in smoke of mentholated cigarettes, immediately abolished the irritation response to acrolein, an agonist of TRPA1, as did eucalyptol (460 ppm), another TRPM8 agonist. Menthol's effects were reversed by a TRPM8 antagonist, AMTB. Menthol's effects were not specific to acrolein, as menthol also attenuated irritation responses to acetic acid, and cyclohexanone, an agonist of the capsaicin receptor, TRPV1. Menthol was efficiently absorbed in the respiratory tract, reaching local concentrations sufficient for activation of sensory TRP channels. These experiments demonstrate that menthol and eucalyptol, through activation of TRPM8, act as potent counterirritants against a broad spectrum of smoke constituents. Through suppression of respiratory irritation, menthol may facilitate smoke inhalation and promote nicotine addiction and smoking-related morbidities. PMID:21903934

  2. Downhole pressure attenuation apparatus

    International Nuclear Information System (INIS)

    This patent describes a process for preventing damage to tool strings and other downhole equipment in a well caused by pressures produced during detonation of one or more downhole explosive devices. It comprises adding to a tool string at least one pressure attenuating apparatus for attenuating the peak pressure wave and quasi-static pressure pulse produced by the explosive devices, the pressure attenuating apparatus including an initially closed relief vent including tubing means supporting a plurality of charge port assemblies each including an explosive filled shaped charge and a prestressed disc, the shaped charges interconnected by a detonating cord, the amount of explosive in each shaped charge being sufficient to rupture its associated disc without damaging surrounding tubular bodies in the well, and a vent chamber defined by the tubing means and providing a liquid free volume, and opening the relief vent substantially contemporaneously with downhole explosive device detonation by detonating the shaped charges to rupture the discs of the charge port assemblies

  3. Control algorithms for dynamic attenuators

    Energy Technology Data Exchange (ETDEWEB)

    Hsieh, Scott S., E-mail: sshsieh@stanford.edu [Department of Radiology, Stanford University, Stanford, California 94305 and Department of Electrical Engineering, Stanford University, Stanford, California 94305 (United States); Pelc, Norbert J. [Department of Radiology, Stanford University, Stanford California 94305 and Department of Bioengineering, Stanford University, Stanford, California 94305 (United States)

    2014-06-15

    Purpose: The authors describe algorithms to control dynamic attenuators in CT and compare their performance using simulated scans. Dynamic attenuators are prepatient beam shaping filters that modulate the distribution of x-ray fluence incident on the patient on a view-by-view basis. These attenuators can reduce dose while improving key image quality metrics such as peak or mean variance. In each view, the attenuator presents several degrees of freedom which may be individually adjusted. The total number of degrees of freedom across all views is very large, making many optimization techniques impractical. The authors develop a theory for optimally controlling these attenuators. Special attention is paid to a theoretically perfect attenuator which controls the fluence for each ray individually, but the authors also investigate and compare three other, practical attenuator designs which have been previously proposed: the piecewise-linear attenuator, the translating attenuator, and the double wedge attenuator. Methods: The authors pose and solve the optimization problems of minimizing the mean and peak variance subject to a fixed dose limit. For a perfect attenuator and mean variance minimization, this problem can be solved in simple, closed form. For other attenuator designs, the problem can be decomposed into separate problems for each view to greatly reduce the computational complexity. Peak variance minimization can be approximately solved using iterated, weighted mean variance (WMV) minimization. Also, the authors develop heuristics for the perfect and piecewise-linear attenuators which do not requirea priori knowledge of the patient anatomy. The authors compare these control algorithms on different types of dynamic attenuators using simulated raw data from forward projected DICOM files of a thorax and an abdomen. Results: The translating and double wedge attenuators reduce dose by an average of 30% relative to current techniques (bowtie filter with tube current

  4. Flexible graphene based microwave attenuators.

    Science.gov (United States)

    Byun, Kisik; Ju Park, Yong; Ahn, Jong-Hyun; Min, Byung-Wook

    2015-02-01

    We demonstrate flexible 3 dB and 6 dB microwave attenuators using multilayer graphene grown by the chemical vapor deposition method. On the basis of the characterized results of multilayer graphene and graphene-Au ohmic contacts, the graphene attenuators are designed and measured. The flexible graphene-based attenuators have 3 dB and 6 dB attenuation with a return loss of less than -15 dB at higher than 5 GHz. The devices have shown durability in a bending cycling test of 100 times. The circuit model of the attenuator based on the characterized results matches the experimental results well. PMID:25590144

  5. Flexible graphene based microwave attenuators

    International Nuclear Information System (INIS)

    We demonstrate flexible 3 dB and 6 dB microwave attenuators using multilayer graphene grown by the chemical vapor deposition method. On the basis of the characterized results of multilayer graphene and graphene–Au ohmic contacts, the graphene attenuators are designed and measured. The flexible graphene-based attenuators have 3 dB and 6 dB attenuation with a return loss of less than −15 dB at higher than 5 GHz. The devices have shown durability in a bending cycling test of 100 times. The circuit model of the attenuator based on the characterized results matches the experimental results well. (paper)

  6. Subtype selective kainic acid receptor agonists

    DEFF Research Database (Denmark)

    Bunch, Lennart; Krogsgaard-Larsen, Povl

    2009-01-01

    (S)-Glutamic acid (Glu) is the major excitatory neurotransmitter in the mammalian central nervous system, activating the plethora of glutamate receptors (GluRs). In broad lines, the GluRs are divided into two major classes: the ionotropic Glu receptors (iGluRs) and the metabotropic Glu receptors ....... In total, over 100 compounds are described by means of chemical structure and available pharmacological data. With this perspective review, it is our intention to ignite and stimulate inspiration for future design and synthesis of novel subtype selective KA receptor agonists....

  7. Hepatic Aryl Hydrocarbon Receptor Attenuates Fibroblast Growth Factor 21 Expression.

    Science.gov (United States)

    Girer, Nathaniel G; Murray, Iain A; Omiecinski, Curtis J; Perdew, Gary H

    2016-07-15

    The Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor involved in many physiological processes. Several studies indicate that AHR is also involved in energy homeostasis. Fibroblast growth factor 21 (FGF21) is an important regulator of the fasting and feeding responses. When administered to various genetic and diet-induced mouse models of obesity, FGF21 can attenuate obesity-associated morbidities. Here, we explore the role of AHR in hepatic Fgf21 expression through the use of a conditional, hepatocyte-targeted AHR knock-out mouse model (Cre(Alb)Ahr(Fx/Fx)). Compared with the congenic parental strain (Ahr(Fx/Fx)), non-fasted Cre(Alb)Ahr(Fx/Fx) mice exhibit a 4-fold increase in hepatic Fgf21 expression, as well as elevated expression of the FGF21-target gene Igfbp1 Furthermore, in vivo agonist activation of AHR reduces hepatic Fgf21 expression during a fast. The Fgf21 promoter contains several putative dioxin response elements (DREs). Using EMSA, we demonstrate that the AHR-ARNT heterodimer binds to a specific DRE that overlaps binding sequences for peroxisome proliferator-activated receptor α (PPARα), carbohydrate response element-binding protein (ChREBP), and cAMP response element-binding protein, hepatocyte specific (CREBH). In addition, we reveal that agonist-activated AHR impairs PPARα-, ChREBP-, and CREBH-mediated promoter activity in Hepa-1 cells. Accordingly, agonist treatment in Hepa-1 cells ablates potent ER stress-driven Fgf21 expression, and pre-treatment with AHR antagonist blocks this effect. Finally, we show that pre-treatment of primary human hepatocytes with AHR agonist diminishes PPARα-, glucose-, and ER stress-driven induction of FGF21 expression, indicating the effect is not mouse-specific. Together, our data show that AHR contributes to hepatic energy homeostasis, partly through the regulation of FGF21 expression and signaling. PMID:27226639

  8. Activation of farnesoid X receptor attenuates hepatic injury in a murine model of alcoholic liver disease

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Weibin [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Institutes of Biomedical Science, Fudan University, Shanghai 200032 (China); Zhu, Bo; Peng, Xiaomin [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Zhou, Meiling, E-mail: meilingzhou2012@gmail.com [Department of Radiology, Zhongshan Hospital of Fudan University and Shanghai Institute of Medical Imaging, Shanghai 200032 (China); Jia, Dongwei, E-mail: jiadongwei@fudan.edu.cn [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Gu, Jianxin [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Institutes of Biomedical Science, Fudan University, Shanghai 200032 (China)

    2014-01-03

    Highlights: •FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. •Activation of FXR attenuated alcohol-induced liver injury and steatosis. •Activation of FXR attenuated cholestasis and oxidative stress in mouse liver. -- Abstract: Alcoholic liver disease (ALD) is a common cause of advanced liver disease, and considered as a major risk factor of morbidity and mortality worldwide. Hepatic cholestasis is a pathophysiological feature observed in all stages of ALD. The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily, and plays an essential role in the regulation of bile acid, lipid and glucose homeostasis. However, the role of FXR in the pathogenesis and progression of ALD remains largely unknown. Mice were fed Lieber-DeCarli ethanol diet or an isocaloric control diet. We used a specific agonist of FXR WAY-362450 to study the effect of pharmacological activation of FXR in alcoholic liver disease. In this study, we demonstrated that FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. Activation of FXR by specific agonist WAY-362450 protected mice from the development of ALD. We also found that WAY-362450 treatment rescued FXR activity, suppressed ethanol-induced Cyp2e1 up-regulation and attenuated oxidative stress in liver. Our results highlight a key role of FXR in the modulation of ALD development, and propose specific FXR agonists for the treatment of ALD patients.

  9. Activation of farnesoid X receptor attenuates hepatic injury in a murine model of alcoholic liver disease

    International Nuclear Information System (INIS)

    Highlights: •FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. •Activation of FXR attenuated alcohol-induced liver injury and steatosis. •Activation of FXR attenuated cholestasis and oxidative stress in mouse liver. -- Abstract: Alcoholic liver disease (ALD) is a common cause of advanced liver disease, and considered as a major risk factor of morbidity and mortality worldwide. Hepatic cholestasis is a pathophysiological feature observed in all stages of ALD. The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily, and plays an essential role in the regulation of bile acid, lipid and glucose homeostasis. However, the role of FXR in the pathogenesis and progression of ALD remains largely unknown. Mice were fed Lieber-DeCarli ethanol diet or an isocaloric control diet. We used a specific agonist of FXR WAY-362450 to study the effect of pharmacological activation of FXR in alcoholic liver disease. In this study, we demonstrated that FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. Activation of FXR by specific agonist WAY-362450 protected mice from the development of ALD. We also found that WAY-362450 treatment rescued FXR activity, suppressed ethanol-induced Cyp2e1 up-regulation and attenuated oxidative stress in liver. Our results highlight a key role of FXR in the modulation of ALD development, and propose specific FXR agonists for the treatment of ALD patients

  10. Pretreatment with adenosine and adenosine A1 receptor agonist protects against intestinal ischemia-reperfusion injury in rat

    Institute of Scientific and Technical Information of China (English)

    V Haktan Ozacmak; Hale Sayan

    2007-01-01

    AIM: To examine the effects of adenosine and A1 receptor activation on reperfusion-induced small intestinal injury.METHODS: Rats were randomized into groups with sham operation, ischemia and reperfusion, and systemic treatments with either adenosine or 2-chloro-N6-cyclopentyladenosine, A1 receptor agonist or 8-cyclopentyl-1,3-dipropylxanthine, A1 receptor antagonist, plus adenosine before ischemia. Following reperfusion, contractions of ileum segments in response to KCl, carbachol and substance P were recorded. Tissue myeloperoxidase,malondialdehyde, and reduced glutathione levels were measured.RESULTS: Ischemia significantly decreased both contraction and reduced glutathione level which were ameliorated by adenosine and agonist administration. Treatment also decreased neutrophil infiltration and membrane lipid peroxidation. Beneficial effects of adenosine were abolished by pretreatment with A1 receptor antagonist.CONCLUSION: The data suggest that adenosine and A1 receptor stimulation attenuate ischemic intestinal injury via decreasing oxidative stress, lowering neutrophil infiltration, and increasing reduced glutathione content.

  11. Strategies for designing synthetic immune agonists.

    Science.gov (United States)

    Wu, Tom Y-H

    2016-08-01

    Enhancing the immune system is a validated strategy to combat infectious disease, cancer and allergy. Nevertheless, the development of immune adjuvants has been hampered by safety concerns. Agents that can stimulate the immune system often bear structural similarities with pathogen-associated molecular patterns found in bacteria or viruses and are recognized by pattern recognition receptors (PRRs). Activation of these PRRs results in the immediate release of inflammatory cytokines, up-regulation of co-stimulatory molecules, and recruitment of innate immune cells. The distribution and duration of these early inflammatory events are crucial in the development of antigen-specific adaptive immunity in the forms of antibody and/or T cells capable of searching for and destroying the infectious pathogens or cancer cells. However, systemic activation of these PRRs is often poorly tolerated. Hence, different strategies have been employed to modify or deliver immune agonists in an attempt to control the early innate receptor activation through temporal or spatial restriction. These approaches include physicochemical manipulation, covalent conjugation, formulation and conditional activation/deactivation. This review will describe recent examples of discovery and optimization of synthetic immune agonists towards clinical application. PMID:27213842

  12. Inhibition of receptor tyrosine kinase signalling by small molecule agonist of T-cell protein tyrosine phosphatase

    Directory of Open Access Journals (Sweden)

    Tähtinen Siri

    2010-01-01

    Full Text Available Abstract Background T-cell protein tyrosine phosphatase (TCPTP/TC45 is a ubiquitously expressed intra-cellular non-receptor protein tyrosine phosphatase involved in the negative regulation of several cancer relevant cellular signalling pathways. We have previously shown that interaction between the α-cytoplasmic tail of α1β1 integrin and TCPTP activates TCPTP by disrupting an inhibitory intra-molecular bond in TCPTP. Thus, inhibition of the regulatory interaction in TCPTP is a desirable strategy for TCPTP activation and attenuation of oncogenic RTK signalling. However, this is challenging with low molecular weight compounds. Methods We developed a high-throughput compatible assay to analyse activity of recombinant TCPTP in vitro. Using this assay we have screened 64280 small molecules to identify novel agonists for TCPTP. Dose-dependent response to TCPTP agonist was performed using the in vitro assay. Inhibition effects and specificity of TCPTP agonists were evaluated using TCPTP expressing and null mouse embryonic fibroblasts. Western blot analysis was used to evaluate attenuation of PDGFRβ and EGFR phosphorylation. Inhibition of VEGF signalling was analysed with VEGF-induced endothelial cell sprouting assays. Results From the screen we identified six TCPTP agonists. Two compounds competed with α1-cytoplasmic domain for binding to TCPTP, suggesting that they activate TCPTP similar to α1-cyt by disrupting the intra-molecular bond in TCPTP. Importantly, one of the compounds (spermidine displayed specificity towards TCPTP in cells, since TCPTP -/- cells were 43-fold more resistant to the compound than TCPTP expressing cells. This compound attenuates PDGFRβ and VEGFR2 signalling in cells in a TCPTP-dependent manner and functions as a negative regulator of EGFR phosphorylation in cancer cells. Conclusions In this study we showed that small molecules mimicking TCPTP-α1 interaction can be used as TCPTP agonists. These data provide the first

  13. Ultrasonic Attenuation in Zircaloy-4

    International Nuclear Information System (INIS)

    In this work the relationship between Zircaloy-4 grain size and ultrasonic attenuation behavior was studied for longitudinal waves in the frequency range of 10-90 MHz. The attenuation was analyzed as a function of frequency for samples with different mechanical and heat treatments having recrystallized and Widmanstatten structures with different grain size. The attenuation behavior was analyzed by different scattering models, depending on grain size, wavelength and frequency

  14. Chopping-Wheel Optical Attenuator

    Science.gov (United States)

    Leviton, Douglas B.

    1988-01-01

    Star-shaped rotating chopping wheel provides adjustable time-averaged attenuation of narrow beam of light without changing length of optical path or spectral distribution of light. Duty cycle or attenuation factor of chopped beam controlled by adjusting radius at which beam intersects wheel. Attenuation factor independent of wavelength. Useful in systems in which chopping frequency above frequency-response limits of photodetectors receiving chopped light. Used in systems using synchronous detection with lock-in amplifiers.

  15. LINE-ABOVE-GROUND ATTENUATOR

    Science.gov (United States)

    Wilds, R.B.; Ames, J.R.

    1957-09-24

    The line-above-ground attenuator provides a continuously variable microwave attenuator for a coaxial line that is capable of high attenuation and low insertion loss. The device consists of a short section of the line-above- ground plane type transmission lime, a pair of identical rectangular slabs of lossy material like polytron, whose longitudinal axes are parallel to and indentically spaced away from either side of the line, and a geared mechanism to adjust amd maintain this spaced relationship. This device permits optimum fineness and accuracy of attenuator control which heretofore has been difficult to achieve.

  16. Unique interaction pattern for a functionally biased ghrelin receptor agonist

    DEFF Research Database (Denmark)

    Sivertsen, Bjørn Behrens; Lang, Manja; Frimurer, Thomas M.;

    2011-01-01

    Based on the conformationally constrained D-Trp-Phe-D-Trp (wFw) core of the prototype inverse agonist [D-Arg(1),D-Phe(5),D-Trp(7,9),Leu(11)]substance P, a series of novel, small, peptide-mimetic agonists for the ghrelin receptor were generated. By using various simple, ring-constrained spacers co...

  17. Highly Potent, Chemically Stable Quorum Sensing Agonists for Vibrio Cholerae

    OpenAIRE

    Perez, Lark J; Karagounis, Theodora K.; Hurley, Amanda; Bassler, Bonnie L.; Semmelhack, Martin F.

    2013-01-01

    In the Vibrio cholerae pathogen, initiation of bacterial quorum sensing pathways serves to suppress virulence. We describe herein a potent and chemically stable small molecule agonist of V. cholerae quorum sensing, which was identified through rational drug design based on the native quorum sensing signal. This novel agonist may serve as a useful lead compound for the control of virulence in V. cholerae.

  18. Adverse effects of beta-agonists: are they clinically relevant?

    Science.gov (United States)

    Abramson, Michael J; Walters, Julia; Walters, E Haydn

    2003-01-01

    Inhaled beta(2)-adrenoceptor agonists (beta(2)-agonists) are the most commonly used asthma medications in many Western countries. Minor adverse effects such as palpitations, tremor, headache and metabolic effects are predictable and dose related. Time series studies suggested an association between the relatively nonselective beta-agonist fenoterol and asthma deaths. Three case-control studies confirmed that among patients prescribed fenoterol, the risk of death was significantly elevated even after controlling for the severity of asthma. The Saskatchewan study not only found an increased risk of death among patients dispensed fenoterol, but also suggested this might be a class effect of beta(2)-agonists. However, in subsequent studies, the long-acting beta(2)-agonist salmeterol was not associated with increased asthma mortality. In a case-control study blood albuterol (salbutamol) concentrations were found to be 2.5 times higher among patients who died of asthma compared with controls. It is speculated that such toxic concentrations could cause tachyarrhythmias under conditions of hypoxia and hypokalemia. The risk of asthma exacerbations and near-fatal attacks may also be increased among patients dispensed fenoterol, but this association may be largely due to confounding by severity. Although salmeterol does not appear to increase the risk of near-fatal attacks, there is a consistent association with the use of nebulized beta(2)-agonists. Nebulized and oral beta(2)-agonists are also associated with an increased risk of cardiovascular death, ischemic heart disease and cardiac failure. Caution should be exercised when first prescribing a beta-agonist for patients with cardiovascular disease. A potential mechanism for adverse effects with regular use of beta(2)-agonists is tachyphylaxis. Tachyphylaxis to the bronchodilator effects of long-acting beta(2)-agonists can occur, but has been consistently demonstrated only for formoterol (eformoterol) a full agonist, rather

  19. Fiber optic attenuator

    Science.gov (United States)

    Buzzetti, Mike F. (Inventor)

    1994-01-01

    A fiber optic attenuator of the invention is a mandrel structure through which a bundle of optical fibers is wrapped around in a complete circle. The mandrel structure includes a flexible cylindrical sheath through which the bundle passes. A set screw on the mandrel structure impacts one side of the sheath against two posts on the opposite side of the sheath. By rotating the screw, the sheath is deformed to extend partially between the two posts, bending the fiber optic bundle to a small radius controlled by rotating the set screw. Bending the fiber optic bundle to a small radius causes light in each optical fiber to be lost in the cladding, the amount depending upon the radius about which the bundle is bent.

  20. Overlapping binding site for the endogenous agonist, small-molecule agonists, and ago-allosteric modulators on the ghrelin receptor

    DEFF Research Database (Denmark)

    Holst, Birgitte; Frimurer, Thomas M; Mokrosinski, Jacek;

    2008-01-01

    mutational map for agonism but it was not identical with the map for the agonist property of these small-molecule ligands. In molecular models, built over the inactive conformation of rhodopsin, low energy conformations of the nonpeptide agonists could be docked to satisfy many of their mutational hits. It...

  1. Cannabinoid agonists rearrange synaptic vesicles at excitatory synapses and depress motoneuron activity in vivo.

    Science.gov (United States)

    García-Morales, Victoria; Montero, Fernando; Moreno-López, Bernardo

    2015-05-01

    Impairment of motor skills is one of the most common acute adverse effects of cannabis. Related studies have focused mainly on psychomotor alterations, and little is known about the direct impact of cannabinoids (CBs) on motoneuron physiology. As key modulators of synaptic function, CBs regulate multiple neuronal functions and behaviors. Presynaptic CB1 mediates synaptic strength depression by inhibiting neurotransmitter release, via a poorly understood mechanism. The present study examined the effect of CB agonists on excitatory synaptic inputs incoming to hypoglossal motoneurons (HMNs) in vitro and in vivo. The endocannabinoid anandamide (AEA) and the synthetic CB agonist WIN 55,212-2 rapidly and reversibly induced short-term depression (STD) of glutamatergic synapses on motoneurons by a presynaptic mechanism. Presynaptic effects were fully reversed by the CB1-selective antagonist AM281. Electrophysiological and electron microscopy analysis showed that WIN 55,212-2 reduced the number of synaptic vesicles (SVs) docked to active zones in excitatory boutons. Given that AM281 fully abolished depolarization-induced depression of excitation, motoneurons can be feasible sources of CBs, which in turn act as retrograde messengers regulating synaptic function. Finally, microiontophoretic application of the CB agonist O-2545 reversibly depressed, presumably via CB1, glutamatergic inspiratory-related activity of HMNs in vivo. Therefore, evidence support that CBs, via presynaptic CB1, induce excitatory STD by reducing the readily releasable pool of SVs at excitatory synapses, then attenuating motoneuron activity. These outcomes contribute a possible mechanistic basis for cannabis-associated motor performance disturbances such as ataxia, dysarthria and dyscoordination. PMID:25595101

  2. Therapeutic Potentials and uses of Cannabinoid Agonists in Health and Disease Conditions

    Directory of Open Access Journals (Sweden)

    A.O. Ibegbu

    2012-04-01

    Full Text Available Cannabis and its derivatives have great therapeutic potential and have been used for centuries for medicinal purposes. The side effects of cannabinoids include euphoric mood changes, acute psychotic episodes, initiation and exacerbation of schizophrenic psychosis in predisposed persons, impaired cognitive and psychomotor performance, tachycardia and hypotension. The production of complex behavioural effects by cannabinoids are mediated by cannabinoid receptors (CB1 and CB2 and by interactions with other neurochemical systems. It has been shown that the therapeutic and physiological effects of cannabinoids are dependent upon whether the administration is acute or chronic and on the route of administration. The physiological effects of cannabis and its derivatives include: reduction in psychomotor coordination and performance, alterations in thermoregulation, endocrine and reproductive functions and gut motility. There is also evidence of agonist selectivity for CB1 receptors coupled to different subtypes of Gi proteins or to Gi versus Go proteins. Cannabinoid-activated receptors distinct from CB1 or CB2 exist in the central nervous system. Cannabinoids are known to inhibit GABA-mediated inhibitory postsynaptic currents in the hippocampus via a presynaptic action at CB1 receptors located on GABAergic terminals. CB1 receptors have also been implicated in the inhibition of glutamatergic excitatory postsynaptic currents. The synthetic cannabinoid, Win 55,212-2, a mixed CB1-CB2 cannabinoid receptor agonist, was found to attenuate hyperalgesia in a rat model of neuropathic pain and suppress opioid-induced emesis in ferrets.

  3. PPAR-γ agonist protects against intestinal injury during necrotizing enterocolitis

    International Nuclear Information System (INIS)

    Necrotizing enterocolitis (NEC) remains a lethal condition for many premature infants. Peroxisome proliferator-activated receptor-γ (PPAR-γ), a member of the nuclear hormone receptor family, has been shown to play a protective role in cellular inflammatory responses; however, its role in NEC is not clearly defined. We sought to examine the expression of PPAR-γ in the intestine using an ischemia-reperfusion (I/R) model of NEC, and to assess whether PPAR-γ agonist treatment would ameliorate I/R-induced gut injury. Swiss-Webster mice were randomized to receive sham (control) or I/R injury to the gut induced by transient occlusion of superior mesenteric artery for 45 min with variable periods of reperfusion. I/R injury resulted in early induction of PPAR-γ expression and activation of NF-κB in small intestine. Pretreatment with PPAR-γ agonist, 15d-PGJ2, attenuated intestinal NF-κB response and I/R-induced gut injury. Activation of PPAR-γ demonstrated a protective effect on small bowel during I/R-induced gut injury.

  4. Adjustable Optical-Fiber Attenuator

    Science.gov (United States)

    Buzzetti, Mike F.

    1994-01-01

    Adjustable fiber-optic attenuator utilizes bending loss to reduce strength of light transmitted along it. Attenuator functions without introducing measurable back-reflection or insertion loss. Relatively insensitive to vibration and changes in temperature. Potential applications include cable television, telephone networks, other signal-distribution networks, and laboratory instrumentation.

  5. Toll-like receptor 2 agonists inhibit human fibrocyte differentiation

    Directory of Open Access Journals (Sweden)

    Maharjan Anu S

    2010-11-01

    Full Text Available Abstract Background In healing wounds, some monocytes enter the wound and differentiate into fibroblast-like cells called fibrocytes. Since Toll-like receptors (TLRs are present on monocytes, and pathogens that can infect a wound have and/or release TLR agonists, we examined whether TLR agonists affect fibrocyte differentiation. Results When human peripheral blood mononuclear cells (PBMCs were cultured with TLR3, TLR4, TLR5, TLR7, TLR8 or TLR9 agonists, there was no significant effect on fibrocyte differentiation, even though enhanced extracellular tumor necrosis factor (TNF-α accumulation and/or increased cell surface CD86 or major histocompatibility complex (MHC class II levels were observed. However, all TLR2 agonists tested inhibited fibrocyte differentiation without any significant effect on cell survival. Adding TLR2 agonists to purified monocytes had no effect on fibrocyte differentiation. However, some TLR2 agonists caused PBMCs to secrete a factor that inhibits the differentiation of purified monocytes into fibrocytes. This factor is not interferon (IFN-α, IFN-γ, interleukin (IL-12, aggregated immunoglobulin G (IgG or serum amyloid P (SAP, factors known to inhibit fibrocyte differentiation. TLR2 agonist-treated PBMCs secrete low levels of IL-6, TNF-α, IFN-γ, granulocyte colony-stimulating factor and tumor growth factor β1, but combinations of these factors had no effect on fibrocyte differentiation from purified monocytes. Conclusions Our results indicate that TLR2 agonists indirectly inhibit fibrocyte differentiation and that, for some TLR2 agonists, this inhibition involves other cell types in the PBMC population secreting an unknown factor that inhibits fibrocyte differentiation. Together, these data suggest that the presence of some bacterial signals can inhibit fibrocyte differentiation and may thus slow wound closure.

  6. Dopamine agonist withdrawal syndrome: implications for patient care.

    Science.gov (United States)

    Nirenberg, Melissa J

    2013-08-01

    Dopamine agonists are effective treatments for a variety of indications, including Parkinson's disease and restless legs syndrome, but may have serious side effects, such as orthostatic hypotension, hallucinations, and impulse control disorders (including pathological gambling, compulsive eating, compulsive shopping/buying, and hypersexuality). The most effective way to alleviate these side effects is to taper or discontinue dopamine agonist therapy. A subset of patients who taper a dopamine agonist, however, develop dopamine agonist withdrawal syndrome (DAWS), which has been defined as a severe, stereotyped cluster of physical and psychological symptoms that correlate with dopamine agonist withdrawal in a dose-dependent manner, cause clinically significant distress or social/occupational dysfunction, are refractory to levodopa and other dopaminergic medications, and cannot be accounted for by other clinical factors. The symptoms of DAWS include anxiety, panic attacks, dysphoria, depression, agitation, irritability, suicidal ideation, fatigue, orthostatic hypotension, nausea, vomiting, diaphoresis, generalized pain, and drug cravings. The severity and prognosis of DAWS is highly variable. While some patients have transient symptoms and make a full recovery, others have a protracted withdrawal syndrome lasting for months to years, and therefore may be unwilling or unable to discontinue DA therapy. Impulse control disorders appear to be a major risk factor for DAWS, and are present in virtually all affected patients. Thus, patients who are unable to discontinue dopamine agonist therapy may experience chronic impulse control disorders. At the current time, there are no known effective treatments for DAWS. For this reason, providers are urged to use dopamine agonists judiciously, warn patients about the risks of DAWS prior to the initiation of dopamine agonist therapy, and follow patients closely for withdrawal symptoms during dopamine agonist taper. PMID:23686524

  7. GPR40 agonist ameliorates liver X receptor-induced lipid accumulation in liver by activating AMPK pathway.

    Science.gov (United States)

    Li, Meng; Meng, Xiangyu; Xu, Jie; Huang, Xiuqing; Li, Hongxia; Li, Guoping; Wang, Shu; Man, Yong; Tang, Weiqing; Li, Jian

    2016-01-01

    Hepatic steatosis is strongly linked to insulin resistance and type 2 diabetes. GPR40 is a G protein-coupled receptor mediating free fatty acid-induced insulin secretion and thus plays a beneficial role in the improvement of diabetes. However, the impact of GPR40 agonist on hepatic steatosis still remains to be elucidated. In the present study, we found that activation of GPR40 by its agonist GW9508 attenuated Liver X receptor (LXR)-induced hepatic lipid accumulation. Activation of LXR in the livers of C57BL/6 mice fed a high-cholesterol diet and in HepG2 cells stimulated by chemical agonist caused increased expression of its target lipogenic genes and subsequent lipid accumulation. All these effects of LXR were dramatically downregulated after GW9508 supplementation. Moreover, GPR40 activation was accompanied by upregulation of AMPK pathway, whereas the inhibitive effect of GPR40 on the lipogenic gene expression was largely abrogated by AMPK knockdown. Taken together, our results demonstrated that GW9508 exerts a beneficial effect to ameliorate LXR-induced hepatic steatosis through regulation of AMPK signaling pathway. PMID:27121981

  8. GPR40 agonist ameliorates liver X receptor-induced lipid accumulation in liver by activating AMPK pathway

    Science.gov (United States)

    Li, Meng; Meng, Xiangyu; Xu, Jie; Huang, Xiuqing; Li, Hongxia; Li, Guoping; Wang, Shu; Man, Yong; Tang, Weiqing; Li, Jian

    2016-01-01

    Hepatic steatosis is strongly linked to insulin resistance and type 2 diabetes. GPR40 is a G protein-coupled receptor mediating free fatty acid-induced insulin secretion and thus plays a beneficial role in the improvement of diabetes. However, the impact of GPR40 agonist on hepatic steatosis still remains to be elucidated. In the present study, we found that activation of GPR40 by its agonist GW9508 attenuated Liver X receptor (LXR)-induced hepatic lipid accumulation. Activation of LXR in the livers of C57BL/6 mice fed a high-cholesterol diet and in HepG2 cells stimulated by chemical agonist caused increased expression of its target lipogenic genes and subsequent lipid accumulation. All these effects of LXR were dramatically downregulated after GW9508 supplementation. Moreover, GPR40 activation was accompanied by upregulation of AMPK pathway, whereas the inhibitive effect of GPR40 on the lipogenic gene expression was largely abrogated by AMPK knockdown. Taken together, our results demonstrated that GW9508 exerts a beneficial effect to ameliorate LXR-induced hepatic steatosis through regulation of AMPK signaling pathway. PMID:27121981

  9. A dual TLR agonist adjuvant enhances the immunogenicity and protective efficacy of the tuberculosis vaccine antigen ID93.

    Directory of Open Access Journals (Sweden)

    Mark T Orr

    Full Text Available With over eight million cases of tuberculosis each year there is a pressing need for the development of new vaccines against Mycobacterium tuberculosis. Subunit vaccines consisting of recombinant proteins are an attractive vaccine approach due to their inherent safety compared to attenuated live vaccines and the uniformity of manufacture. Addition of properly formulated TLR agonist-containing adjuvants to recombinant protein vaccines enhances the antigen-specific CD4(+ T cell response characterized by IFN-γ and TNF, both of which are critical for the control of TB. We have developed a clinical stage vaccine candidate consisting of a recombinant fusion protein ID93 adjuvanted with the TLR4 agonist GLA-SE. Here we examine whether ID93+GLA-SE can be improved by the addition of a second TLR agonist. Addition of CpG containing DNA to ID93+GLA-SE enhanced the magnitude of the multi-functional TH1 response against ID93 characterized by co-production of IFN-γ, TNF, and IL-2. Addition of CpG also improved the protective efficacy of ID93+GLA-SE. Finally we demonstrate that this adjuvant synergy between GLA and CpG is independent of TRIF signaling, whereas TRIF is necessary for the adjuvant activity of GLA-SE in the absence of CpG.

  10. Seismic attenuation in fractured media

    International Nuclear Information System (INIS)

    The prime objective of this paper is to quantitatively estimate seismic attenuation caused by fractures with different physical parameters. In seismic wave simulation, the fractured media are treated as the anisotropic media and fractures are represented by frequency-dependent elastic constants. Based on numerical experiments with three different parameters, namely viscosity, porosity and the Lamé parameters, this paper has the following observations. First, seismic attenuation is not affected by the viscosity within fractures, although it increases with the increase of porosity and decreases with the increase of the Lamé parameters within fractures. Among the latter two parameters, seismic attenuation is more sensitive to the Lamé parameters than to the porosity. Second, for the attenuation anisotropy, low frequencies have more anisotropic effect than high frequencies. For example, a 50 Hz wavefield has the strongest anisotropy effect if compared to 100 and 150 Hz wavefields. The attenuation anisotropy for low frequency (say 50 Hz) is more sensitive to the viscosity than the porosity and the Lamé parameters have the weakest effect among these three parameters. These observations suggest that low-frequency seismic attenuation, and especially the attenuation anisotropy in low frequency, would have great potential for fluid discrimination within fractured media. (paper)

  11. Agonist-promoted desensitization and phosphorylation of α1-adrenergic receptors coupled to stimulation of phosphatidylinositol metabolism

    International Nuclear Information System (INIS)

    In the DDT1 MF-2 hamster vas deferens smooth muscle cell line the α1-adrenergic receptor (α1-AR) agonist norepinephrine (NE) promotes rapid attenuation of α1-AR-mediated phosphatidylinositol (PI) metabolism which is paralleled by rapid phosphorylation of the α1-AR. Cells were labeled by incubation with 32P/sub i/. Coincubation with NE (100 μM) significantly increases the rate of 32P-labeling of both PI and phosphatidic acid. Pretreatment of cells with 100 μM NE (in the presence of 1 μM propranolol to prevent β-AR interactions) results in a drastic attenuation of the NE response on PI metabolism. α1-AR from labeled cells can be solubilized and purified by affinity chromatography on Affigel-A55414 and wheat germ agglutinin agarose chromatography. SDS-PAGE of purified α1-AR shows a NE-promoted increase in phosphorylation of the M/sub r/ 80K ligand binding peptide. Stoichiometry of phosphorylation increases from ∼ 1 mol phosphate/mol α1-AR in the basal condition to ∼ 2.5 after NE treatment. Both desensitization and phosphorylation are rapid being maximal within 10-20 min of agonist exposure. These results together with previous findings that phorbol esters promote rapid α1-AR uncoupling and phosphorylation suggest that receptor phosphorylation is an important mechanism of regulation of α1-AR receptor responsiveness

  12. Partial agonist therapy in schizophrenia: relevance to diminished criminal responsibility.

    Science.gov (United States)

    Gavaudan, Gilles; Magalon, David; Cohen, Julien; Lançon, Christophe; Léonetti, Georges; Pélissier-Alicot, Anne-Laure

    2010-11-01

    Pathological gambling (PG), classified in the DSM-IV among impulse control disorders, is defined as inappropriate, persistent gaming for money with serious personal, family, and social consequences. Offenses are frequently committed to obtain money for gambling. Pathological gambling, a planned and structured behavioral disorder, has often been described as a complication of dopamine agonist treatment in patients with Parkinson's disease. It has never been described in patients with schizophrenia receiving dopamine agonists. We present two patients with schizophrenia, previously treated with antipsychotic drugs without any suggestion of PG, who a short time after starting aripiprazole, a dopamine partial agonist, developed PG and criminal behavior, which totally resolved when aripiprazole was discontinued. Based on recent advances in research on PG and adverse drug reactions to dopamine agonists in Parkinson's disease, we postulate a link between aripiprazole and PG in both our patients with schizophrenia and raise the question of criminal responsibility. PMID:20579229

  13. IMIDAZOLINE RECEPTOR AGONISTS: DO WE KNOW EVERYTHING ABOUT THEIR CAPABILITIES?

    Directory of Open Access Journals (Sweden)

    D. V. Nebieridze

    2015-12-01

    Full Text Available The role of selective I1 imidazoline receptor agonists and moxonidine in particular , in modern antihypertensive therapy is discussed. Moxonidine advantages, namely positive effects on insulin resistance, endothelial dysfunction, lipid profile, and plasma fibrinolytic activity are considered.

  14. Octopaminergic agonists for the cockroach neuronal octopamine receptor

    Directory of Open Access Journals (Sweden)

    Akinori Hirashima

    2003-04-01

    Full Text Available The compounds 1-(2,6-diethylphenylimidazolidine-2-thione and 2-(2,6-diethylphenylimidazolidine showed the almost same activity as octopamine in stimulating adenylate cyclase of cockroach thoracic nervous system among 70 octopamine agonists, suggesting that only these compounds are full octopamine agonists and other compounds are partial octopamine agonists. The quantitative structure-activity relationship of a set of 22 octopamine agonists against receptor 2 in cockroach nervous tissue, was analyzed using receptor surface modeling. Three-dimensional energetics descriptors were calculated from receptor surface model/ligand interaction and these three-dimensional descriptors were used in quantitative structure-activity relationship analysis. A receptor surface model was generated using some subset of the most active structures and the results provided useful information in the characterization and differentiation of octopaminergic receptor.

  15. Selective 5-HT2C agonists as potential antidepressants.

    Science.gov (United States)

    Leysen, D C

    1999-02-01

    The antidepressants currently used need improvement, especially in terms of efficacy, relapse rate and onset of action. In this review the clinical and experimental data which support the rationale for 5-HT2C agonists in the treatment of depression are listed. Next, the results obtained with the non-selective 5-HT2C agonists on the market and in clinical development are described. Finally, the preclinical data on the more selective 5-HT2C agonists are summarized. These recent preclinical results reveal a greater potency and effect size compared to fluoxetine, good tolerability and no evidence of tolerance development. Selective 5-HT2C agonists might become innovative drugs for the treatment of depression, panic, obsessive-compulsive disorder (OCD), some forms of aggression and eating disorders. PMID:16160946

  16. Development of a radioreceptor assay for β2 adrenergic agonists

    International Nuclear Information System (INIS)

    Several β2 adrenergic agonists are illegally used as growth promoters in meat production. We have developed and evaluated a radioreceptor assay for the multianalyte detection of these compounds. The method is based on a competition for binding with receptors (plasma membranes prepared from bovine teat muscles) between a radioactive tracer (3H-dihydroalprenolol) and β2 agonist residues present in the samples. The method has been validated for three β2 agonists (clenbuterol, mabuterol and cimaterol) in bovine urine samples. The detection limit (mean of ''blank'' values + 3 SEM) in urine was 2.4 ppb clenbuterol. Using this procedure, samples containing at least 5 ppb of clenbuterol, mabuterol or cimaterol could be identified as positive for the presence of β2 agonists. (orig.)

  17. Dexmedetomidine attenuates isoflurane-induced cognitive impairment through antioxidant, anti-inflammatory and anti-apoptosis in aging rat

    OpenAIRE

    Wang, Xiaoning; Zhao, Binjiang; Li, Xue

    2015-01-01

    As a kind of α2 adrenergic receptor agonists, dexmedetomidine generates sedation, anti-anxiety and anesthesia effects by hyperpolarizing noradrenergic nerve cells in locus coeruleus. This study was designed to investigate the neuroprotective of dexmedetomidine attenuates isoflurane-induced cognitive impairment, and the possible underlying mechanism in aging rat. Firstly, we used isoflurane-induced aging rat model to analyze the therapeutical effect of dexmedetomidine on cognitive impairment. ...

  18. Comparison of the efficacy of dexmedetomidine with that of esmolol in attenuating laryngoscopic and intubation response after rapid sequence induction

    OpenAIRE

    Yallapragada, Srivishnu Vardhan; Vidadala, Krishna Santh; Vemuri, Nagendra Nath; Shaik, Mastan Saheb

    2014-01-01

    Context: Laryngoscopy and tracheal intubation produce sympathetic overdrive by catecholamine release resulting in hypertension and tachycardia. Various agents are being tried to combat the intubation response over years. Aims: This study is aimed at comparing dexmedetomidine which is a highly selective alpha-2 agonist with an ultra-short acting beta blocker, esmolol to see which among the two is better in attenuating the hemodynamic response to laryngoscopy and tracheal intubation. Settings a...

  19. The EP3 Agonist Sulprostone Enhances Platelet Adhesion But Not Thrombus Formation Under Flow Conditions.

    Science.gov (United States)

    Pasterk, Lisa; Philipose, Sonia; Eller, Kathrin; Marsche, Gunther; Heinemann, Akos; Schuligoi, Rufina

    2015-01-01

    Platelets express the EP2, EP3 and EP4 receptors. Prostaglandin (PG) E2 has a biphasic effect on platelets. Low concentrations of PGE2 enhance platelet aggregation through the activation of the EP3 receptors, while at high concentrations it attenuates aggregation via the EP4 receptor. Consequently, EP3 receptor inhibition was shown to inhibit artherothrombosis, but had no influence on bleeding time in vivo. In this study, we investigated the role of the EP3 receptor in adhesion and thrombus formation under flow conditions in vitro. The EP3 agonist sulprostone caused an increase in the adhesion of washed platelets to fibrinogen as well as to collagen under low shear stress, an effect that was blocked by the EP3 antagonist L-798106. In contrast, when whole blood was perfused over collagen-coated surfaces, sulprostone did not enhance binding and thrombus formation of platelets on collagen; at high concentrations it even attenuated this response. We conclude that in more physiological models of thrombus formation, the role for EP3 receptors is limited, indirectly suggesting that the primary action of PGE2 in haemostasis might be an inhibitory one. PMID:26228833

  20. Quantifying Agonist Activity at G Protein-coupled Receptors

    OpenAIRE

    Ehlert, Frederick J.; Suga, Hinako; Griffin, Michael T.

    2011-01-01

    When an agonist activates a population of G protein-coupled receptors (GPCRs), it elicits a signaling pathway that culminates in the response of the cell or tissue. This process can be analyzed at the level of a single receptor, a population of receptors, or a downstream response. Here we describe how to analyze the downstream response to obtain an estimate of the agonist affinity constant for the active state of single receptors.

  1. Agonist Replacement for Stimulant Dependence: A Review of Clinical Research

    OpenAIRE

    Stoops, William W.; Rush, Craig R.

    2013-01-01

    Stimulant use disorders are an unrelenting public health concern worldwide. Agonist replacement therapy is among the most effective strategies for managing substance use disorders including nicotine and opioid dependence. The present paper reviewed clinical data from human laboratory self-administration studies and clinical trials to determine whether agonist replacement therapy is a viable strategy for managing cocaine and/or amphetamine use disorders. The extant literature suggests that ago...

  2. Beta-adrenergic agonists as additive in beef cattle

    OpenAIRE

    Marcelo Vedovatto; Camila Celeste Brandão Ferreira Ítavo; João Artêmio Marin Beltrame; Ricardo Carneiro Brumatti; Gumercindo Loriano Franco

    2014-01-01

    The agonists receptor beta-adrenergic (β-AA) are present in virtually all types of mammalian cells and are stimulated by catecholamines (epinephrine and norepinephrine) produced by the organism itself. The β-AA agonists are synthetic substances with similar structure to these amines. When provided in the diet they alter the body composition of animals, affecting the distribution of nutrients toward to protein deposition, and decreasing lipogenesis. Although the mechanisms of action are not fu...

  3. In silico discovery of novel Retinoic Acid Receptor agonist structures

    OpenAIRE

    Samuels Herbert H; Schapira Matthieu; Raaka Bruce M; Abagyan Ruben

    2001-01-01

    Abstract Background Several Retinoic Acid Receptors (RAR) agonists have therapeutic activity against a variety of cancer types; however, unacceptable toxicity profiles have hindered the development of drugs. RAR agonists presenting novel structural and chemical features could therefore open new avenues for the discovery of leads against breast, lung and prostate cancer or leukemia. Results We have analysed the induced fit of the active site residues upon binding of a known ligand. The derived...

  4. Should We Use PPAR Agonists to Reduce Cardiovascular Risk?

    Directory of Open Access Journals (Sweden)

    Jennifer G. Robinson

    2008-01-01

    Full Text Available Trials of peroxisome proliferator-activated receptor (PPAR agonists have shown mixed results for cardiovascular prevention. Fibrates are PPAR- agonists that act primarily to improve dyslipidemia. Based on low- and high-density lipoprotein cholesterol (LDL and HDL effects, gemfibrozil may be of greater cardiovascular benefit than expected, fenofibrate performed about as expected, and bezafibrate performed worse than expected. Increases in both cardiovascular and noncardiovascular serious adverse events have been observed with some fibrates. Thiazolidinediones (TZDs are PPAR- agonists used to improve impaired glucose metabolism but also influence lipids. Pioglitazone reduces atherosclerotic events in diabetic subjects, but has no net cardiovascular benefit due to increased congestive heart failure risk. Rosiglitazone may increase the risk of atherosclerotic events, and has a net harmful effect on the cardiovascular system when congestive heart failure is included. The primary benefit of TZDs appears to be the prevention of diabetic microvascular complications. Dual PPAR-/ agonists have had unacceptable adverse effects but more selective agents are in development. PPAR- and pan-agonists are also in development. It will be imperative to prove that future PPAR agonists not only prevent atherosclerotic events but also result in a net reduction on total cardiovascular events without significant noncardiovascular adverse effects with long-term use.

  5. GW501516, a PPARδ agonist, ameliorates tubulointerstitial inflammation in proteinuric kidney disease via inhibition of TAK1-NFκB pathway in mice.

    Directory of Open Access Journals (Sweden)

    Xu Yang

    Full Text Available Peroxisome proliferator-activated receptors (PPARs are a nuclear receptor family of ligand-inducible transcription factors, which have three different isoforms: PPARα, δ and γ. It has been demonstrated that PPARα and γ agonists have renoprotective effects in proteinuric kidney diseases; however, the role of PPARδ agonists in kidney diseases remains unclear. Thus, we examined the renoprotective effect of GW501516, a PPARδ agonist, in a protein-overload mouse nephropathy model and identified its molecular mechanism. Mice fed with a control diet or GW501516-containing diet were intraperitoneally injected with free fatty acid (FFA-bound albumin or PBS(-. In the control group, protein overload caused tubular damages, macrophage infiltration and increased mRNA expression of MCP-1 and TNFα. These effects were prevented by GW501516 treatment. In proteinuric kidney diseases, excess exposure of proximal tubular cells to albumin, FFA bound to albumin or cytokines such as TNFα is detrimental. In vitro studies using cultured proximal tubular cells showed that GW501516 attenuated both TNFα- and FFA (palmitate-induced, but not albumin-induced, MCP-1 expression via direct inhibition of the TGF-β activated kinase 1 (TAK1-NFκB pathway, a common downstream signaling pathway to TNFα receptor and toll-like receptor-4. In conclusion, we demonstrate that GW501516 has an anti-inflammatory effect in renal tubular cells and may serve as a therapeutic candidate to attenuate tubulointerstitial lesions in proteinuric kidney diseases.

  6. Attenuation of morphine antinociceptive tolerance by cannabinoid CB1 and CB2 receptor antagonists.

    Science.gov (United States)

    Altun, Ahmet; Yildirim, Kemal; Ozdemir, Ercan; Bagcivan, Ihsan; Gursoy, Sinan; Durmus, Nedim

    2015-09-01

    Cannabinoid CB1 and CB2 receptor antagonists may be useful for their potential to increase or prolong opioid analgesia while attenuating the development of opioid tolerance. The aim of this study was to investigate the effects of AM251 (a selective CB1 antagonist) and JTE907 (a selective CB2 antagonist) on morphine analgesia and tolerance in rats. Adult male Wistar albino rats weighing 205-225 g were used in these experiments. To constitute morphine tolerance, we used a 3 day cumulative dosing regimen. After the last dose of morphine was injected on day 4, morphine tolerance was evaluated by analgesia tests. The analgesic effects of morphine (5 mg/kg), ACEA (a CB1 receptor agonist, 5 mg/kg), JWH-015 (a CB2 receptor agonist, 5 mg/kg), AM251 (1 mg/kg) and JTE907 (5 mg/kg) were considered at 30-min intervals (0, 30, 60, 90, and 120 min) by tail-flick and hot-plate analgesia tests. Our findings indicate that ACEA and JWH907 significantly increased morphine analgesia and morphine antinociceptive tolerance in the analgesia tests. In contrast, the data suggested that AM251 and JTE907 significantly attenuated the expression of morphine tolerance. In conclusion, we observed that co-injection of AM251 and JTE907 with morphine attenuated expression of tolerance to morphine analgesic effects and decreased the morphine analgesia. PMID:25894754

  7. Pyrrolo- and Pyridomorphinans: Non-selective opioid antagonists and delta opioid agonists/mu opioid partial agonists

    OpenAIRE

    V. Kumar; Clark, M J; Traynor, J. R.; Lewis, J W; Husbands, S M

    2014-01-01

    Opioid ligands have found use in a number of therapeutic areas, including for the treatment of pain and opiate addiction (using agonists) and alcohol addiction (using antagonists such as naltrexone and nalmefene). The reaction of imines, derived from the opioid ligands oxymorphone and naltrexone, with Michael acceptors leads to pyridomorphinans with structures similar to known pyrrolo- and indolomorphinans. One of the synthesized compounds, 5e, derived from oxymorphone had substantial agonist...

  8. Evaluation of agonist-antagonist properties of nitrogen mustard and cyano derivatives of delta 8-tetrahydrocannabinol.

    Science.gov (United States)

    Wiley, J L; Compton, D R; Gordon, P M; Siegel, C; Singer, M; Dutta, A; Lichtman, A H; Balster, R L; Razdan, R K; Martin, B R

    1996-01-01

    delta 8-Tetrahydrocannabinol (delta 8-THC) is a naturally occurring cannabinoid with a characteristic pharmacological profile of in vivo effects. Previous studies have shown that modification of the structure of delta 8-THC by inclusion of a nitrogen-containing functional group alters this profile and may alkylate the cannabinoid receptor, similar to the manner in which beta-funaltrexamine (beta-FNA) alkylates the micro-opioid receptor. Two novel analogs of delta 8-THC were synthesized: a nitrogen mustard analog with a dimethylheptyl side chain (NM-delta 8-THC) and a cyano analog with a dimethylpentyl side chain (CY-delta 8-THC). Both analogs showed high affinity for brain cannabinoid receptors and when administered acutely, produced characteristic delta 9-THC-like effects in mice, including locomotor suppression, hypothermia, antinociception and catalepsy. CY-delta 8-THC shared discriminative stimulus effects with CP 55,940; for NM-delta 8-THC, these effects also occurred, but were delayed. Although both compounds attenuated the effects of delta 9-THC in the mouse behavioral tests, evaluation of potential antagonist effects of these compounds was complicated by the fact that two injections of delta 9-THC produced similar results, suggesting that acute tolerance or desensitization might account for the observations. NM-delta 8-THC, but not CY-delta 8-THC, attenuated the discriminative stimulus effects of CP 55,940 in rats several days following injection. Hence, addition of a nitrogen-containing functional group to a traditional cannabinoid structure does not eliminate agonist effects and may produce delayed attenuation of cannabinoid-induced pharmacological effects. PMID:9076759

  9. Estimation of Water Vapour Attenuation And Rain Attenuation

    Directory of Open Access Journals (Sweden)

    K.Kalyana Srinivas

    2015-04-01

    Full Text Available Attenuation due to and water vapour and rain can severely degrade the radio wave propagation at centimeter or millimeter wavelengths. It restricts the path length of radio communication systems and limits the use of higher frequencies for line-of-sight microwave links and satellite communications. The attenuation will pose a greater problem to communication as the frequency of occurrence of heavy rain increases.In a tropical region, like Malaysia, where excessive rainfall is a common phenomenon throughout the year, the knowledge of the rain attenuation at the frequency of operation is extremely required for the design of a reliable terrestrial and earth space communication link at a particular location.

  10. Are Dopamine Agonists Neuroprotective in Parkinson′s Disease?

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    Dopamine (DA) agonists are playing increasingly important role in the treatment of not only advanced Parkinson′s disease (PD) and in PD patient with levodopa (L-DOPA)-induced motor fluctuations,but also in early treatment of the disease.This shift has been largely due to the demonstrated L-DOPA-sparing effect of DA agonists and their putative neuroprotective effect,based largely on experimental in vitro and in vivo studies.In this article we review the evidence of neuroprotection by DA agonists pramipexole,ropinirole,pergolide,bromocriptine and apomorphine in cell cultures and animal models of nigral injury.Most of the studies suggest that DA agonists exert their neuroprotection via directly scavenging free radicals or increasing the activities of radical-scavenging enzymes,and enhancing neurotrophic activity.The finding that pramipexole can normalize mitochondrial membrane potential and inhibit activity of caspase-3 in cytoplasmic hybrid cells made from mitochondrial DNA of nonfamilial Alzheimer′s disease patients,however,suggests even a broader implication for the neuroprotective role of DA agonists.Although the clinical evidence for neuroprotection by DA agonists is still limited,the preliminary results from several on-going clinical trials are promising.Several longitudinal studies are currently in progress designed to demonstrate a delay or slowing of progresion of PD using various surrogate markers of neuronal degeneration such as 18 F-L-DOPA PET and 123 I β-CIT SPECT.The results of these experimental and clinical studies will improve our understanding of the action of DA agonists and provide critical information needed for planning future therapeutic strategies in PD and related neurodegenerative disorders.``

  11. Are Dopamine Agonists Neuroprotective in Parkinson‘s disease?

    Institute of Scientific and Technical Information of China (English)

    乐卫东; Jank.J

    2002-01-01

    Dopamine(DA) agonists are playing increasingly important role in the treatment of not only advanced Parkinson's disease(PD) and in PD patient with levodopa(L-DO-PA)-induced motor fluctuations,but also in early treatment of the disease.This shift has been largely due to the demonstrated L-DOPA-sparing effect of DA agonists and their putative neuroprotective effect,based largely on experimental in vitro and in vivo studies.In this article we review the evidence of neuroprotection by DA agonists pramipexole,ropinirole,pergolide,bromocriptine and apomorphine in cell cultures and animal models of nigral injury.Most of the studies suggest that DA agonists exert their neuroprotection via directly scavenging free radicals or increasing the activities of radical-scavenging enzymes,and enhancing neurotrophic activity.The finding that pramipexole can normalize mitochondrial membrane potential and inhibit activity of caspase-3 in cytoylasmic hybrid cells made from mitochondrial DNA of nonfamilial Alzheimer's disease patients,however,suggests even a broader implication for the neuroprotective role of DA agonists.Although the clinical evidence for neuroprotection by DA agonists is still limited,the preliminary results from several on-going clinal trials are promising.Several longitudinal studies are currently in progress designed to demonstrate a delay or slowing of progresion of PD using various surrogate markers of neuronal degeneration such as18F-L-DOPA PET and123I β-CIT SPECT.The results of these experimental and clinical studies will improve our understanding of the action of DA agonists and provide critical information needed for planning future therapeutic strategies in PD and related neurodegenerative disorders.

  12. Severe hemorrhage attenuates cardiopulmonary chemoreflex control of regional sympathetic outputs via NTS adenosine receptors.

    Science.gov (United States)

    Minic, Zeljka; Li, Cailian; O'Leary, Donal S; Scislo, Tadeusz J

    2014-09-15

    Selective stimulation of inhibitory A1 and facilitatory A2a adenosine receptor subtypes located in the nucleus of the solitary tract (NTS) powerfully inhibits cardiopulmonary chemoreflex (CCR) control of regional sympathetic outputs via different mechanisms: direct inhibition of glutamate release and facilitation of an inhibitory neurotransmitter release, respectively. However, it remains unknown whether adenosine naturally released into the NTS has similar inhibitory effects on the CCR as the exogenous agonists do. Our previous study showed that adenosine is released into the NTS during severe hemorrhage and contributes to reciprocal changes of renal (decreases) and adrenal (increases) sympathetic nerve activity observed in this setting. Both A1 and A2a adenosine receptors are involved. Therefore, we tested the hypothesis that, during severe hemorrhage, CCR control of the two sympathetic outputs is attenuated by adenosine naturally released into the NTS. We compared renal and adrenal sympathoinhibitory responses evoked by right atrial injections of 5HT3 receptor agonist phenylbiguanide (2-8 μg/kg) under control conditions, during hemorrhage, and during hemorrhage preceded by blockade of NTS adenosine receptors with bilateral microinjections of 8-(p-sulfophenyl) theophylline (1 nmol/100 nl) in urethane/chloralose anesthetized rats. CCR-mediated inhibition of renal and adrenal sympathetic activity was significantly attenuated during severe hemorrhage despite reciprocal changes in the baseline activity levels, and this attenuation was removed by bilateral blockade of adenosine receptors in the caudal NTS. This confirmed that adenosine endogenously released into the NTS has a similar modulatory effect on integration of cardiovascular reflexes as stimulation of NTS adenosine receptors with exogenous agonists. PMID:25063794

  13. The attenuation and the attenuators: strategies and tactics

    Directory of Open Access Journals (Sweden)

    Antonio Briz

    2013-12-01

    Full Text Available This work is inscribed in a research project (ES.POR.ATENUAÇÃO that seeks to analyze and explain the attenuator activity in different regional varieties of Spanish and Portuguese, in order to perform, subsequently, different contrastive intralinguistic and interlinguistic studies. In this article, we explain some of the theoretical and methodological principles on which are based the qualitative and quantitative analysis. And especially, we will refer to the concept of attenuation (Briz 1995, 2002, 2003, 2005, 2007a, 2012.

  14. 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

    glycine-free or a glycine-bound subunit. Agonist-free subunits were created by incorporating T204A and R65K mutations, which disrupted glycine binding to both (+) and (-) subunit interfaces. In heteromeric receptors comprising wild-type and R65K,T204A,R271C triple-mutant subunits, the fluorescence...... response exhibited a drastically reduced glycine sensitivity relative to the current response. Two conclusions can be drawn from this. First, because the labeled glycine-free subunits were activated by glycine binding to neighboring wild-type subunits, our results provide evidence for a cooperative...... activation mechanism. However, because the fluorescent label on glycine-free subunits does not reflect movements at the channel gate, we conclude that glycine binding also produces a local non-concerted conformational change that is not essential for receptor activation....

  15. Antipruritic effect of cold-induced and transient receptor potential-agonist-induced counter-irritation on histaminergic itch in humans

    DEFF Research Database (Denmark)

    Andersen, Hjalte H.; Melholt, Camilla; Hilborg, Sigurd D.; Jerwiarz, Anne; Randers, Amalie; Simoni, Amalie; Elberling, Jesper; Arendt-Nielsen, Lars

    2016-01-01

    A frequent empirical observation is that cold-induced counter-irritation may attenuate itch. The aim of this randomized, single-blinded, exploratory study was to evaluate the counter-irritation effects of cold-stimulation and topical application of transient receptor potential TRPA1/M8-agonists...... (trans-cinnamaldehyde/L-menthol, respectively), on histamine-induced itch, wheal and neurogenic inflammation in 13 healthy volunteers. Histamine 1% was applied to the volar forearms using skin prick-testing lancets. Recorded outcome-parameters were itch intensity, wheal reactions and neurogenic......-menthol and trans-cinnamaldehyde had antipruritic efficacy similar to doxepin (p < 0.05). Cold-induced counter-irritation had an inhibitory effect on histaminergic itch, suggesting that agonists of cold transduction receptors could be of potential antipruritic value....

  16. Sound attenuation in magnetorheological fluids

    Science.gov (United States)

    Rodríguez-López, J.; Elvira, L.; Resa, P.; Montero de Espinosa, F.

    2013-02-01

    In this work, the attenuation of ultrasonic elastic waves propagating through magnetorheological (MR) fluids is analysed as a function of the particle volume fraction and the magnetic field intensity. Non-commercial MR fluids made with iron ferromagnetic particles and two different solvents (an olive oil based solution and an Araldite-epoxy) were used. Particle volume fractions of up to 0.25 were analysed. It is shown that the attenuation of sound depends strongly on the solvent used and the volume fraction. The influence of a magnetic field up to 212 mT was studied and it was found that the sound attenuation increases with the magnetic intensity until saturation is reached. A hysteretic effect is evident once the magnetic field is removed.

  17. Biochemical and functional interactions of a selective kappa opioid agonist with calcium

    Energy Technology Data Exchange (ETDEWEB)

    VonVoigtlander, P.F.; Ochoa, M.C.; Lewis, R.A.

    1987-01-01

    The discovery of the selective kappa opioid receptor agonist, U-50488H, has provided a tool for the study of the mechanisms and function of the kappa receptor-effector. We have investigated the interactions of this compound with calcium in several biochemical and functional studies to assess the involvement of calcium mechanisms in the kappa receptor-linked effector. In rat brain synaptosomes, U-50488H attenuated the uptake of /sup 45/Ca++ induced by K+ (40 mM) depolarization. This effect was concentration-related (U-50488H 10(-5) to 10(-7) M), was apparent in short (8-second) but not longer (1-minute) term incubations, and did not occur in the presence of a non-polarizing concentration (5.6 mM) of K+. Naloxone (10(-7) M) did not block this effect of U-50488H (10(-6) M), and higher concentrations (10(-5) M) alone blocked calcium uptake. We have found that the binding of the depolarizing amino acid analog, kainic acid, is enhanced by CaCl2. U-50488H (10(-4) to 10(-6) M) blocks this enhancement of /sup 3/H-kainic acid binding in vitro and also blocks the in vivo effects of kainic acid. In mice, intravenous injection of kainic acid causes scratching, convulsions, and death, depending on the dose administered. U-50488H blocks all of these effects (ED50 = 4.5 mg/kg for antagonism of convulsions induced by 27.5 mg/kg kainic acid). The convulsions induced by intracerebroventricularly administered kainic acid are also blocked by U-50488H as are those induced by similarly administered Bay K 8644, a calcium channel activator. All of these anticonvulsant effects of U-50488H were antagonized by naltrexone. Together these data indicate that the kappa agonist U-50488H has functionally relevant interactions with depolarization-related Ca++ mechanisms in the central nervous system.

  18. Biochemical and functional interactions of a selective kappa opioid agonist with calcium

    International Nuclear Information System (INIS)

    The discovery of the selective kappa opioid receptor agonist, U-50488H, has provided a tool for the study of the mechanisms and function of the kappa receptor-effector. We have investigated the interactions of this compound with calcium in several biochemical and functional studies to assess the involvement of calcium mechanisms in the kappa receptor-linked effector. In rat brain synaptosomes, U-50488H attenuated the uptake of 45Ca++ induced by K+ (40 mM) depolarization. This effect was concentration-related (U-50488H 10(-5) to 10(-7) M), was apparent in short (8-second) but not longer (1-minute) term incubations, and did not occur in the presence of a non-polarizing concentration (5.6 mM) of K+. Naloxone (10(-7) M) did not block this effect of U-50488H (10(-6) M), and higher concentrations (10(-5) M) alone blocked calcium uptake. We have found that the binding of the depolarizing amino acid analog, kainic acid, is enhanced by CaCl2. U-50488H (10(-4) to 10(-6) M) blocks this enhancement of 3H-kainic acid binding in vitro and also blocks the in vivo effects of kainic acid. In mice, intravenous injection of kainic acid causes scratching, convulsions, and death, depending on the dose administered. U-50488H blocks all of these effects (ED50 = 4.5 mg/kg for antagonism of convulsions induced by 27.5 mg/kg kainic acid). The convulsions induced by intracerebroventricularly administered kainic acid are also blocked by U-50488H as are those induced by similarly administered Bay K 8644, a calcium channel activator. All of these anticonvulsant effects of U-50488H were antagonized by naltrexone. Together these data indicate that the kappa agonist U-50488H has functionally relevant interactions with depolarization-related Ca++ mechanisms in the central nervous system

  19. Alpha-2 agonists as pain therapy in horses.

    Science.gov (United States)

    Valverde, Alexander

    2010-12-01

    Alpha-2 agonists, such as xylazine, clonidine, romifidine, detomidine, medetomidine, and dexmedetomidine, are potent analgesic drugs that also induce physiologic and behavioral changes, such as hypertension, bradycardia, atrioventricular block, excessive sedation and ataxia, all of which can potentially limit their systemic use as analgesics in some clinical cases. The use of medetomidine and dexmetomidine has been introduced for equine anesthesia/analgesia, and although not approved in this species, their increased specificity for alpha-2 receptors may offer some potential advantages over the traditional alpha-2 agonists. Similarly, other routes of administration and benefits of alpha-2 agonists are recognized in the human and laboratory animal literature, which may prove useful in the equine patient if validated in the near future. This review presents this relevant information. PMID:21056297

  20. Principles of agonist recognition in Cys-loop receptors

    Directory of Open Access Journals (Sweden)

    Timothy eLynagh

    2014-04-01

    Full Text Available Cys-loop receptors are ligand-gated ion channels that are activated by a structurally diverse array of neurotransmitters, including acetylcholine, serotonin, glycine and GABA. After the term chemoreceptor emerged over 100 years ago, there was some wait until affinity labeling, molecular cloning, functional studies and X-ray crystallography experiments identified the extracellular interface of adjacent subunits as the principal site of agonist binding. The question of how subtle differences at and around agonist-binding sites of different Cys-loop receptors can accommodate transmitters as chemically diverse as glycine and serotonin has been subject to intense research over the last three decades. This review outlines the functional diversity and current structural understanding of agonist-binding sites, including those of invertebrate Cys-loop receptors. Together, this provides a framework to understand the atomic determinants involved in how these valuable therapeutic targets recognize and bind their ligands.

  1. In silico discovery of novel Retinoic Acid Receptor agonist structures

    Directory of Open Access Journals (Sweden)

    Samuels Herbert H

    2001-06-01

    Full Text Available Abstract Background Several Retinoic Acid Receptors (RAR agonists have therapeutic activity against a variety of cancer types; however, unacceptable toxicity profiles have hindered the development of drugs. RAR agonists presenting novel structural and chemical features could therefore open new avenues for the discovery of leads against breast, lung and prostate cancer or leukemia. Results We have analysed the induced fit of the active site residues upon binding of a known ligand. The derived binding site models were used to dock over 150,000 molecules in silico (or virtually to the structure of the receptor with the Internal Coordinates Mechanics (ICM program. Thirty ligand candidates were tested in vitro. Conclusions Two novel agonists resulting from the predicted receptor model were active at 50 nM. One of them displays novel structural features which may translate into the development of new ligands for cancer therapy.

  2. Muscarinic receptor agonists stimulate matrix metalloproteinase 1-dependent invasion of human colon cancer cells

    International Nuclear Information System (INIS)

    Highlights: ► Muscarinic receptor agonists stimulated robust human colon cancer cell invasion. ► Anti-matrix metalloproteinase1 antibody pre-treatment blocks cell invasion. ► Bile acids stimulate MMP1 expression, cell migration and MMP1-dependent invasion. -- Abstract: Mammalian matrix metalloproteinases (MMPs) which degrade extracellular matrix facilitate colon cancer cell invasion into the bloodstream and extra-colonic tissues; in particular, MMP1 expression correlates strongly with advanced colon cancer stage, hematogenous metastasis and poor prognosis. Likewise, muscarinic receptor signaling plays an important role in colon cancer; muscarinic receptors are over-expressed in colon cancer compared to normal colon epithelial cells. Muscarinic receptor activation stimulates proliferation, migration and invasion of human colon cancer cells. In mouse intestinal neoplasia models genetic ablation of muscarinic receptors attenuates carcinogenesis. In the present work, we sought to link these observations by showing that MMP1 expression and activation plays a mechanistic role in muscarinic receptor agonist-induced colon cancer cell invasion. We show that acetylcholine, which robustly increases MMP1 expression, stimulates invasion of HT29 and H508 human colon cancer cells into human umbilical vein endothelial cell monolayers – this was abolished by pre-incubation with atropine, a non-selective muscarinic receptor inhibitor, and by pre-incubation with anti-MMP1 neutralizing antibody. Similar results were obtained using a Matrigel chamber assay and deoxycholyltaurine (DCT), an amidated dihydroxy bile acid associated with colon neoplasia in animal models and humans, and previously shown to interact functionally with muscarinic receptors. DCT treatment of human colon cancer cells resulted in time-dependent, 10-fold increased MMP1 expression, and DCT-induced cell invasion was also blocked by pre-treatment with anti-MMP1 antibody. This study contributes to understanding

  3. Muscarinic receptor agonists stimulate matrix metalloproteinase 1-dependent invasion of human colon cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Raufman, Jean-Pierre, E-mail: jraufman@medicine.umaryland.edu [Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD (United States); Cheng, Kunrong; Saxena, Neeraj; Chahdi, Ahmed; Belo, Angelica; Khurana, Sandeep; Xie, Guofeng [Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD (United States)

    2011-11-18

    Highlights: Black-Right-Pointing-Pointer Muscarinic receptor agonists stimulated robust human colon cancer cell invasion. Black-Right-Pointing-Pointer Anti-matrix metalloproteinase1 antibody pre-treatment blocks cell invasion. Black-Right-Pointing-Pointer Bile acids stimulate MMP1 expression, cell migration and MMP1-dependent invasion. -- Abstract: Mammalian matrix metalloproteinases (MMPs) which degrade extracellular matrix facilitate colon cancer cell invasion into the bloodstream and extra-colonic tissues; in particular, MMP1 expression correlates strongly with advanced colon cancer stage, hematogenous metastasis and poor prognosis. Likewise, muscarinic receptor signaling plays an important role in colon cancer; muscarinic receptors are over-expressed in colon cancer compared to normal colon epithelial cells. Muscarinic receptor activation stimulates proliferation, migration and invasion of human colon cancer cells. In mouse intestinal neoplasia models genetic ablation of muscarinic receptors attenuates carcinogenesis. In the present work, we sought to link these observations by showing that MMP1 expression and activation plays a mechanistic role in muscarinic receptor agonist-induced colon cancer cell invasion. We show that acetylcholine, which robustly increases MMP1 expression, stimulates invasion of HT29 and H508 human colon cancer cells into human umbilical vein endothelial cell monolayers - this was abolished by pre-incubation with atropine, a non-selective muscarinic receptor inhibitor, and by pre-incubation with anti-MMP1 neutralizing antibody. Similar results were obtained using a Matrigel chamber assay and deoxycholyltaurine (DCT), an amidated dihydroxy bile acid associated with colon neoplasia in animal models and humans, and previously shown to interact functionally with muscarinic receptors. DCT treatment of human colon cancer cells resulted in time-dependent, 10-fold increased MMP1 expression, and DCT-induced cell invasion was also blocked by pre

  4. Synthesis of Selective A3 and M1 Receptor Agonists

    OpenAIRE

    Snee, Stephen

    2011-01-01

    Detailed within this thesis is the synthesis of three A1 agonists which were designed by Muscagen using computational studies. The agonists are derived from condensation of the modified adenosine: (4S,6R)-6-(6-chloro-9H-purin-9-yl)-N,2,2-trimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide with novel heterocyclic primary amines.The amines 5-(aminomethyl)-N,N-diethyl-7-methyloxazolo[4,5-b]pyridin-2-amine, 5-(1-aminoethyl)-N,N,7-trimethyloxazolo[4,5-b]pyridin-2-amine and 5-(1-aminoethyl)-N,...

  5. Adenosine A1 receptor agonists inhibit trigeminovascular nociceptive transmission

    DEFF Research Database (Denmark)

    Goadsby, P J; Hoskin, K L; Storer, R J;

    2002-01-01

    There is a considerable literature to suggest that adenosine A1 receptor agonists may have anti-nociceptive effects, and we sought to explore the role of adenosine A1 receptors in a model of trigeminovascular nociceptive transmission. Cats were anaesthetized (alpha-chloralose 60 mg/kg, intraperit......There is a considerable literature to suggest that adenosine A1 receptor agonists may have anti-nociceptive effects, and we sought to explore the role of adenosine A1 receptors in a model of trigeminovascular nociceptive transmission. Cats were anaesthetized (alpha-chloralose 60 mg...

  6. Subtype-selective nicotinic acetylcholine receptor agonists can improve cognitive flexibility in an attentional set shifting task.

    Science.gov (United States)

    Wood, Christopher; Kohli, Shivali; Malcolm, Emma; Allison, Claire; Shoaib, Mohammed

    2016-06-01

    Nicotinic acetylcholine receptors (nAChRs) are considered to be viable targets to enhance cognition in patients diagnosed with schizophrenia. Activation of nAChRs with selective nicotinic receptor agonists may provide effective means to pharmacologically treat cognitive deficits observed in schizophrenia. Cognitive flexibility is one aspect of cognition, which can be assessed in a rodent model of the attentional set-shifting task (ASST). The aim of the present study was two-fold, firstly, to evaluate the efficacy of a series of subtype selective nAChR agonists, such as those that target α7 and α4β2 nAChR subtypes in non-compromised rodents. Secondly, nicotine as a prototypic agonist was evaluated for its effects to restore attentional deficits produced by sub-chronic ketamine exposure in the ASST. Male hooded Lister rats underwent habituation, consisting of a simple odour and medium discrimination with subsequent assessment 24 h later. In experimentally naïve rats, α7 subtype selective agonists, compound-A and SSR180711 along with PNU-120596, an α7 positive allosteric modulator (PAM), were compared against the β2* selective agonist, 5IA-85380. All compounds except for PNU-120596 were observed to significantly improve extra-dimensional (ED) shift performance, nicotine, 5IA-85380 and SSR180711 further enhanced the final reversal (REV3) stage of the task. In another experiment, sub-chronic ketamine treatment produced robust deficits during the ED and the REV3 stages of the discriminations; rodents required significantly more trials to reach criterion during these discriminations. These deficits were attenuated in rodents treated acutely with nicotine (0.1 mg/kg SC) 10 min prior to the ED shift. These results highlight the potential utility of targeting nAChRs to enhance cognitive flexibility, particularly the α7 and β2* receptor subtypes. The improvement with nicotine was much greater in rodents that were impaired following the sub-chronic ketamine

  7. Josephson tunnel junction microwave attenuator

    DEFF Research Database (Denmark)

    Koshelets, V. P.; Shitov, S. V.; Shchukin, A. V.;

    1993-01-01

    A new element for superconducting electronic circuitry-a variable attenuator-has been proposed, designed, and successfully tested. The principle of operation is based on the change in the microwave impedance of a superconductor-insulator-superconductor (SIS) Josephson tunnel junction when dc biased...

  8. Compact plasmonic variable optical attenuator

    DEFF Research Database (Denmark)

    Leosson, Kristjan; Rosenzveig, Tiberiu; Hermannsson, Pétur Gordon;

    2008-01-01

    We demonstrate plasmonic nanowire-based thermo-optic variable optical attenuators operating in the 1525-1625 nm wavelength range. The devices have a footprint as low as 1 mm, extinction ratio exceeding 40 dB, driving voltage below 3 V, and full modulation bandwidth of 1 kHz. The polarization...

  9. Attenuation of Vrancea events revisited

    International Nuclear Information System (INIS)

    New aspects of the frequency-dependent attenuation of the seismic waves traveling from Vrancea subcrustal sources toward NW (Transylvanian Basin) and SE (Romanian Plain) are evidenced by the recent experimental data made available by the CALIXTO'99 tomography experiment. The observations validate the previous theoretical computations performed for the assessment, by means of a deterministic approach, of the seismic hazard in Romania. They reveal an essential aspect of the seismic ground motion attenuation, that has important implications on the probabilistic assessment of seismic hazard from Vrancea intermediate-depth earthquakes. The attenuation toward NW is shown to be a much stronger frequency-dependent effect than the attenuation toward SE and the seismic hazard computed by the deterministic approach fits satisfactorily well the observed ground motion distribution in the low-frequency band (< 1 Hz). The apparent contradiction with the historically-based intensity maps arises mainly from a systematic difference in the vulnerability (buildings eigenperiod) of the buildings in the intra- and extra-Carpathians regions. (author)

  10. Stormwater Attenuation by Green Roofs

    Science.gov (United States)

    Sims, A.; O'Carroll, D. M.; Robinson, C. E.; Smart, C. C.

    2014-12-01

    Innovative municipal stormwater management technologies are urgently required in urban centers. Inadequate stormwater management can lead to excessive flooding, channel erosion, decreased stream baseflows, and degraded water quality. A major source of urban stormwater is unused roof space. Green roofs can be used as a stormwater management tool to reduce roof generated stormwater and generally improve the quality of runoff. With recent legislation in some North American cities, including Toronto, requiring the installation of green roofs on large buildings, research on the effectiveness of green roofs for stormwater management is important. This study aims to assess the hydrologic response of an extensive sedum green roof in London, Ontario, with emphasis on the response to large precipitation events that stress municipal stormwater infrastructure. A green roof rapidly reaches field capacity during large storm events and can show significantly different behavior before and after field capacity. At field capacity a green roof has no capillary storage left for retention of stormwater, but may still be an effective tool to attenuate peak runoff rates by transport through the green roof substrate. The attenuation of green roofs after field capacity is linked to gravity storage, where gravity storage is the water that is temporarily stored and can drain freely over time after field capacity has been established. Stormwater attenuation of a modular experimental green roof is determined from water balance calculations at 1-minute intervals. Data is used to evaluate green roof attenuation and the impact of field capacity on peak flow rates and gravity storage. In addition, a numerical model is used to simulate event based stormwater attenuation. This model is based off of the Richards equation and supporting theory of multiphase flow through porous media.

  11. Ferrite attenuator modulation improves antenna performance

    Science.gov (United States)

    Hooks, J. C.; Larson, S. G.; Shorkley, F. H.; Williams, B. T.

    1970-01-01

    Ferrite attenuator inserted into appropriate waveguide reduces the gain of the antenna element which is causing interference. Modulating the ferrite attenuator to change the antenna gain at the receive frequency permits ground tracking until the antenna is no longer needed.

  12. Innovations in agonist maintenance treatment of opioid-dependent patients

    NARCIS (Netherlands)

    C. Haasen; W. van den Brink

    2006-01-01

    Purpose of review To provide an overview of published studies on agonist maintenance treatment options for opioid-dependent patients. Recent findings The recent publication of controlled trials confirms earlier clinical evidence of the efficacy of diamorphine (heroin) in the treatment of opioid depe

  13. Free Fatty Acid Receptor 1 (FFA1/GPR40) Agonists

    DEFF Research Database (Denmark)

    Christiansen, Elisabeth; Due-Hansen, Maria E; Urban, Christian;

    2012-01-01

    FFA1 (GPR40) is a new target for treatment of type 2 diabetes. We recently identified the potent FFA1 agonist TUG-469 (5). Inspired by the structurally related TAK-875, we explored the effects of a mesylpropoxy appendage on 5. The appendage significantly lowers lipophilicity and improves metabolic...

  14. N-methyl-D-aspartic acid receptor agonists

    DEFF Research Database (Denmark)

    Madsen, U; Frydenvang, Karla Andrea; Ebert, B;

    1996-01-01

    (R,S)-2-Amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid [(R,S)-AMAA, 4] is a potent and selective agonist at the N-methyl-D-aspartic acid (NMDA) subtype of excitatory amino acid receptors. Using the Ugi "four-component condensation" method, the two diastereomers (2R)- and (2S)-2-[3-(benzylox...

  15. Glucagon-like peptide 1 receptor agonist (GLP-1 RA)

    DEFF Research Database (Denmark)

    von Scholten, Bernt Johan; Hansen, Tine Willum; Goetze, Jens Peter;

    2015-01-01

    AIMS: In a short-term study including 31 patients with type 2 diabetes, glucagon-like peptide 1 receptor agonist (GLP-1 RA) treatment was associated with a significant reversible decline in GFR. Twenty-three patients re-initiated GLP-1 RA treatment after the primary study, and the aim was to...

  16. Synthetic RORγt Agonists Enhance Protective Immunity.

    Science.gov (United States)

    Chang, Mi Ra; Dharmarajan, Venkatasubramanian; Doebelin, Christelle; Garcia-Ordonez, Ruben D; Novick, Scott J; Kuruvilla, Dana S; Kamenecka, Theodore M; Griffin, Patrick R

    2016-04-15

    The T cell specific RORγ isoform RORγt has been shown to be the key lineage-defining transcription factor to initiate the differentiation program of TH17 and TC17 cells, cells that have demonstrated antitumor efficacy. RORγt controls gene networks that enhance immunity including increased IL17 production and decreased immune suppression. Both synthetic and putative endogenous agonists of RORγt have been shown to increase the basal activity of RORγt enhancing TH17 cell proliferation. Here, we show that activation of RORγt using synthetic agonists drives proliferation of TH17 cells while decreasing levels of the immune checkpoint protein PD-1, a mechanism that should enhance antitumor immunity while blunting tumor associated adaptive immune resistance. Interestingly, putative endogenous agonists drive proliferation of TH17 cells but do not repress PD-1. These findings suggest that synthetic agonists of RORγt should activate TC17/TH17 cells (with concomitant reduction in the Tregs population), repress PD-1, and produce IL17 in situ (a factor associated with good prognosis in cancer). Enhanced immunity and blockage of immune checkpoints has transformed cancer treatment; thus such a molecule would provide a unique approach for the treatment of cancer. PMID:26785144

  17. Pharmacophore-driven identification of PPARγ agonists from natural sources

    DEFF Research Database (Denmark)

    Petersen, R. K.; Christensen, Kathrine Bisgaard; Assimopoulou, A. N.;

    2011-01-01

    medicine. From the resulting hits, we selected methyl oleanonate, a compound found, among others, in Pistacia lentiscus var. Chia oleoresin (Chios mastic gum). The acid of methyl oleanonate, oleanonic acid, was identified as a PPARγ agonist through bioassay-guided chromatographic fractionations of Chios...

  18. Activation of farnesoid X receptor attenuates hepatic injury in a murine model of alcoholic liver disease.

    Science.gov (United States)

    Wu, Weibin; Zhu, Bo; Peng, Xiaomin; Zhou, Meiling; Jia, Dongwei; Gu, Jianxin

    2014-01-01

    Alcoholic liver disease (ALD) is a common cause of advanced liver disease, and considered as a major risk factor of morbidity and mortality worldwide. Hepatic cholestasis is a pathophysiological feature observed in all stages of ALD. The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily, and plays an essential role in the regulation of bile acid, lipid and glucose homeostasis. However, the role of FXR in the pathogenesis and progression of ALD remains largely unknown. Mice were fed Lieber-DeCarli ethanol diet or an isocaloric control diet. We used a specific agonist of FXR WAY-362450 to study the effect of pharmacological activation of FXR in alcoholic liver disease. In this study, we demonstrated that FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. Activation of FXR by specific agonist WAY-362450 protected mice from the development of ALD. We also found that WAY-362450 treatment rescued FXR activity, suppressed ethanol-induced Cyp2e1 up-regulation and attenuated oxidative stress in liver. Our results highlight a key role of FXR in the modulation of ALD development, and propose specific FXR agonists for the treatment of ALD patients. PMID:24269813

  19. ENHANCEMENTS TO NATURAL ATTENUATION: SELECTED CASE STUDIES

    Energy Technology Data Exchange (ETDEWEB)

    Vangelas, K; W. H. Albright, W; E. S. Becvar, E; C. H. Benson, C; T. O. Early, T; E. Hood, E; P. M. Jardine, P; M. Lorah, M; E. Majche, E; D. Major, D; W. J. Waugh, W; G. Wein, G; O. R. West, O

    2007-05-15

    In 2003 the US Department of Energy (DOE) embarked on a project to explore an innovative approach to remediation of subsurface contaminant plumes that focused on introducing mechanisms for augmenting natural attenuation to achieve site closure. Termed enhanced attenuation (EA), this approach has drawn its inspiration from the concept of monitored natural attenuation (MNA).

  20. β-Adrenoreceptor agonists in the management of pain associated with renal colic: a systematic review

    OpenAIRE

    Tabner, Andrew John; Johnson, Graham David; Fakis, Apostolos; Surtees, Jane; Lennon, Robert Iain

    2016-01-01

    Objectives To determine whether β-adrenoreceptor agonists are effective analgesics for patients with renal colic through a systematic review of the literature. Setting Adult emergency departments or acute assessment units. Participants Human participants with proven or suspected renal colic. Interventions β-adrenoreceptor agonists. Outcome measures Primary: level of pain at 30 min following administration of the β-agonist. Secondary: level of pain at various time points following β-agonist ad...

  1. Synthesis and structure-activity relationships of novel indazolyl glucocorticoid receptor partial agonists.

    Science.gov (United States)

    Gilmore, John L; Sheppeck, James E; Wang, Jim; Dhar, T G Murali; Cavallaro, Cullen; Doweyko, Arthur M; Mckay, Lorraine; Cunningham, Mark D; Habte, Sium F; Nadler, Steven G; Dodd, John H; Somerville, John E; Barrish, Joel C

    2013-10-01

    SAR was used to further develop an indazole class of non-steroidal glucocorticoid receptor agonists aided by a GR LBD (ligand-binding domain)-agonist co-crystal structure described in the accompanying paper. Progress towards discovering a dissociated GR agonist guided by human in vitro assays biased the optimization of this compound series towards partial agonists that possessed excellent selectivity against other nuclear hormone receptors. PMID:23916594

  2. Agonist-promoted desensitization and phosphorylation of. cap alpha. /sub 1/-adrenergic receptors coupled to stimulation of phosphatidylinositol metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Leeb-Lundberg, L.M.F.; Cotecchia, S.; Caron, M.G.; Lefkowitz, R.J.

    1986-03-05

    In the DDT/sub 1/ MF-2 hamster vas deferens smooth muscle cell line the ..cap alpha../sub 1/-adrenergic receptor (..cap alpha../sub 1/-AR) agonist norepinephrine (NE) promotes rapid attenuation of ..cap alpha../sub 1/-AR-mediated phosphatidylinositol (PI) metabolism which is paralleled by rapid phosphorylation of the ..cap alpha../sub 1/-AR. Cells were labeled by incubation with /sup 32/P/sub i/. Coincubation with NE (100 ..mu..M) significantly increases the rate of /sup 32/P-labeling of both PI and phosphatidic acid. Pretreatment of cells with 100 ..mu..M NE (in the presence of 1 ..mu..M propranolol to prevent ..beta..-AR interactions) results in a drastic attenuation of the NE response on PI metabolism. ..cap alpha../sub 1/-AR from labeled cells can be solubilized and purified by affinity chromatography on Affigel-A55414 and wheat germ agglutinin agarose chromatography. SDS-PAGE of purified ..cap alpha../sub 1/-AR shows a NE-promoted increase in phosphorylation of the M/sub r/ 80K ligand binding peptide. Stoichiometry of phosphorylation increases from approx. 1 mol phosphate/mol ..cap alpha../sub 1/-AR in the basal condition to approx. 2.5 after NE treatment. Both desensitization and phosphorylation are rapid being maximal within 10-20 min of agonist exposure. These results together with previous findings that phorbol esters promote rapid ..cap alpha../sub 1/-AR uncoupling and phosphorylation suggest that receptor phosphorylation is an important mechanism of regulation of ..cap alpha../sub 1/-AR receptor responsiveness.

  3. Influence of metabotropic glutamate receptor agonists on the inhibitory effects of adenosine A1 receptor activation in the rat hippocampus.

    Science.gov (United States)

    de Mendonça, A; Ribeiro, J A

    1997-08-01

    1. Glutamate and other amino acids are the main excitatory neurotransmitters in many brain regions, including the hippocampus, by activating ion channel-coupled glutamate receptors, as well as metabotropic receptors linked to G proteins and second messenger systems. Several conditions which promote the release of glutamate, like frequency stimulation and hypoxia, also lead to an increase in the extracellular levels of the important neuromodulator, adenosine. We studied whether the activation of different subgroups of metabotropic glutamate receptors (mGluR) could modify the known inhibitory effects of a selective adenosine A1 receptor agonist on synaptic transmission in the hippocampus. The experiments were performed on hippocampal slices taken from young (12-14 days old) rats. Stimulation was delivered to the Schaffer collateral/commissural fibres, and evoked field excitatory postsynaptic potentials (fe. p.s.p.) recorded extracellularly from the stratum radiatum in the CAI area. 2. The concentration-response curve for the inhibitory effects of the selective adenosine A1 receptor agonist, N6-cyclopentyladenosine (CPA; 2-50 nM), on the fe.p.s.p. slope (EC50 = 12.5 (9.2-17.3; 95% confidence intervals)) was displaced to the right by the group I mGluR selective agonist, (R,S)-3,5-dihydroxyphenylglycine (DPHG; 10 microM) (EC50 = 27.2 (21.4-34.5) nM, n = 4). The attenuation of the inhibitory effect of CPA (10 nM) on the fe.p.s.p. slope by DHPG (10 microM) was blocked in the presence of the mGluR antagonist (which blocks group I and II mGluR), (R,S)-alpha-methyl-4-carboxyphenylglycine (MCPG; 500 microM). DHPG (10 microM) itself had an inhibitory effect of 20.1 +/- 1.9% (n = 4) on the fe.p.s.p. slope. 3. The concentration-response curves for the inhibitory effects of CPA (2-20 nM) on the fe.p.s.p. slope were not modified either in the presence of the group II mGluR selective agonist, (2S,3S,4S)-alpha-(carboxycyclopropyl)glycine (L-CCG-I; 1 microM), or in the presence of

  4. The retinoic acid receptor agonist Am80 increases hippocampal ADAM10 in aged SAMP8 mice.

    Science.gov (United States)

    Kitaoka, Kazuyoshi; Shimizu, Noriyuki; Ono, Koji; Chikahisa, Sachiko; Nakagomi, Madoka; Shudo, Koichi; Ishimura, Kazunori; Séi, Hiroyoshi; Yoshizaki, Kazuo

    2013-09-01

    The retinoic acid (RA, a vitamin A metabolite) receptor (RAR) is a transcription factor. Vitamin A/RA administration improves the Alzheimer's disease (AD)- and age-related attenuation of memory/learning in mouse models. Recently, a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) was identified as a key molecule in RA-mediated anti-AD mechanisms. We investigated the effect of chronic administration of the RAR agonist Am80 (tamibarotene) on ADAM10 expression in senescence-accelerated mice (SAMP8). Moreover, we estimated changes in the expression of the amyloid precursor protein (APP), amyloid beta (Aβ), and hairy/enhancer of split (Hes), which are mediated by ADAM10. Spatial working memory and the levels of a hippocampal proliferation marker (Ki67) were also assessed in these mice. ADAM10 mRNA and protein expression was significantly reduced in the hippocampus of 13-month-old SAMP8 mice; their expression improved significantly after Am80 administration. Further, after Am80 administration, the expression levels of Hes5 and Ki67 were restored and the deterioration of working memory was suppressed, whereas APP and Aβ levels remained unchanged. Our results suggest that Am80 administration effectively improves dementia by activating the hippocampal ADAM10-Notch-Hes5 proliferative pathway. PMID:23624141

  5. The FXR agonist obeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats.

    Science.gov (United States)

    Verbeke, Len; Farre, Ricard; Verbinnen, Bert; Covens, Kris; Vanuytsel, Tim; Verhaegen, Jan; Komuta, Mina; Roskams, Tania; Chatterjee, Sagnik; Annaert, Pieter; Vander Elst, Ingrid; Windmolders, Petra; Trebicka, Jonel; Nevens, Frederik; Laleman, Wim

    2015-02-01

    Bacterial translocation (BTL) drives pathogenesis and complications of cirrhosis. Farnesoid X-activated receptor (FXR) is a key transcription regulator in hepatic and intestinal bile metabolism. We studied potential intestinal FXR dysfunction in a rat model of cholestatic liver injury and evaluated effects of obeticholic acid (INT-747), an FXR agonist, on gut permeability, inflammation, and BTL. Rats were gavaged with INT-747 or vehicle during 10 days after bile-duct ligation and then were assessed for changes in gut permeability, BTL, and tight-junction protein expression, immune cell recruitment, and cytokine expression in ileum, mesenteric lymph nodes, and spleen. Auxiliary in vitro BTL-mimicking experiments were performed with Transwell supports. Vehicle-treated bile duct-ligated rats exhibited decreased FXR pathway expression in both jejunum and ileum, in association with increased gut permeability through increased claudin-2 expression and related to local and systemic recruitment of natural killer cells resulting in increased interferon-γ expression and BTL. After INT-747 treatment, natural killer cells and interferon-γ expression markedly decreased, in association with normalized permeability selectively in ileum (up-regulated claudin-1 and occludin) and a significant reduction in BTL. In vitro, interferon-γ induced increased Escherichia coli translocation, which remained unaffected by INT-747. In experimental cholestasis, FXR agonism improved ileal barrier function by attenuating intestinal inflammation, leading to reduced BTL and thus demonstrating a crucial protective role for FXR in the gut-liver axis. PMID:25592258

  6. Dose-dependent effects of celecoxib on CB-1 agonist-induced antinociception in the mice

    Directory of Open Access Journals (Sweden)

    Mohammad Reza Zarrindast

    2009-04-01

    Full Text Available "nObjective: Endocannabinoid produce analgesia that is comparable which of opioids. The mechanism of antinociceptive effects of (∆ - 9 tetrahydrocannabinol (THC is suggested to be through cyclooxygenase (COX pathway. In the present work, the effect of two extreme dose ranges of celecoxib (mg/kg and ng/kg, a cyclooxygenase-2 (COX-2 antagonist, on arachidonylcyclopropylamide (ACPA, a selective CB1 agonist induced antinociception in mice was examined. "nMethods: We have investigated the interaction between celecoxib, at the doses of mg/kg (50, 100, 200 and 400 i.p.  and ultra low dose (ULD (25 and 50 ng/kg, i.p., on the antinociceptive effect of intracerebroventricular (i.c.v. administration of ACPA (0.004, 0.0625 and 1 μg/mice, using formalin test in mice. "nResults: I.C.V. administration of ACPA induced antinociception. Intraperitoneal administration of celecoxib (mg/kg and its ULD (ng/kg attenuated and potentiated, ACPA antinociceptive effects, respectively. "nConclusion: It is concluded that the mg/kg doses of COX-2 antagonist showed opposite effects compare to the ultra-low dose of the drug.

  7. A Dopamine Receptor D2-Type Agonist Attenuates the Ability of Stress to Alter Sleep in Mice

    OpenAIRE

    Jefferson, F.; Ehlen, J. C.; Williams, N S; Montemarano, J. J.; Paul, K. N.

    2014-01-01

    Although sleep disruptions that accompany stress reduce quality of life and deteriorate health, the mechanisms through which stress alters sleep remain obscure. Psychological stress can alter sleep in a variety of ways, but it has been shown to be particularly influential on rapid eye movement (REM) sleep. Prolactin (PRL), a sexually dimorphic, stress-sensitive hormone whose basal levels are higher in females, has somnogenic effects on REM sleep. In the current study, we examined the relation...

  8. Attenuation in silica-based optical fibers

    DEFF Research Database (Denmark)

    Wandel, Marie Emilie

    2006-01-01

    absorption peaks in order to investigate the cause of an unusual high attenuation in a series of transmission fibers. Strong indications point to Ni2+ in octahedral coordination as being the cause of the high attenuation. The attenuation of fibers having a high core refractive index is analyzed and the cause...... well as the viscosity profile a lower attenuation of high index fibers can be obtained. The design of dispersion compensating fibers using the super mode approach is described, the object being to design dispersion compensating fibers for dispersion compensating fiber modules having a low attenuation......, described by a high figure of merit. The major trade offs encountered when designing dispersion compensating fibers with high figure of merit are to obtain a very negative dispersion, low attenuation and low micro bend loss at the same time. The model for predicting the attenuation of high index fibers is...

  9. Illegal use of beta-adrenergic agonists: European Community.

    Science.gov (United States)

    Kuiper, H A; Noordam, M Y; van Dooren-Flipsen, M M; Schilt, R; Roos, A H

    1998-01-01

    The use of veterinary medicinal products within the European Community is governed by a series of directives and regulations that describe the requirements for safety, quality, and efficacy of these products. Veterinary therapeutic use of beta-agonists has only been approved in the case of clenbuterol for bronchodilatation in horses and calves and for tocolysis in cows. No beta-agonists have been permitted in the European Community for growth-promoting purposes in farm animals. Surveillance for the presence of residues of veterinary agents in food-producing animals and meat is regulated by the Directive 86/469/EEC containing specific guidelines for sampling procedures on farms and in slaughterhouses. The level and frequency of sampling is dependent on the category of compounds and animal species. When positive samples have been identified (above certain action levels), sampling intensity is increased. Results of monitoring programs in EU member states during 1992 and 1993 for the occurrence of residues of beta-agonists in food-producing animals vary substantially with respect to the percentages of positive samples, ranging from 0 to 7%. The variability is partly explained by differences in sampling strategies, detection methods, and action levels applied. Identification of the proper matrices for sampling and detection of beta-agonists is important. In the case of clenbuterol, hair and choroid retinal tissue are appropriate tissues because clenbuterol accumulates in these matrices. A clear decrease in the use of clenbuterol in cattle has been observed in The Netherlands, Germany, Northern Ireland, and Spanish Basque Country over the last 3 yr. This is partly due to intensified surveillance activities at farms and slaughterhouses by governmental agencies and production sector organizations. There are data on human intoxication following consumption of liver or meat from cattle treated with beta-agonists. At the concentrations of clenbuterol measured in contaminated

  10. Interactions of dopamine agonists with brain D1 receptors labeled by 3H-antagonists. Evidence for the presence of high and low affinity agonist-binding states

    International Nuclear Information System (INIS)

    The interactions of dopaminergic agonists and antagonists with 3H-antagonist labeled D1 dopamine receptors of rat striatum have been characterized. [3H]Flupentixol has been found to selectively label D1 dopamine receptors when its binding to D2 dopamine receptors is blocked by the inclusion of D2 selective concentrations of unlabeled spiroperidol or domperidone. Antagonist/3H-antagonist competition curves are of uniformly steep slope (nH . 1.0) suggesting the presence of a single D1 dopamine receptor. Agonist/3H-antagonist competition curves are extremely shallow (nH less than or equal to 0.5) for agonists of high relative efficacy, suggesting the presence of heterogeneous populations of agonist-binding states of the D1 dopamine receptor. Computer-modeling techniques were used to estimate affinities and relative site densities for these heterogeneous binding states. This analysis indicates that the ratio of agonist affinities for low and high affinity agonist-binding states is correlated with agonist relative efficacies in activating adenylate cyclase in membrane homogenates. Under the assay conditions employed, the addition of saturating concentrations of guanine nucleotides reduced, but did not abolish, the relative density of high affinity agonist-binding sites. These binding data can, at least in part, be explained by postulating two states of the D1 dopamine receptor, inducible by agonists but not by antagonists and modulated by guanine nucleotides

  11. PPAR GAMMA AGONISTS: AN EFFECTIVE STRATEGY FOR CANCER TREATMENT

    Directory of Open Access Journals (Sweden)

    Divya G.S

    2013-10-01

    Full Text Available PPAR-γ regulates cellular differentiation, development and metabolism. They play these essential roles by functioning as transcription factors regulating the expression of genes. The PPARs mainly are of three types α, β and γ. The PPAR-γ expressed in three forms γ1, γ2 and γ3 present in different tissues. When PPAR binds its ligand, transcription of target gene is increased or decreased. Tzds were able to induce cell differentiation and apoptosis or inhibit cell proliferation both in vitro and in vivo. However, widespread use of thiazolidinediones (TZDs, the clinically used synthetic PPAR gamma agonists, has been limited by adverse effects. So in this review we are suggesting some new molecules other than thiazolidine diones which can act as potential anticancer agents, after explaining the mechanism of action of PPAR-γ agonists as anticancer agents especially thiazolidinediones.

  12. Biological Rationale for the Use of PPARγ Agonists in Glioblastoma

    OpenAIRE

    Hayley Patricia Ellis; Kathreena Mary Kurian

    2014-01-01

    Glioblastoma multiforme (GBM) is the most common primary intrinsic central nervous system tumor and has an extremely poor overall survival with only 10% patients being alive after 5 years. There has been interesting preliminary evidence suggesting that diabetic patients receiving peroxisome proliferator-activated receptor gamma (PPARγ) agonists, a group of anti-diabetic, thiazolidinedione drugs, have an increased median survival for glioblastoma. Although thiazolidinediones are effective oral...

  13. In Vitro Evaluation of TLR4 Agonist Activity: Formulation Effects

    OpenAIRE

    Misquith, Ayesha; Millie Fung, H. W.; Dowling, Quinton M.; Guderian, Jeffrey A.; Vedvick, Thomas S.; Fox, Christopher B.

    2013-01-01

    Effective in vitro evaluation of vaccine adjuvants would allow higher throughput screening compared to in vivo studies. However, vaccine adjuvants comprise a wide range of structures and formulations ranging from soluble TLR agonists to complex lipid-based formulations. The effects of formulation parameters on in vitro bioactivity assays and the correlations with in vivo adjuvant activity is not well understood. In the present work, we employ the Limulus amebocyte lysate assay and a human mac...

  14. Alternation of Agonists and Antagonists During Turtle Hindlimb Motor Rhythms

    OpenAIRE

    Stein, Paul S.G.

    2010-01-01

    In a variety of vertebrates, including turtle, many classical and contemporary studies of spinal cord neuronal networks generating rhythmic motor behaviors emphasize a Reciprocal Model with alternation of agonists and antagonists, alternation of excitatory and inhibitory postsynaptic potentials, and reciprocal inhibition. Some studies of spinal cord neuronal networks, including those in turtle during scratch motor rhythms, describe a Balanced Model with concurrent excitatory and inhibitory po...

  15. Melatonin agonists for treatment of sleep and depressive disorders

    OpenAIRE

    Pandi-Perumal, Seithikurippu R.; Brown, Gregory M.; Daniel P. Cardinali; Venkataramanujan Srinivasan

    2011-01-01

    Melatonin the hormone secreted by the pineal gland has been effective in improving sleep both in normal sleepers and insomniacs and has been used successfully in treating sleep and circadian rhythm sleep disorders. The lack of consistency in the reports published by the authors is attributed to the differential bioavailabilty and short half-life of melatonin. Sleep disturbances are also prominent features of depressive disorders. To overcome this problem, melatonergic agonists with sleep prom...

  16. Discriminative learning occasioned by the administration of a dopamine agonist

    OpenAIRE

    Keller, Sabine; Delius, Juan

    2001-01-01

    Rationale: The repeated administration of psychostimulants usually brings about a progressive increment of the behavioral responses that they induce. We examined to what extent this sensitization is due to an associative learning process. Objectives: The dopamine agonist apomorphine elicits stereotyped pecking in pigeons, a response that increases with successive intramuscular injections. We tested whether this sensitized pecking would be discriminatively directed at environmental stimuli tha...

  17. Improving the developability profile of pyrrolidine progesterone receptor partial agonists

    Energy Technology Data Exchange (ETDEWEB)

    Kallander, Lara S.; Washburn, David G.; Hoang, Tram H.; Frazee, James S.; Stoy, Patrick; Johnson, Latisha; Lu, Qing; Hammond, Marlys; Barton, Linda S.; Patterson, Jaclyn R.; Azzarano, Leonard M.; Nagilla, Rakesh; Madauss, Kevin P.; Williams, Shawn P.; Stewart, Eugene L.; Duraiswami, Chaya; Grygielko, Eugene T.; Xu, Xiaoping; Laping, Nicholas J.; Bray, Jeffrey D.; Thompson, Scott K. (GSKPA)

    2010-09-17

    The previously reported pyrrolidine class of progesterone receptor partial agonists demonstrated excellent potency but suffered from serious liabilities including hERG blockade and high volume of distribution in the rat. The basic pyrrolidine amine was intentionally converted to a sulfonamide, carbamate, or amide to address these liabilities. The evaluation of the degree of partial agonism for these non-basic pyrrolidine derivatives and demonstration of their efficacy in an in vivo model of endometriosis is disclosed herein.

  18. Synthesis of fluorinated agonist of sphingosine-1-phosphate receptor 1.

    Science.gov (United States)

    Aliouane, Lucie; Chao, Sovy; Brizuela, Leyre; Pfund, Emmanuel; Cuvillier, Olivier; Jean, Ludovic; Renard, Pierre-Yves; Lequeux, Thierry

    2014-09-01

    The bioactive metabolite sphingosine-1-phosphate (S1P), a product of sphingosine kinases (SphKs), mediates diverse biological processes such as cell differentiation, proliferation, survival and angiogenesis. A fluorinated analogue of S1P receptor agonist has been synthesized by utilizing a ring opening reaction of oxacycles by a lithiated difluoromethylphosphonate anion as the key reaction. In vitro activity of this S1P analogue is also reported. PMID:25047939

  19. Phentolamine--an unexpected agonist in the rabbit.

    OpenAIRE

    Angus, J. A.; Lew, M. J.

    1984-01-01

    Phentolamine (0.1-10 microM) caused an anomalous rightward shift of the relationship between the number of electrical field pulses and tachycardia in the rabbit isolated right atrium. Phentolamine was apparently acting as a presynaptic agonist on sympathetic nerve endings to inhibit transmitter release. The effect was prevented by benextramine treatment and antagonized 10 fold by yohimbine (1 microM) but not by prazosin (0.1 microM). In ganglion-blocked (mecamylamine) conscious or anaesthetiz...

  20. Beta-adrenergic agonists as additive in beef cattle

    Directory of Open Access Journals (Sweden)

    Marcelo Vedovatto

    2014-10-01

    Full Text Available The agonists receptor beta-adrenergic (β-AA are present in virtually all types of mammalian cells and are stimulated by catecholamines (epinephrine and norepinephrine produced by the organism itself. The β-AA agonists are synthetic substances with similar structure to these amines. When provided in the diet they alter the body composition of animals, affecting the distribution of nutrients toward to protein deposition, and decreasing lipogenesis. Although the mechanisms of action are not fully understood, these may cause morphological and physiological changes such as increased blood flow decrease in plasma insulin, decreased lipogenesis, and muscle hypertrophy mainly in type II fibers. We also observed changes in motility and secretions grastointestinal tract, beyond the direct influence on the rumen bacteria, altering the digestibility of the diet. The β-AA agonists released in some countries for use in beef cattle are ractopamine hydrochloride and zilpaterol hydrochloride. According to literature data, the inclusion of these additives in the diet of feedlot cattle has been associated with an increase infeed efficiency with the increase in daily weight gain and with equal or lower feed intake. Carcass characteristics improvement was verified in carcass weight, and increased loin eye area, but with the possibility to decrease the subcutaneous fat thickness and marbling. Reviews in sensory panel of meat from animals consuming β-AA agonists showed decreased tenderness and juiciness. Thus β-AA improve performance and carcass characteristics, but more studies are needed to confirm whether they have negative influence on the organoleptic characteristics of the meat.

  1. Imaging Rayleigh wave attenuation with USArray

    Science.gov (United States)

    Bao, Xueyang; Dalton, Colleen A.; Jin, Ge; Gaherty, James B.; Shen, Yang

    2016-07-01

    The EarthScope USArray provides an opportunity to obtain detailed images of the continental upper mantle at an unprecedented scale. The majority of mantle models derived from USArray data to date contain spatial variations in seismic-wave speed; however, in many cases these data sets do not by themselves allow a non-unique interpretation. Joint interpretation of seismic attenuation and velocity models can improve upon the interpretations based only on velocity and provide important constraints on the temperature, composition, melt content, and volatile content of the mantle. The surface wave amplitudes that constrain upper-mantle attenuation are sensitive to factors in addition to attenuation, including the earthquake source excitation, focusing and defocusing by elastic structure, and local site amplification. Because of the difficulty of isolating attenuation from these other factors, little is known about the attenuation structure of the North American upper mantle. In this study, Rayleigh wave traveltime and amplitude in the period range 25-100 s are measured using an interstation cross-correlation technique, which takes advantage of waveform similarity at nearby stations. Several estimates of Rayleigh wave attenuation and site amplification are generated at each period, using different approaches to separate the effects of attenuation and local site amplification on amplitude. It is assumed that focusing and defocusing effects can be described by the Laplacian of the traveltime field. All approaches identify the same large-scale patterns in attenuation, including areas where the attenuation values are likely contaminated by unmodelled focusing and defocusing effects. Regionally averaged attenuation maps are constructed after removal of the contaminated attenuation values, and the variations in intrinsic shear attenuation that are suggested by these Rayleigh wave attenuation maps are explored.

  2. Emerging strategies for exploiting cannabinoid receptor agonists as medicines.

    Science.gov (United States)

    Pertwee, Roger G

    2009-02-01

    Medicines that activate cannabinoid CB(1) and CB(2) receptor are already in the clinic. These are Cesamet (nabilone), Marinol (dronabinol; Delta(9)-tetrahydrocannabinol) and Sativex (Delta(9)-tetrahydrocannabinol with cannabidiol). The first two of these medicines can be prescribed to reduce chemotherapy-induced nausea and vomiting. Marinol can also be prescribed to stimulate appetite, while Sativex is prescribed for the symptomatic relief of neuropathic pain in adults with multiple sclerosis and as an adjunctive analgesic treatment for adult patients with advanced cancer. One challenge now is to identify additional therapeutic targets for cannabinoid receptor agonists, and a number of potential clinical applications for such agonists are mentioned in this review. A second challenge is to develop strategies that will improve the efficacy and/or the benefit-to-risk ratio of a cannabinoid receptor agonist. This review focuses on five strategies that have the potential to meet either or both of these objectives. These are strategies that involve: (i) targeting cannabinoid receptors located outside the blood-brain barrier; (ii) targeting cannabinoid receptors expressed by a particular tissue; (iii) targeting up-regulated cannabinoid receptors; (iv) targeting cannabinoid CB(2) receptors; or (v) 'multi-targeting'. Preclinical data that justify additional research directed at evaluating the clinical importance of each of these strategies are also discussed. PMID:19226257

  3. Suppression of atherosclerosis by synthetic REV-ERB agonist

    Energy Technology Data Exchange (ETDEWEB)

    Sitaula, Sadichha [Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458 (United States); Billon, Cyrielle [Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104 (United States); Kamenecka, Theodore M.; Solt, Laura A. [Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458 (United States); Burris, Thomas P., E-mail: burristp@slu.edu [Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104 (United States)

    2015-05-08

    The nuclear receptors for heme, REV-ERBα and REV-ERBβ, play important roles in the regulation of metabolism and inflammation. Recently it was demonstrated that reduced REV-ERBα expression in hematopoetic cells in LDL receptor null mice led to increased atherosclerosis. We sought to determine if synthetic REV-ERB agonists that we have developed might have the ability to suppress atherosclerosis in this model. A previously characterized synthetic REV-ERB agonist, SR9009, was used to determine if activation of REV-ERB activity would affect atherosclerosis in LDL receptor deficient mice. Atherosclerotic plaque size was significantly reduced (p < 0.05) in mice administered SR9009 (100 mg/kg) for seven weeks compared to control mice (n = 10 per group). SR9009 treatment of bone marrow-derived mouse macrophages (BMDM) reduced the polarization of BMDMs to proinflammatory M1 macrophage while increasing the polarization of BMDMs to anti-inflammatory M2 macrophages. Our results suggest that pharmacological targeting of REV-ERBs may be a viable therapeutic option for treatment of atherosclerosis. - Highlights: • Synthetic REV-ERB agonist treatment reduced atherosclerosis in a mouse model. • Pharmacological activation of REV-ERB decreased M1 macrophage polarization. • Pharmacological activation of REV-ERB increased M2 macrophage polarization.

  4. Biological Rationale for the Use of PPARγ Agonists in Glioblastoma

    Directory of Open Access Journals (Sweden)

    Hayley Patricia Ellis

    2014-03-01

    Full Text Available Glioblastoma Multiforme (GBM is the most common primary intrinsic CNS tumour and has an extremely poor overall survival, despite advances in neurosurgery, chemotherapy and radiation therapy. There has been interesting preliminary evidence suggesting that patients receiving the group of anti-diabetic drugs known as PPARγ (Peroxisome proliferator-activated receptor gamma agonists have a lower incidence of glioma. The nuclear hormone receptor PPARγ has been found to be expressed in high grade gliomas, and its activation has been shown to have several antineoplastic effects on human and rat glioma cell lines, and in some instances an additional protective increase in antioxidant enzymes has been observed in normal astrocytes. At present, no clinical trials are underway with regards to treating glioma patients using PPARγ agonists, as Pioglitazone and Rosiglitazone are only FDA-approved for use in treatment of type-2 diabetes. This review presents the case for evaluating the potential of PPARγ agonists as novel adjuvants in the treatment of high grade glioma. We introduce the PPARγ pathway, PPARγ gene and its products and examine recent research in glioblastoma.

  5. Cryptochinones from Cryptocarya chinensis act as farnesoid X receptor agonists.

    Science.gov (United States)

    Lin, Hsiang-Ru; Chou, Tsung-Hsien; Huang, Din-Wen; Chen, Ih-Sheng

    2014-09-01

    Cryptochinones A-D are tetrahydroflavanones isolated from the leaves of Cryptocarya chinensis, an evergreen tree whose extracts are believed to have a variety of health benefits. The origin of their possible bioactivity is unclear. The farnesoid X receptor (FXR) is a member of nuclear receptor superfamily that has been widely targeted for developing treatments for chronic liver disease and for hyperglycemia. We studied whether cryptochinones A-D, which are structurally similar to known FXR ligands, may act at this target. Indeed, in mammalian one-hybrid and transient transfection reporter assays, cryptochinones A-D transactivated FXR to modulate promoter action including GAL4, SHP, CYP7A1, and PLTP promoters in dose-dependent manner, while they exhibited similar agonistic activity as chenodeoxycholic acid (CDCA), an endogenous FXR agonist. Through molecular modeling docking studies we evaluated their ability to bind to the FXR ligand binding pocket. Our results indicate that cryptochinones A-D can behave as FXR agonists. PMID:25127166

  6. Suppression of atherosclerosis by synthetic REV-ERB agonist

    International Nuclear Information System (INIS)

    The nuclear receptors for heme, REV-ERBα and REV-ERBβ, play important roles in the regulation of metabolism and inflammation. Recently it was demonstrated that reduced REV-ERBα expression in hematopoetic cells in LDL receptor null mice led to increased atherosclerosis. We sought to determine if synthetic REV-ERB agonists that we have developed might have the ability to suppress atherosclerosis in this model. A previously characterized synthetic REV-ERB agonist, SR9009, was used to determine if activation of REV-ERB activity would affect atherosclerosis in LDL receptor deficient mice. Atherosclerotic plaque size was significantly reduced (p < 0.05) in mice administered SR9009 (100 mg/kg) for seven weeks compared to control mice (n = 10 per group). SR9009 treatment of bone marrow-derived mouse macrophages (BMDM) reduced the polarization of BMDMs to proinflammatory M1 macrophage while increasing the polarization of BMDMs to anti-inflammatory M2 macrophages. Our results suggest that pharmacological targeting of REV-ERBs may be a viable therapeutic option for treatment of atherosclerosis. - Highlights: • Synthetic REV-ERB agonist treatment reduced atherosclerosis in a mouse model. • Pharmacological activation of REV-ERB decreased M1 macrophage polarization. • Pharmacological activation of REV-ERB increased M2 macrophage polarization

  7. Dopamine agonist activity of EMD 23,448

    Energy Technology Data Exchange (ETDEWEB)

    Martin, G.E.; Pettibone, D.J. (Merck Sharp and Dohme Research Laboratories, West Point, Pennsylvania (USA). Dept. of Pharmacology)

    1985-01-01

    EMD 23,448 was examined in tests of dopaminergic function and was found to be an atypical dopamine (DA) agonist. EMD 23,448 was a weak or inactive DA agonist when examined in tests of normal postsynaptic DA receptor function: production of stereotypy in the rat (ED/sub 50/ greater than sign 5.0 mg/kg.i.p.); production of emesis in beagles (minimum effective dose = 81..mu..g/kg i.v.); and, enhanced locomotor activity of the mouse (no excitation in doses <=50 mg/i.p.). Moreover, EMD 23,448 was relatively weak in competing for (/sup 3/H)-apomorphine binding to rat striatal membranes (Ki, 205 nM). On the other hand, this indolyl-3-butylamine did activate supersensitive postsynaptic DA receptors. Specifically, it elicited contralateral turning in rats with a unilateral 6-hydroxydopamine lesion of the substantia nigra (ED/sub 50/ value = 0.9 mg/kg) and did elicit stereotypy in rats given chronic daily haloperidol treatments. EMD 23,448 also exerted pharmacological effects in tests designed to measure activation of dopamine autoreceptors. It inhibited the ..gamma..-butyrolactone-induced increase in striatal dopa levels (ED/sub 50/ = 1 mg/kg i.p.) and produced a dose-related fall in the locomotor activity of the mouse. The results are discussed and contrasted with data derived for apomorphine and the putatively selective autoreceptor agonist (+-)-3-PPP.

  8. Rational design of humanized dual-agonist antibodies.

    Science.gov (United States)

    Zhang, Yong; Liu, Yan; Wang, Ying; Schultz, Peter G; Wang, Feng

    2015-01-14

    The ultralong heavy chain complementarity determining region 3 (CDR3H) of bovine antibody BLV1H12 folds into a novel "stalk-knob" structural motif and has been exploited to generate novel agonist antibodies through replacement of the "knob" domain with cytokines and growth factors. By translating this unique "stalk-knob" architecture to the humanized antibody trastuzumab (referred to hereafter by its trade name, Herceptin, Genentech USA), we have developed a versatile approach to the generation of human antibody agonists. Human erythropoietin (hEPO) or granulocyte colony-stimulating factor (hGCSF) was independently fused into CDR3H, CDR2H, or CDR3L of Herceptin using an engineered "stalk" motif. The fusion proteins express in mammalian cells in good yields and have similar in vitro biological activities compared to hEPO and hGCSF. On the basis of these results we then generated a bi-functional Herceptin-CDR fusion protein in which both hEPO and hGCSF were grafted into the heavy- and light-chain CDR3 loops, respectively. This bi-functional antibody fusion exhibited potent EPO and GCSF agonist activities. This work demonstrates the versatility of the CDR-fusion strategy for generating functional human antibody chimeras and provides a novel approach to the development of multi-functional antibody-based therapeutics. PMID:25494484

  9. EET agonist prevents adiposity and vascular dysfunction in rats fed a high fat diet via a decrease in Bach 1 and an increase in HO-1 levels.

    Science.gov (United States)

    Sodhi, Komal; Puri, Nitin; Inoue, Kazuyoshi; Falck, John R; Schwartzman, Michal L; Abraham, Nader G

    2012-08-01

    Recent reports have shown interplay between EETs (epoxides) and the heme oxygenase (HO) system in attenuating adipogenesis in cell culture models; prompting an examination of the effectiveness of EET agonist on obesity and associated cardio-metabolic dysfunction. Patho-physiological effects of an EET agonist (NUDSA) were contrasted in the absence and in the presence of stannous mesoporphyrin (an HO inhibitor) in SD rats fed a high fat (58%, HF) for 16 weeks. Animals on HF diet exhibited enhanced oxidative stress, increased levels of inflammatory cytokines and decreased levels of adiponectin along with reduced vascular and adipose tissue levels of EETs, HO-1; as compared to control rats (11% dietary fat). Treatment with NUDSA not only reversed serum adiponectin and vascular and adipose tissue levels of EETs and HO-1, but also, decreased blood pressure, subcutaneous and visceral fat content and serum TNFα and IL-6 levels in rats on HF diet. Aortic endothelial function, peNOS expression and adipose tissue markers of energy homeostasis i.e. pAMPK, Sirt1 and FAS, impaired in rats fed a HF diet, were restored in animals treated with this EET agonist. That NUDSA enhanced HO-1 expression, was accompanied by increase in p-GSK-3β and pAKT levels along with attenuation of adipose tissue levels of Bach 1--the transcriptional suppresser of HO-1 expression. Prevention of these beneficial effects of NUDSA, in animals on HF diet and concurrently exposed to NUDSA and SnMP, supports the role of EET-HO interaction in mediating such effects. Taken together, our findings suggest that the EETs stimulate HO-1 expression via suppression of Bach 1 and interplay of these two systems affords vascular and metabolic protection in diet induced obesity. PMID:22209722

  10. Adrenergic activation attenuates astrocyte swelling induced by hypotonicity and neurotrauma.

    Science.gov (United States)

    Vardjan, Nina; Horvat, Anemari; Anderson, Jamie E; Yu, Dou; Croom, Deborah; Zeng, Xiang; Lužnik, Zala; Kreft, Marko; Teng, Yang D; Kirov, Sergei A; Zorec, Robert

    2016-06-01

    Edema in the central nervous system can rapidly result in life-threatening complications. Vasogenic edema is clinically manageable, but there is no established medical treatment for cytotoxic edema, which affects astrocytes and is a primary trigger of acute post-traumatic neuronal death. To test the hypothesis that adrenergic receptor agonists, including the stress stimulus epinephrine protects neural parenchyma from damage, we characterized its effects on hypotonicity-induced cellular edema in cortical astrocytes by in vivo and in vitro imaging. After epinephrine administration, hypotonicity-induced swelling of astrocytes was markedly reduced and cytosolic 3'-5'-cyclic adenosine monophosphate (cAMP) was increased, as shown by a fluorescence resonance energy transfer nanosensor. Although, the kinetics of epinephrine-induced cAMP signaling was slowed in primary cortical astrocytes exposed to hypotonicity, the swelling reduction by epinephrine was associated with an attenuated hypotonicity-induced cytosolic Ca(2+) excitability, which may be the key to prevent astrocyte swelling. Furthermore, in a rat model of spinal cord injury, epinephrine applied locally markedly reduced neural edema around the contusion epicenter. These findings reveal new targets for the treatment of cellular edema in the central nervous system. GLIA 2016;64:1034-1049. PMID:27018061

  11. SEISMIC ATTENUATION FOR RESERVOIR CHARACTERIZATION

    Energy Technology Data Exchange (ETDEWEB)

    Joel Walls; M.T. Taner; Naum Derzhi; Gary Mavko; Jack Dvorkin

    2003-12-01

    We have developed and tested technology for a new type of direct hydrocarbon detection. The method uses inelastic rock properties to greatly enhance the sensitivity of surface seismic methods to the presence of oil and gas saturation. These methods include use of energy absorption, dispersion, and attenuation (Q) along with traditional seismic attributes like velocity, impedance, and AVO. Our approach is to combine three elements: (1) a synthesis of the latest rock physics understanding of how rock inelasticity is related to rock type, pore fluid types, and pore microstructure, (2) synthetic seismic modeling that will help identify the relative contributions of scattering and intrinsic inelasticity to apparent Q attributes, and (3) robust algorithms that extract relative wave attenuation attributes from seismic data. This project provides: (1) Additional petrophysical insight from acquired data; (2) Increased understanding of rock and fluid properties; (3) New techniques to measure reservoir properties that are not currently available; and (4) Provide tools to more accurately describe the reservoir and predict oil location and volumes. These methodologies will improve the industry's ability to predict and quantify oil and gas saturation distribution, and to apply this information through geologic models to enhance reservoir simulation. We have applied for two separate patents relating to work that was completed as part of this project.

  12. A pivotal role of FOS-mediated BECN1/Beclin 1 upregulation in dopamine D2 and D3 receptor agonist-induced autophagy activation

    Science.gov (United States)

    Wang, Jian-Da; Cao, Yu-Lan; Li, Qian; Yang, Ya-Ping; Jin, Mengmeng; Chen, Dong; Wang, Fen; Wang, Guang-Hui; Qin, Zheng-Hong; Hu, Li-Fang; Liu, Chun-Feng

    2015-01-01

    Autophagy dysfunction is implicated in the pathogenesis of Parkinson disease (PD). BECN1/Beclin 1 acts as a critical regulator of autophagy and other cellular processes; yet, little is known about the function and regulation of BECN1 in PD. In this study, we report that dopamine D2 and D3 receptor (DRD2 and DRD3) activation by pramipexole and quinpirole could enhance BECN1 transcription and promote autophagy activation in several cell lines, including PC12, MES23.5 and differentiated SH-SY5Y cells, and also in tyrosine hydroxylase positive primary midbrain neurons. Moreover, we identified a novel FOS (FBJ murine osteosarcoma viral oncogene homolog) binding sequence (5′-TGCCTCA-3′) in the rat and human Becn1/BECN1 promoter and uncovered an essential role of FOS binding in the enhancement of Becn1 transcription in PC12 cells in response to the dopamine agonist(s). In addition, we demonstrated a critical role of intracellular Ca2+ elevation, followed by the enhanced phosphorylation of CAMK4 (calcium/calmodulin-dependent protein kinase IV) and CREB (cAMP responsive element binding protein) in the increases of FOS expression and autophagy activity. More importantly, pramipexole treatment ameliorated the SNCA/α-synuclein accumulation in rotenone-treated PC12 cells that overexpress wild-type or A53T mutant SNCA by promoting autophagy flux. This effect was also demonstrated in the substantia nigra and the striatum of SNCAA53T transgenic mice. The inhibition of SNCA accumulation by pramipexole was attenuated by cotreatment with the DRD2 and DRD3 antagonists and Becn1 siRNAs. Thus, our findings suggest that DRD2 and DRD3 agonist(s) may induce autophagy activation via a BECN1-dependent pathway and have the potential to reduce SNCA accumulation in PD. PMID:26649942

  13. Synergism between a serotonin 5-HT2A receptor (5-HT2AR) antagonist and 5-HT2CR agonist suggests new pharmacotherapeutics for cocaine addiction.

    Science.gov (United States)

    Cunningham, Kathryn A; Anastasio, Noelle C; Fox, Robert G; Stutz, Sonja J; Bubar, Marcy J; Swinford, Sarah E; Watson, Cheryl S; Gilbertson, Scott R; Rice, Kenner C; Rosenzweig-Lipson, Sharon; Moeller, F Gerard

    2013-01-16

    Relapse to cocaine dependence, even after extended abstinence, involves a number of liability factors including impulsivity (predisposition toward rapid, unplanned reactions to stimuli without regard to negative consequences) and cue reactivity (sensitivity to cues associated with cocaine-taking which can promote cocaine-seeking). These factors have been mechanistically linked to serotonin (5-hydroxytryptamine, 5-HT) signaling through the 5-HT(2A) receptor (5-HT(2A)R) and 5-HT(2C)R; either a selective 5-HT(2A)R antagonist or a 5-HT(2C)R agonist suppresses impulsivity and cocaine-seeking in preclinical models. We conducted proof-of-concept analyses to evaluate whether a combination of 5-HT(2A)R antagonist plus 5-HT(2C)R agonist would have synergistic effects over these liability factors for relapse as measured in a 1-choice serial reaction time task and cocaine self-administration/reinstatement assay. Combined administration of a dose of the selective 5-HT(2A)R antagonist M100907 plus the 5-HT(2C)R agonist WAY163909, each ineffective alone, synergistically suppressed cocaine-induced hyperactivity, inherent and cocaine-evoked impulsive action, as well as cue- and cocaine-primed reinstatement of cocaine-seeking behavior. The identification of synergism between a 5-HT(2A)R antagonist plus a 5-HT(2C)R agonist to attenuate these factors important in relapse indicates the promise of a bifunctional ligand as an anti-addiction pharmacotherapeutic, setting the stage to develop new ligands with improved efficacy, potency, selectivity, and in vivo profiles over the individual molecules. PMID:23336050

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

    Directory of Open Access Journals (Sweden)

    Christopher F Rider

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

  15. The treatment of Parkinson's disease with dopamine agonists

    Directory of Open Access Journals (Sweden)

    Frank, Wilhelm

    2008-06-01

    Full Text Available Parkinson’s disease is a chronic degenerative organic disease with unknown causes. A disappearance of cells with melanin in the substantia nigra is considered as biological artefact of the disease, which causes a degenerative loss of neurons in the corpus striatum of mesencephalon. This structure produces also the transmitter substance dopamine. Due to this disappearance of cells dopamine is not produced in a sufficient quantity which is needed for movement of the body. The questions of this report are concerned the efficiency and safety of a treatment with dopamine agonists. Furthermore the cost-effectiveness is investigated as well as ethic questions. The goal is to give recommendation for the use of dopamine agonists to the German health system. A systematic literature search was done. The identified studies have different methodological quality and investigate different hypothesis and different outcome criteria. Therefore a qualitative method of information synthesis was chosen. Since the introduction of L-Dopa in the 1960´s it is considered as the most effective substance to reduce all the cardinal symptoms of Parkinson disease. This substance was improved in the course of time. Firstly some additional substances were given (decarbonxylase inhibitors, catechol-o-transferase inhibitors (COMT-inhibitors, monoaminoxydase-inhibitors (MAO-inhibitors and NMDA-antagonists (N-Methyl-d-aspartat-antagonists. In the practical therapy of Parkinson dopamine agonists play an important role, because they directly use the dopamine receptors. The monotherapy of Parkinson disease is basically possible and is used in early stages of the disease. Clinical practise has shown, that an add on therapy with dopamine agonists can led to a reduction of the dose of L-dopa and a reduction of following dyskinesia. The studies for effectiveness include studies for the initial therapy, monotherapy and add-on-therapy. Basically there is a good effectiveness of dopamine

  16. Differential dust attenuation in CALIFA galaxies

    Science.gov (United States)

    Vale Asari, N.; Cid Fernandes, R.; Amorim, A. L.; Lacerda, E. A. D.; Schlickmann, M.; Wild, V.; Kennicutt, R. C.

    2016-06-01

    Dust attenuation has long been treated as a simple parameter in SED fitting. Real galaxies are, however, much more complicated: The measured dust attenuation is not a simple function of the dust optical depth, but depends strongly on galaxy inclination and the relative distribution of stars and dust. We study the nebular and stellar dust attenuation in CALIFA galaxies, and propose some empirical recipes to make the dust treatment more realistic in spectral synthesis codes. By adding optical recombination emission lines, we find better constraints for differential attenuation. Those recipes can be applied to unresolved galaxy spectra, and lead to better recovered star formation rates.

  17. Ultrasonic attenuation in cuprate superconductors

    Indian Academy of Sciences (India)

    T Gupta; D M Gaitonde

    2002-05-01

    We calculate the longitudinal ultrasonic attenuation rate (UAR) in clean d-wave superconductors in the Meissner and the mixed phases. In the Meissner phase we calculate the contribution of previously ignored processes involving the excitation of a pair of quasi-holes or quasi-particles. There is a contribution ∝ in the regime B ≪ F ≪ 0 and a contribution ∝ 1/ in the regime F ≪ B ≪ 0. We find that these contributions to the UAR are large and cannot be ignored. In the mixed phase, using a semi-classical description, we calculate the electronic quasi-particle contribution to the UAR which at very low , has a independent term proportional to $\\sqrt{H}$.

  18. Attenuation characteristics of gypsum wallboard

    International Nuclear Information System (INIS)

    Increased cost of lead is promoting enhanced usage of common building materials for shielding in diagnostic medical and dental facilities where only a few half-value layers (HVLs) are needed. Attenuation of primary beam X-ray photons in gypsum wallboard as a function of kVp, filtration, and wallboard thickness have been measured. Findings, obtained using a Victoreen 555 with an 0.1 DAS probe in poor geometry, are substantially in agreement with the sparse data in the literature but extend to thicker wall configurations and different kVp and filtration parameters. These findings are of value in maximizing the benefit/cost ratio for diagnostic shielding, and strengthen the conviction that, where used for shielding purposes, common building materials must be installed carefully and HVL-depth dependence considered thoroughly. (author)

  19. Antinociceptive properties of selective MT(2) melatonin receptor partial agonists.

    Science.gov (United States)

    López-Canul, Martha; Comai, Stefano; Domínguez-López, Sergio; Granados-Soto, Vinicio; Gobbi, Gabriella

    2015-10-01

    Melatonin is a neurohormone involved in the regulation of both acute and chronic pain whose mechanism is still not completely understood. We have recently demonstrated that selective MT2 melatonin receptor partial agonists have antiallodynic properties in animal models of chronic neuropathic pain by modulating ON/OFF cells of the descending antinociceptive system. Here, we examined the antinociceptive properties of the selective MT2 melatonin receptor partial agonists N-{2-[(3-methoxyphenyl)phenylamino]ethyl}acetamide (UCM765) and N-{2-[(3-bromophenyl)-(4-fluorophenyl)amino]ethyl}acetamide (UCM924) in two animal models of acute and inflammatory pain: the hot-plate and formalin tests. UCM765 and UCM924 (5-40 mg/kg, s.c.) dose-dependently increased the temperature of the first hind paw lick in the hot-plate test, and decreased the total time spent licking the injected hind paw in the formalin test. Antinociceptive effects of UCM765 and UCM924 were maximal at the dose of 20mg/kg. At this dose, the effects of UCM765 and UCM924 were similar to those produced by 200 mg/kg acetaminophen in the hot-plate test, and by 3 mg/kg ketorolac or 150 mg/kg MLT in the formalin test. Notably, antinociceptive effects of the two MT2 partial agonists were blocked by the pre-treatment with the MT2 antagonist 4-phenyl-2-propionamidotetralin (4P-PDOT, 10 mg/kg) in both paradigms. These results demonstrate the antinociceptive properties of UCM765 and UCM924 in acute and inflammatory pain models and corroborate the concept that MT2 melatonin receptor may be a novel target for analgesic drug development. PMID:26162699

  20. Agonist binding to high-affinity dopamine sites

    Energy Technology Data Exchange (ETDEWEB)

    Tedesco, J.L.

    1985-01-01

    The authors have characterized the dopamine D/sub 3/ site and its binding requirements. The dopamine D/sub 3/ site in calf caudate crude homogenate has a site density of 214-230 fmoles/mg. protein by both /sup 3/H-apomorphine (/sup 3/H-AOP) and /sup 3/H-dopamine (/sup 3/H-DA) Scatchard analysis of specific binding (SB). Stereospecific subsets of /sup 3/H-APO and /sup 3/H-DA sites were defined by the use of agonist and antagonist enantiomer-pairs as a rigorous test for D/sub 3/ site heterogeneity. IC/sub 50/ values for both /sup 3/H-APO and /sup 3/H-DA SB sites were assessed for 55 agonist ligands and an excellent correlation was obtained. The authors conclude that both /sup 3/H-ligands label the same D/sub 3/ site. The D/sub 3/ site affinities of 105 dopamine-agonist ligands, in particular 2-aminotetralins,, aporphines and flexible dopamine analogues were measured. Low D/sub 3/-site affinities of N-quaternary analogues confirm the need for a lone pair. Subadditivity of substituents' effects in semi-flexible DA analogues confirms their postulate that sidechain conformation is the critical determinant of affinity. They conclude that there are at least two high-affinity ligand conformations of the DA sidechain pharmacophore. These binding requirements are presented as two interface-Geometry tetrahedral models of the double H-bond interface between the D/sub 3/ site and the ideal ligand.

  1. Simple parameterization of nuclear attenuation data

    CERN Document Server

    Akopov, N; Akopov, Z

    2007-01-01

    Based on the nuclear attenuation data obtained by the HERMES experiment on nitrogen and krypton nuclei, it is shown that the nuclear attenuation $R_M^{h}$ can be parametrised in a form of a linear polynomial $P_1=a_{11}$ + $\\tau a_{12}$, where $\\tau$ is the formation time, which depends on the energy of the virtual photon $\

  2. Docking-mechanism attenuator with electromechanical damper

    Science.gov (United States)

    Syromyatnikov, V. S.

    1971-01-01

    Theoretical and practical problems involved in the application of electromechanical damping for spacecraft docking-mechanism attenuation are discussed. Some drawbacks of hydraulic dampers used for the purpose are pointed out. The basic scheme of the attenuator with the electromechanical damper is given.

  3. Theory of standing spin-wave attenuation

    International Nuclear Information System (INIS)

    Exchange attenuation of standing spin waves is calculated for an ultrathin magnetic of the order of exchange length thick. Because of the boundary conditions the wave vectors of spin waves in such films high values that are proportional to the inverse film thickness. The exchange attenuation at such wave vectors becomes dominant and can result in smearing of the standing spin wave spectrum

  4. Precision Model for Microwave Rotary Vane Attenuator

    DEFF Research Database (Denmark)

    Guldbrandsen, Tom

    1979-01-01

    A model for a rotary vane attenuator is developed to describe the attenuator reflection and transmission coefficients in detail. All the parameters of the model can be measured in situ, i.e., without diassembling any part. The tranmission errors caused by internal reflections are calculated from...

  5. Ramelteon: A melatonin receptor agonist for the treatment of insomnia

    Directory of Open Access Journals (Sweden)

    Devi V

    2008-01-01

    Full Text Available Ramelteon is a novel MT1 and MT2 melatonin receptor selective agonist recently approved for the treatment of insomnia characterized by difficulty in sleep onset. It is a nonscheduled drug since it lacks the potential for abuse and does not interact with neurotransmitter receptors most associated with these phenomena. Although the effects of ramelteon use> 5 weeks are unknown, the available data confirms its safety and efficacy for short-term use. Clinical use and future research should uncover more information about ramelteon′s properties.

  6. INSIGHT AGONISTES: A READING OF SOPHOCLES'S OEDIPUS THE KING.

    Science.gov (United States)

    Mahon, Eugene J

    2015-07-01

    In this reading of Sophocles's Oedipus the King, the author suggests that insight can be thought of as the main protagonist of the tragedy. He personifies this depiction of insight, calling it Insight Agonistes, as if it were the sole conflicted character on the stage, albeit masquerading at times as several other characters, including gods, sphinxes, and oracles. This psychoanalytic reading of the text lends itself to an analogy between psychoanalytic process and Sophocles's tragic hero. The author views insight as always transgressing against, always at war with a conservative, societal, or intrapsychic chorus of structured elements. A clinical vignette is presented to illustrate this view of insight. PMID:26198605

  7. Principles of agonist recognition in Cys-loop receptors

    DEFF Research Database (Denmark)

    Lynagh, Timothy Peter; Pless, Stephan Alexander

    2014-01-01

    diverse as glycine and serotonin has been subject to intense research over the last three decades. This review outlines the functional diversity and current structural understanding of agonist-binding sites, including those of invertebrate Cys-loop receptors. Together, this provides a framework to......Cys-loop receptors are ligand-gated ion channels that are activated by a structurally diverse array of neurotransmitters, including acetylcholine, serotonin, glycine, and GABA. After the term "chemoreceptor" emerged over 100 years ago, there was some wait until affinity labeling, molecular cloning...

  8. Discovery of a potent and selective GPR120 agonist

    DEFF Research Database (Denmark)

    Shimpukade, Bharat; Hudson, Brian D; Hovgaard, Christine Kiel;

    2012-01-01

    GPR120 is a receptor of unsaturated long-chain fatty acids reported to mediate GLP-1 secretion, insulin sensitization, anti-inflammatory, and anti-obesity effects and is therefore emerging as a new potential target for treatment of type 2 diabetes and metabolic diseases. Further investigation is...... however hindered by the lack of suitable receptor modulators. Screening of FFA1 ligands provided a lead with moderate activity on GPR120 and moderate selectivity over FFA1. Optimization led to the discovery of the first potent and selective GPR120 agonist....

  9. AG-4:A NICOTINIC AGONIST ENDOWED WITH ANTIAMNESIC PROPERTIES

    OpenAIRE

    Ghelardini, C; Galeotti, N; Di Cesare Mannelli, L.; S. Dei; F. GUALTIERI; Bartolini, A.

    2000-01-01

    The effect of the nicotinic agonist AG-4 on memory processes was evaluated in the mouse passive avoidance test. AG-4 (100 mg per mouse icv) prevented amnesia induced by scopolamine (1.5 mg kg–1 ip), mecamylamine (20 mg kg–1 ip), and dihydro-b-erythroidine (10 mg per mouse icv). In the same experimental conditions, AG-4 (100 mg per mouse icv) also prevented baclofen (2 mg kg–1 ip), clonidine (0.125 mg kg–1 ip), and diphenhydramine (20 mg kg–1 ip) amnesia in mice. AG-4 exerted an an...

  10. Clenbuterol, a beta(2)-agonist, retards atrophy in denervated muscles

    Science.gov (United States)

    Zeman, Richard J.; Ludemann, Robert; Etlinger, Joseph D.

    1987-01-01

    The effects of a beta(2) agonist, clenbuterol, on the protein content as well as on the contractile strength and the muscle fiber cross-sectional area of various denervated muscles from rats were investigated. It was found that denervated soleus, anterior tibialis, and gastrocnemius muscles, but not the extensor digitorum longus, of rats treated for 2-3 weeks with clenbuterol contained 95-110 percent more protein than denervated controls. The twofold difference in the protein content of denervated solei was paralleled by similar changes in contractile strength and muscle fiber cross-sectional area.

  11. Ultrasound fields in an attenuating medium

    DEFF Research Database (Denmark)

    Jensen, Jørgen Arendt; Gandhi,, D; O'Brien,, W.D., Jr.

    Ultrasound fields propagating in tissue will undergo changes in shape not only due to diffraction, but also due to the frequency dependent attenuation. Linear fields can be fairly well predicted for a non-attenuating medium like water by using the Tupholme-Stepanishen method for calculating the...... spatial impulse response, whereas the field cannot readily be found for an attenuating medium. In this paper we present a simulation program capable of calculating the field in a homogeneous attenuating medium. The program splits the aperture into rectangles and uses a far-field approximation for each of...... the rectangles and sums all contributions to arrive at the spatial impulse response for the aperture and field point. This approach makes it possible to model all transducer apertures, and the program can readily calculate the emitted, pulse-echo and continuous wave field. Attenuation is included by...

  12. Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064

    Energy Technology Data Exchange (ETDEWEB)

    Bass, Jonathan Y.; Caldwell, Richard D.; Caravella, Justin A.; Chen, Lihong; Creech, Katrina L.; Deaton, David N.; Madauss, Kevin P.; Marr, Harry B.; McFadyen, Robert B.; Miller, Aaron B.; Parks, Derek J.; Todd, Dan; Williams, Shawn P.; Wisely, G. Bruce; (GSKNC)

    2010-09-27

    Starting from the known FXR agonist GW 4064 1a, a series of alternately 3,5-substituted isoxazoles was prepared. Several of these analogs were potent full FXR agonists. A subset of this series, with a tether between the isoxazole ring and the 3-position aryl substituent, were equipotent FXR agonists to GW 4064 1a, with the 2,6-dimethyl phenol analog 1t having greater FRET FXR potency than GW 4064 1a.

  13. beta-Adrenoceptor agonists enhance 5-hydroxytryptamine-mediated behavioural responses.

    OpenAIRE

    Cowen, P. J.; Grahame-Smith, D.G.; Green, A R; Heal, D. J.

    1982-01-01

    The beta-adrenoceptor agonists, salbutamol, terbutaline and clenbuterol, were investigated for their effect on 5-hydroxytryptamine-mediated (5-HT) hyperactivity. 2 The lipophilic beta-adrenoceptor agonist, clenbuterol (5 mg/kg) enhanced the behaviours induced by quipazine (25 mg/kg), including headweaving, forepaw treading and hind-limb abduction and thus increased automated activity recording. Clenbuterol (5 mg/kg) also enhanced the hyperactivity syndrome produced by the 5-HT agonist, 5-meth...

  14. Discovery of potent and selective nonsteroidal indazolyl amide glucocorticoid receptor agonists.

    Science.gov (United States)

    Sheppeck, James E; Gilmore, John L; Xiao, Hai-Yun; Dhar, T G Murali; Nirschl, David; Doweyko, Arthur M; Sack, Jack S; Corbett, Martin J; Malley, Mary F; Gougoutas, Jack Z; Mckay, Lorraine; Cunningham, Mark D; Habte, Sium F; Dodd, John H; Nadler, Steven G; Somerville, John E; Barrish, Joel C

    2013-10-01

    Modification of a phenolic lead structure based on lessons learned from increasing the potency of steroidal glucocorticoid agonists lead to the discovery of exceptionally potent, nonsteroidal, indazole GR agonists. SAR was developed to achieve good selectivity against other nuclear hormone receptors with the ultimate goal of achieving a dissociated GR agonist as measured by human in vitro assays. The specific interactions by which this class of compounds inhibits GR was elucidated by solving an X-ray co-crystal structure. PMID:23953070

  15. Peroxisome proliferator-activated receptor δ agonist, HPP593, prevents renal necrosis under chronic ischemia.

    Directory of Open Access Journals (Sweden)

    Larisa V Fedorova

    Full Text Available The Goldblatt's 2 kidney 1 clip (2K1C rat animal model of renovascular hypertension is characterized by ischemic nephropathy of the clipped kidney. 2K1C rats were treated with a specific peroxisome proliferator-activated receptor δ (PPARδ agonist, HPP593. Clipped kidneys from untreated rats developed tubular and glomerular necrosis and massive interstitial, periglomerular and perivascular fibrosis. HPP593 kidneys did not exhibit any histochemical features of necrosis; fibrotic lesions were present only in perivascular areas. Necrosis in the untreated clipped kidneys was associated with an increased oxidative stress, up regulation and mitochondrial translocation of the pro-death protein BNIP3 specifically in tubules. In the kidneys of HPP593-treated rats oxidative stress was attenuated and BNIP3 protein decreased notably in the mitochondrial fraction when compared to untreated animals. In untreated clipped kidneys, mitochondria were dysfunctional as revealed by perturbations in the levels of MCAD, COXIV, TFAM, and Parkin proteins and AMPK activation, while in HPP593-treated rats these proteins remained at the physiological levels. Nuclear amounts of oxidative stress-responsive proteins, NRF1 and NRF2 were below physiological levels in treated kidneys. Mitochondrial biogenesis and autophagy were inhibited similarly in both treated and untreated 2K1C kidneys as indicated by a decrease in PGC1-α and deficiency of the autophagy-essential proteins LC3-II and ATG5. However, HPP593 treatment resulted in increased accumulation of p62 protein, an autophagic substrate and an enhancer of NRF2 activity. Therefore, inhibition of BNIP3 activation by the preservation of mitochondrial function and control of oxidative stress by PPARδ is the most likely mechanism to account for the prevention of necrotic death in the kidney under conditions of persistent ischemia.

  16. Effects of Alda-1, an Aldehyde Dehydrogenase-2 Agonist, on Hypoglycemic Neuronal Death.

    Directory of Open Access Journals (Sweden)

    Tetsuhiko Ikeda

    Full Text Available Hypoglycemic encephalopathy (HE is caused by a lack of glucose availability to neuronal cells, and no neuroprotective drugs have been developed as yet. Studies on the pathogenesis of HE and the development of new neuroprotective drugs have been conducted using animal models such as the hypoglycemic coma model and non-coma hypoglycemia model. However, both models have inherent problems, and establishment of animal models that mimic clinical situations is desirable. In this study, we first developed a short-term hypoglycemic coma model in which rats could be maintained in an isoelectric electroencephalogram (EEG state for 2 min and subsequent hyperglycemia without requiring anti-seizure drugs and an artificial ventilation. This condition caused the production of 4-hydroxy-2-nonenal (4-HNE, a cytotoxic aldehyde, in neurons of the hippocampus and cerebral cortex, and a marked increase in neuronal death as evaluated by Fluoro-Jade B (FJB staining. We also investigated whether N-(1,3-benzodioxole-5-ylmethyl-2,6-dichlorobenzamide (Alda-1, a small-molecule agonist of aldehyde dehydrogenase-2, could attenuate 4-HNE levels and reduce hypoglycemic neuronal death. After confirming that EEG recordings remained isoelectric for 2 min, Alda-1 (8.5 mg/kg or vehicle (dimethyl sulfoxide; DMSO was administered intravenously with glucose to maintain a blood glucose level of 250 to 270 mg/dL. Fewer 4-HNE and FJB-positive cells were observed in the cerebral cortex of Alda-1-treated rats than in DMSO-treated rats 24 h after glucose administration (P = 0.002 and P = 0.020. Thus, activation of the ALDH2 pathway could be a molecular target for HE treatment, and Alda-1 is a potentially neuroprotective agent that exerts a beneficial effect on neurons when intravenously administered simultaneously with glucose.

  17. Analysis of agonist dissociation constants as assessed by functional antagonism in guinea pig left atria

    International Nuclear Information System (INIS)

    In electrically driven guinea pig left atria, positive inotropic responses to (-)-isoprenaline and the selective beta 1-adrenoceptor agonist RO363 were obtained in the absence and in the presence of the functional antagonists adenosine, carbachol, gallopamil, nifedipine, and Ro 03-7894. Each of the functional antagonists reduced the maximum response to both agonists and produced nonparallel rightward shifts in the cumulative concentration effect curves. For both agonists, dissociation constants (KA) were calculated using the equation described by Furchgott (1966) for irreversible antagonism. For RO363, which is a partial agonist with high agonist activity, the equations outlined for functional interaction by Mackay (1981) were also employed to calculate KA values. The KA values obtained by each method were compared with the dissociation constants (KD) for the two agonists determined from their ability to displace the radioligand (-)-[125I]iodocyanopindolol from beta 1-adrenoceptors in guinea pig left atrial membrane preparations. The estimates of KA varied substantially from KD values. The KD values were taken as more accurate estimates of the true values for the dissociation constants because a high degree of correlation exists between pKD and pD2 values for a number of other beta-adrenoceptor agonists that behave as partial agonists and between pKD and pKB values for a number of beta-adrenoceptor antagonists. Thus, it appears that there are serious limitations in the current theory for using functional antagonism as a means of obtaining agonist dissociation constants

  18. Dopamine agonist-induced substance addiction: the next piece of the puzzle.

    Science.gov (United States)

    Evans, Andrew

    2011-02-01

    Traditional antiparkinson treatment strategies strive to balance the antiparkinson effects of dopaminergic drugs with the avoidance of motor response complications. Dopamine agonists have an established role in delaying the emergence of motor response complications or reducing motor "off" periods. The recent recognition of a range of "behavioural addictions" that are linked to dopamine agonist use has highlighted the role of dopamine in brain reward function and addiction disorders in general. Dopamine agonists have now even been linked occasionally to new substance addictions. The challenge now for the Parkinsonologist is to also balance the net benefits of using dopamine agonists for their motor effects with avoiding the harm from behavioural compulsions. PMID:20980151

  19. Sustained wash-resistant receptor activation responses of GPR119 agonists.

    Science.gov (United States)

    Hothersall, J Daniel; Bussey, Charlotte E; Brown, Alastair J; Scott, James S; Dale, Ian; Rawlins, Philip

    2015-09-01

    G protein-coupled receptor 119 (GPR119) is involved in regulating metabolic homoeostasis, with GPR119 agonists targeted for the treatment of type-2 diabetes and obesity. Using the endogenous agonist oleoylethanolamide and a number of small molecule synthetic agonists we have investigated the temporal dynamics of receptor signalling. Using both a dynamic luminescence biosensor-based assay and an endpoint cAMP accumulation assay we show that agonist-driven desensitization is not a major regulatory mechanism for GPR119 despite robust activation responses, regardless of the agonist used. Temporal analysis of the cAMP responses demonstrated sustained signalling resistant to washout for some, but not all of the agonists tested. Further analysis indicated that the sustained effects of one synthetic agonist AR-231,453 were consistent with a role for slow dissociation kinetics. In contrast, the sustained responses to MBX-2982 and AZ1 appeared to involve membrane deposition. We also detect wash-resistant responses to AR-231,453 at the level of physiologically relevant responses in an endogenous expression system (GLP-1 secretion in GLUTag cells). In conclusion, our findings indicate that in a recombinant expression system GPR119 activation is sustained, with little evidence of pronounced receptor desensitization, and for some ligands persistent agonist responses continue despite removal of excess agonist. This provides novel understanding of the temporal responses profiles of potential drug candidates targetting GPR119, and highlights the importance of carefully examining the the mechanisms through which GPCRs generate sustained responses. PMID:26101059

  20. Structural complexes of the agonist, inverse agonist and antagonist bound C5a receptor: insights into pharmacology and signaling.

    Science.gov (United States)

    Rana, Soumendra; Sahoo, Amita Rani; Majhi, Bharat Kumar

    2016-04-26

    The C5a receptor (C5aR) is a pharmacologically important G-protein coupled receptor (GPCR) that interacts with (h)C5a, by recruiting both the "orthosteric" sites (site1 at the N-terminus and site2 at the ECS, extra cellular surface) on C5aR in a two site-binding model. However, the complex pharmacological landscape and the distinguishing chemistry operating either at the "orthosteric" site1 or at the functionally important "orthosteric" site2 of C5aR are still not clear, which greatly limits the understanding of C5aR pharmacology. One of the major bottlenecks is the lack of an experimental structure or a refined model structure of C5aR with appropriately defined active sites. The study attempts to understand the pharmacology at the "orthosteric" site2 of C5aR rationally by generating a highly refined full-blown model structure of C5aR through advanced molecular modeling techniques, and further subjecting it to automated docking and molecular dynamics (MD) studies in the POPC bilayer. The first series of structural complexes of C5aR respectively bound to a linear native peptide agonist ((h)C5a-CT), a small molecule inverse agonist (NDT) and a cyclic peptide antagonist (PMX53) are reported, apparently establishing the unique pharmacological landscape of the "orthosteric" site2, which also illustrates an energetically distinct but coherent competitive chemistry ("cation-π" vs. "π-π" interactions) involved in distinguishing the established ligands known for targeting the "orthosteric" site2 of C5aR. Over a total of 1 μs molecular dynamics (MD) simulation in the POPC bilayer, it is evidenced that while the agonist prefers a "cation-π" interaction, the inverse agonist prefers a "cogwheel/L-shaped" interaction in contrast to the "edge-to-face/T-shaped" type π-π interactions demonstrated by the antagonist by engaging the F275(7.28) of the C5aR. In the absence of a NMR or crystallographically guided model structure of C5aR, the computational model complexes not only

  1. Role of estrogen receptor β selective agonist in ameliorating portal hypertension in rats with CCl4-induced liver cirrhosis

    Science.gov (United States)

    Zhang, Cheng-Gang; Zhang, Bin; Deng, Wen-Sheng; Duan, Ming; Chen, Wei; Wu, Zhi-Yong

    2016-01-01

    AIM: To investigate the role of diarylpropionitrile (DPN), a selective agonist of estrogen receptor β (ERβ), in liver cirrhosis with portal hypertension (PHT) and isolated hepatic stellate cells (HSCs). METHODS: Female Sprague-Dawley rats were ovariectomized (OVX), and liver cirrhosis with PHT was induced by CCl4 injection. DPN and PHTPP, the selective ERβ agonist and antagonist, were used as drug interventions. Liver fibrosis was assessed by hematoxylin and eosin (HE) and Masson’s trichrome staining and by analyzing smooth muscle actin expression. Hemodynamic parameters were determined in vivo using colored microspheres technique. Protein expression and phosphorylation were determined by immunohistochemical staining and Western blot analysis. Messenger RNA levels were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Collagen gel contraction assay was performed using gel lattices containing HSCs treated with DPN, PHTPP, or Y-27632 prior to ET-1 addition. RESULTS: Treatment with DPN in vivo greatly lowered portal pressure and improved hemodynamic parameters without affecting mean arterial pressure, which was associated with the attenuation of liver fibrosis and intrahepatic vascular resistance (IHVR). In CCl4-treated rat livers, DPN significantly decreased the expression of RhoA and ROCK II, and even suppressed ROCK II activity. Moreover, DPN remarkedly increased the levels of endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS, and promoted the activities of protein kinase G (PKG), which is an NO effector in the liver. Furthermore, DPN reduced the contractility of activated HSCs in the 3-dimensional stress-relaxed collagen lattices, and decreased the ROCK II activity in activated HSCs. Finally, in vivo/in vitro experiments demonstrated that MLC activity was inhibited by DPN. CONCLUSION: For OVX rats with liver cirrhosis, DPN suppressed liver RhoA/ROCK signal, facilitated NO/PKG pathways, and decreased IHVR, giving rise to

  2. Pharmacology and toxicology of Cannabis derivatives and endocannabinoid agonists.

    Science.gov (United States)

    Gerra, Gilberto; Zaimovic, Amir; Gerra, Maria L; Ciccocioppo, Roberto; Cippitelli, Andrea; Serpelloni, Giovanni; Somaini, Lorenzo

    2010-01-01

    For centuries Cannabis sativa and cannabis extracts have been used in natural medicine. Delta(9)-tetrahydrocannabinol (THC) is the main active ingredient of Cannabis. THC seems to be responsible for most of the pharmacological and therapeutic actions of cannabis. In a few countries THC extracts (i.e. Sativex) or THC derivatives such as nabilone, and dronabinol are used in the clinic for the treatment of several pathological conditions like chemotherapy-induced nausea and vomiting, multiple sclerosis and glaucoma. On the other hand the severe side effects and the high abuse liability of these agents represent a serious limitation in their medical use. In addition, diversion in the use of these active ingredients for recreational purpose is a concern. Over recent years, alternative approaches using synthetic cannabinoid receptor agonists or agents acting as activators of the endocannabinoid systems are under scrutiny with the hope to develop more effective and safer clinical applications. Likely, in the near future few of these new molecules will be available for clinical use. The present article review recent study and patents with focus on the cannabinoid system as a target for the treatment of central nervous system disorders with emphasis on agonists. PMID:19832688

  3. Cariprazine:New dopamine biased agonist for neuropsychiatric disorders.

    Science.gov (United States)

    De Deurwaerdère, P

    2016-02-01

    Cariprazine (RGH-188, MP-214, Vraylar[TM]) is a new dopamine receptor ligand developed for the treatment of several neuropsychiatric diseases including schizophrenia and bipolar disorders. Cariprazine displays higher affinity at dopamine D3 receptors and a similar affinity at D2 and 5-HT2B receptors. At variance with some atypical antipsychotics, its affinity at 5-HT1A, 5-HT2A and histamine H1 receptors is modest compared with its three main targets. Cariprazine could correspond to a biased agonist at dopamine receptors, displaying either antagonist or partial agonist properties depending on the signaling pathways linked to D2/D3 receptors. The compound crosses the blood-brain barrier, as revealed by positron emission tomography and pharmacokinetic studies in various species. Two main metabolites result mainly from the activity of CYP34A and display properties similar to those of the parent drug. Behavioral data report that cariprazine is efficacious in animal models addressing positive, negative and cognitive symptoms of schizophrenia with no extrapyramidal side effects. In September 2015, the FDA approved the use of cariprazine for the treatment of schizophrenia and type I bipolar disorder. The efficacy of cariprazine in other neuropsychiatric diseases is currently being evaluated in preclinical and clinical studies. Side effects have been observed in humans, including extrapyramidal side effects and akathisia of mild to moderate intensity. PMID:27092339

  4. Suppression of atherosclerosis by synthetic REV-ERB agonist.

    Science.gov (United States)

    Sitaula, Sadichha; Billon, Cyrielle; Kamenecka, Theodore M; Solt, Laura A; Burris, Thomas P

    2015-05-01

    The nuclear receptors for heme, REV-ERBα and REV-ERBβ, play important roles in the regulation of metabolism and inflammation. Recently it was demonstrated that reduced REV-ERBα expression in hematopoetic cells in LDL receptor null mice led to increased atherosclerosis. We sought to determine if synthetic REV-ERB agonists that we have developed might have the ability to suppress atherosclerosis in this model. A previously characterized synthetic REV-ERB agonist, SR9009, was used to determine if activation of REV-ERB activity would affect atherosclerosis in LDL receptor deficient mice. Atherosclerotic plaque size was significantly reduced (p < 0.05) in mice administered SR9009 (100 mg/kg) for seven weeks compared to control mice (n = 10 per group). SR9009 treatment of bone marrow-derived mouse macrophages (BMDM) reduced the polarization of BMDMs to proinflammatory M1 macrophage while increasing the polarization of BMDMs to anti-inflammatory M2 macrophages. Our results suggest that pharmacological targeting of REV-ERBs may be a viable therapeutic option for treatment of atherosclerosis. PMID:25800870

  5. Toll-Like Receptor 9 Agonists for Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Davide Melisi

    2014-08-01

    Full Text Available The immune system has acquired increasing importance as a key player in cancer maintenance and growth. Thus, modulating anti-tumor immune mediators has become an attractive strategy for cancer treatment. Toll-like receptors (TLRs have gradually emerged as potential targets of newer immunotherapies. TLR-9 is preferentially expressed on endosome membranes of B-cells and plasmacytoid dendritic cells (pDC and is known for its ability to stimulate specific immune reactions through the activation of inflammation-like innate responses. Several synthetic CpG oligonucleotides (ODNs have been developed as TLR-9 agonists with the aim of enhancing cancer immune surveillance. In many preclinical models, CpG ODNs were found to suppress tumor growth and proliferation both in monotherapy and in addition to chemotherapies or target therapies. TLR-9 agonists have been also tested in several clinical trials in patients with solid tumors. These agents showed good tolerability and usually met activity endpoints in early phase trials. However, they have not yet been demonstrated to significantly impact survival, neither as single agent treatments, nor in combination with chemotherapies or cancer vaccines. Further investigations in larger prospective studies are required.

  6. How does agonistic behaviour differ in albino and pigmented fish?

    Science.gov (United States)

    Slavík, Ondřej; Horký, Pavel; Wackermannová, Marie

    2016-01-01

    In addition to hypopigmentation of the skin and red iris colouration, albino animals also display distinct physiological and behavioural alterations. However, information on the social interactions of albino animals is rare and has mostly been limited to specially bred strains of albino rodents and animals from unique environments in caves. Differentiating between the effects of albinism and domestication on behaviour in rodents can be difficult, and social behaviour in cave fish changes according to species-specific adaptations to conditions of permanent darkness. The agonistic behaviours of albino offspring of pigmented parents have yet to be described. In this study, we observed agonistic behaviour in albino and pigmented juvenile Silurus glanis catfish. We found that the total number of aggressive interactions was lower in albinos than in pigmented catfish. The distance between conspecifics was also analysed, and albinos showed a tendency towards greater separation from their same-coloured conspecifics compared with pigmented catfish. These results demonstrate that albinism can be associated with lower aggressiveness and with reduced shoaling behaviour preference, as demonstrated by a tendency towards greater separation of albinos from conspecifics. PMID:27114883

  7. Plasmodium falciparum: attenuation by irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Waki, S.; Yonome, I.; Suzuki, M.

    1983-12-01

    The effect of irradiation on the in vitro growth of Plasmodium falciparum was investigated. The cultured malarial parasites at selected stages of development were exposed to gamma rays and the sensitivity of each stage was determined. The stages most sensitive to irradiation were the ring forms and the early trophozoites; late trophozoites were relatively insensitive. The greatest resistance was shown when parasites were irradiated at a time of transition from the late trophozoite and schizont stages to young ring forms. The characteristics of radiosensitive variation in the parasite cycle resembled that of mammalian cells. Growth curves of parasites exposed to doses of irradiation upto 150 gray had the same slope as nonirradiated controls but parasites which were exposed to 200 gray exhibited a growth curve which was less steep than that for parasites in other groups. Less than 10 organisms survived from the 10(6) parasites exposed to this high dose of irradiation; the possibility exists of obtaining radiation-attenuated P. falciparum.

  8. Beta attenuation transmission system (BATS)

    International Nuclear Information System (INIS)

    The beta attenuation transmission system (BATS) is an automated radiation gauge designed for quantitative measurement of component thickness in explosive detonators. The BATS was designed and built by Group M-1, the Nondestructive Testing Group, of the Los Alamos Scientific Laboratory to measure the areal thickness, in mg/cm2, of a cylinder of high explosive (HE) enclosed within a plastic holder. The problem is to determine the density of the HE. A 90Sr source is collimated by a 0.25 x 1.59-mm slit, and the transmitted beta-particle flux is detected by a plastic scintillator, coupled to a photomultiplier tube. The detonator is transported through the radiation beam by a leadscrew, ballnut, stepping-motor combination. Continuous analog position data are available, derived from the output from a linear-actuated potentiometer attached to the scanner. A linear electrometer amplifies the detected signal, which is then integrated for a preselected time, to obtain the desired statistical accuracy. A microprocessor (μP) is used to control the scanner position and to make the data readings at the assigned positions. The data are stored, and, at the completion of the scan, are processed into the desired format. The final answer is displayed to the operator or output to a peripheral device for permanent record. The characteristics of the radiation source, the collimator, the signal detection and conditioning, and the final results are described in detail. The scanner and the microprocessor control system are briefly outlined

  9. Beta attenuation transmission system (BATS)

    Energy Technology Data Exchange (ETDEWEB)

    Hagan, R.C.; Fullbright, H.J.

    1977-01-01

    The beta attenuation transmission system (BATS) is an automated radiation gauge designed for quantitative measurement of component thickness in explosive detonators. The BATS was designed and built by Group M-1, the Nondestructive Testing Group, of the Los Alamos Scientific Laboratory to measure the areal thickness, in mg/cm/sup 2/, of a cylinder of high explosive (HE) enclosed within a plastic holder. The problem is to determine the density of the HE. A /sup 90/Sr source is collimated by a 0.25 x 1.59-mm slit, and the transmitted beta-particle flux is detected by a plastic scintillator, coupled to a photomultiplier tube. The detonator is transported through the radiation beam by a leadscrew, ballnut, stepping-motor combination. Continuous analog position data are available, derived from the output from a linear-actuated potentiometer attached to the scanner. A linear electrometer amplifies the detected signal, which is then integrated for a preselected time, to obtain the desired statistical accuracy. A microprocessor (..mu..P) is used to control the scanner position and to make the data readings at the assigned positions. The data are stored, and, at the completion of the scan, are processed into the desired format. The final answer is displayed to the operator or output to a peripheral device for permanent record. The characteristics of the radiation source, the collimator, the signal detection and conditioning, and the final results are described in detail. The scanner and the microprocessor control system are briefly outlined.

  10. Attenuation Tomography of the Upper Mantle

    Science.gov (United States)

    Adenis, A.; Debayle, E.; Ricard, Y. R.

    2014-12-01

    We present a 3-D model of surface wave attenuation in the upper mantle. The model is constrained by a large data set of fundamental and higher Rayleigh mode observations. This data set consists of about 1,800,000 attenuation curves measured in the period range 50-300s by Debayle and Ricard (2012). A careful selection allows us to reject data for which measurements are likely biased by the poor knowledge of the scalar seismic moment or by a ray propagation too close to a node of the source radiation pattern. For each epicenter-station path, elastic focusing effects due to seismic heterogeneities are corrected using DR2012 and the data are turned into log(1/Q). The selected data are then combined in a tomographic inversion using the non-linear least square formalism of Tarantola and Valette (1982). The obtained attenuation maps are in agreement with the surface tectonic for periods and modes sensitive to the top 200km of the upper mantle. Low attenuation regions correlate with continental shields while high attenuation regions are located beneath young oceanic regions. The attenuation pattern becomes more homogeneous at depths greater than 200 km and the maps are dominated by a high quality factor signature beneath slabs. We will discuss the similarities and differences between the tomographies of seismic velocities and of attenuations.

  11. Ovariectomy and subsequent treatment with estrogen receptor agonists tune the innate immune system of the hippocampus in middle-aged female rats.

    Directory of Open Access Journals (Sweden)

    Miklós Sárvári

    Full Text Available The innate immune system including microglia has a major contribution to maintenance of the physiological functions of the hippocampus by permanent monitoring of the neural milieu and elimination of tissue-damaging threats. The hippocampus is vulnerable to age-related changes ranging from gene expression to network connectivity. The risk of hippocampal deterioration increases with the decline of gonadal hormone supply. To explore the impact of hormone milieu on the function of the innate immune system in middle-aged female rats, we compared mRNA expression in the hippocampus after gonadal hormone withdrawal, with or without subsequent estrogen replacement using estradiol and isotype-selective estrogen receptor (ER agonists. Targeted profiling assessed the status of the innate immune system (macrophage-associated receptors, complement, inhibitory neuronal ligands, local estradiol synthesis (P450 aromatase and estrogen reception (ER. Results established upregulation of macrophage-associated (Cd45, Iba1, Cd68, Cd11b, Cd18, Fcgr1a, Fcgr2b and complement (C3, factor B, properdin genes in response to ovariectomy. Ovariectomy upregulated Cd22 and downregulated semaphorin3A (Sema3a expression, indicating altered neuronal regulation of microglia. Ovariectomy also led to downregulation of aromatase and upregulation of ERα gene. Of note, analogous changes were observed in the hippocampus of postmenopausal women. In ovariectomized rats, estradiol replacement attenuated Iba1, Cd11b, Fcgr1a, C3, increased mannose receptor Mrc1, Cd163 and reversed Sema3a expression. In contrast, reduced expression of aromatase was not reversed by estradiol. While the effects of ERα agonist closely resembled those of estradiol, ERβ agonist was also capable of attenuating the expression of several macrophage-associated and complement genes. These data together indicate that the innate immune system of the aging hippocampus is highly responsive to the gonadal hormone milieu

  12. Maximum likelihood estimation of the attenuated ultrasound pulse

    DEFF Research Database (Denmark)

    Rasmussen, Klaus Bolding

    1994-01-01

    The attenuated ultrasound pulse is divided into two parts: a stationary basic pulse and a nonstationary attenuation pulse. A standard ARMA model is used for the basic pulse, and a nonstandard ARMA model is derived for the attenuation pulse. The maximum likelihood estimator of the attenuated...... ultrasound pulse, which includes a maximum likelihood attenuation estimator, is derived. The results of this correspondence are of great importance for deconvolution and attenuation imaging in medical ultrasound...

  13. Graphene-based Electronically Tuneable Microstrip Attenuator

    Directory of Open Access Journals (Sweden)

    L. Pierantoni

    2014-06-01

    Full Text Available This paper presents the design of a graphene- based electronically tuneable microstrip attenuator operating at a frequency of 5 GHz. The use of graphene as a variable resistor is discussed and the modelling of its electromagnetic properties at microwave frequencies is fully addressed. The design of the graphene-based attenuator is described. The structure integrates a patch of graphene, whose characteristics can range from being a fairly good conductor to a highly lossy material, depending on the applied voltage. By applying the proper voltage through two high-impedance bias lines, the surface resistivity of graphene can be modified, thereby changing the insertion loss of the microstrip attenuator.

  14. Attenuation caused by infrequently updated covariates in survival analysis

    DEFF Research Database (Denmark)

    Andersen, Per Kragh; Liestøl, Knut

    Attenuation; Cox regression model; Measurement errors; Survival analysis; Time-dependent covariates......Attenuation; Cox regression model; Measurement errors; Survival analysis; Time-dependent covariates...

  15. DEXMEDETOMIDINE FOR ATTENUATION OF PRESSOR RESPONSE OF LARYNGOSCOPY AND INTUBATION

    Directory of Open Access Journals (Sweden)

    Priti Kolarkar

    2015-02-01

    Full Text Available BACKGROUND: Laryngoscopy and tracheal intubation causes intense autonomic reflex responses consisting of increased circulating catacholamines, tachycardia, hypertension, myocardial oxygen demand, and dysarrythmias. To obtund haemodynamic response lignocaine, opiods, nitroprusside, nitroglycerine, vearpamil, nifedipine, esmolol, clonidine and recently, dexmedetomidine have been stu died. AIMS AND OBJECTIVES: We investigated whether dexmedetomidine a α2 agonist could attenuate sympathoadrenal response (Heart rate and MAP to laryngoscopy and intubation. MATERIALS AND METHODS: Eighty patients, ASA grade I/II, undergoing routine general anesthesia were randomly premedicated by i . v . dexmedetomidine 0.6μg or saline. Heart rate (HR, mean arterial pressure (MAP, were measured before, after the premedication, after thiopental, after succinylcholine at laryngoscopy, immediately after intuba tion and then 1 min. 3 min. and 5 min after intubation. STATISTICAL ANALYSIS: Descriptive and inferential statistics using chi - square test, z - test and wilcoxon sign rank test was done. Software used in the analysis was SPSS 17.0 version and Graph Pad Prism 5.0. Data was reported as mean value ± SD & p - value <0.05 is considered as level of significance. RESULTS: The demographic profile was comparable . After intubation the MAP in the control group (z=.5.35, p=<0.05 at laryngoscopy and z=9.95, p< 0.05 after intubation was higher than that in the dexmedetomidine group (z=8, p=0.000 and exceeded the baseline value(p<0.05 The heart rate also showed less fluctuation in the dexmedetomidine group than in the control group. Though there was rise in bot h the groups, it was more in control group than dexmedetomidine group (z=7.73, p<0.05 at laryngoscopy and z=9.22, p<0.05 after intubation . Thus the pressor response to laryngoscopy and intubation were effectively decreased by dexmedetomidine and were high ly significant on comparison (p<0.05 . CONCLUSION: i v

  16. The GABAA receptor agonist THIP is neuroprotective in organotypic hippocampal slice cultures

    DEFF Research Database (Denmark)

    Kristensen, Bjarne Winther; Noraberg, Jens; Zimmer, Jens

    2003-01-01

    The potential neuroprotective effects of the GABA(A) receptor agonists THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) and muscimol, and the selective GluR5 kainate receptor agonist ATPA ((RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid), which activates GABAergic interneu...

  17. Quantitative phosphoproteomics dissection of 7TM receptor signaling using full and biased agonists

    DEFF Research Database (Denmark)

    Christensen, Gitte Lund; Kelstrup, Christian; Lyngsø, Christina;

    2010-01-01

    performed a global quantitative phosphoproteomics analysis of the AT1R signaling network. We analyzed ligand-stimulated SILAC cells by high-resolution mass spectrometry (LTQ Orbitrap MS) and compared the phosphoproteomes of the AT1R agonist Angiotensin II and the biased agonist SII Angiotensin II, which...

  18. The dopamine D1 receptor agonist SKF-82958 effectively increases eye blinking count in common marmosets.

    Science.gov (United States)

    Kotani, Manato; Kiyoshi, Akihiko; Murai, Takeshi; Nakako, Tomokazu; Matsumoto, Kenji; Matsumoto, Atsushi; Ikejiri, Masaru; Ogi, Yuji; Ikeda, Kazuhito

    2016-03-01

    Eye blinking is a spontaneous behavior observed in all mammals, and has been used as a well-established clinical indicator for dopamine production in neuropsychiatric disorders, including Parkinson's disease and Tourette syndrome [1,2]. Pharmacological studies in humans and non-human primates have shown that dopamine agonists/antagonists increase/decrease eye blinking rate. Common marmosets (Callithrix jacchus) have recently attracted a great deal of attention as suitable experimental animals in the psychoneurological field due to their more developed prefrontal cortex than rodents, easy handling compare to other non-human primates, and requirement for small amounts of test drugs. In this study, we evaluated the effects of dopamine D1-4 receptors agonists on eye blinking in common marmosets. Our results show that the dopamine D1 receptor agonist SKF-82958 and the non-selective dopamine receptor agonist apomorphine significantly increased common marmosets eye blinking count, whereas the dopamine D2 agonist (+)-PHNO and the dopamine D3 receptor agonist (+)-PD-128907 produced somnolence in common marmosets resulting in a decrease in eye blinking count. The dopamine D4 receptor agonists PD-168077 and A-41297 had no effect on common marmosets' eye blinking count. Finally, the dopamine D1 receptor antagonist SCH 39166 completely blocked apomorphine-induced increase in eye blinking count. These results indicate that eye blinking in common marmosets may be a useful tool for in vivo screening of novel dopamine D1 receptor agonists as antipsychotics. PMID:26675887

  19. The interplay between agonistic character displacement and reproductive interference in rubyspot damselflies (Hetaerina spp.)

    OpenAIRE

    Drury, Jonathan

    2014-01-01

    Aggressive interactions between species are common despite being relatively understudied. Agonistic character displacement (ACD) theory makes predictions about how selection should act on traits that mediate the occurrence of interspecific aggressive interactions. Previous research on rubyspot damseflies (Hetaerina spp.) documented several cases of divergent agonistic character displacement acting on wing coloration and competitor recognition to diminish wasteful interspecific aggression. How...

  20. Concerns with beta2-agonists in pediatric asthma - a clinical perspective

    NARCIS (Netherlands)

    Kersten, Elin T G; Koppelman, Gerard H; Thio, Bernard J

    2016-01-01

    Beta2-adrenoreceptor agonists (β2-agonists) are extensively used in the treatment of childhood asthma. However, there have been concerns regarding their adverse effects and safety. In 2005, the FDA commissioned a "Black Box Warning" communicating the potential for an increased risk for serious asthm

  1. Radiation-attenuated vaccine for lungworm disease

    International Nuclear Information System (INIS)

    The work done at the Indian Veternary Research Institute, Izatnagar, on the development of a vaccine for lungworm diseases is reported. Research work done includes: (1) studies on the epidemiology and the incidence of the lungworm infections, (ii) studies on the radiation-attenuated lungworm Dictyocaulus filaria vaccine, (iii) studies on other parasites using ionizing radiation, (iv) incidence of lungworm infection in sheep in Jammu and Kashmir State, (v) suitable dose of gamma radiation for attenuation, (vi) laboratory studies with radiation-attenuated D. filaria vaccine, (vii) serology of D. filaria infection, (viii) field trials with the radiation-attenuated vaccine, (ix) immune response of previously exposed lambs to vaccination, (x) comparative susceptibility of sheep and goats to infection with D. filaria, (xi) quantitative studies of D. filaria in lambs and (xii) production and supply of lungworm vaccine. (A.K.)

  2. Attenuation layer for magnetostatic wave (MSW) absorbers

    Science.gov (United States)

    Glass, H. L.; Adkins, L. R.; Stearns, F. S.

    1984-09-01

    A new technique has been developed for the suppression of MSW end reflections which give rise to passband ripple. The basic idea is to provide a thin film of highly attenuating epitaxial material at the ends of a MSW delay line while preserving high quality YIG in the active region of the device. The GGG wafer preparation is a three step process which involves: (1) the growth of the attenuation layer, (2) the removal of this layer from the central region of the wafer and (3) the growth of high quality YIG on the remaining structure. Delay lines using the attenuation layer for end terminations have been evaluated experimentally and compared to devices utilizing other termination methods. The results indicate that the attenuation layer method produces ripple suppression characteristics which are the equal of those obtained with other termination techniques. The advantage of this new method lies in its suitability for large quantity fabrication requirements.

  3. Post-Retrieval Extinction Attenuates Cocaine Memories

    OpenAIRE

    Sartor, Gregory C.; Aston-Jones, Gary

    2013-01-01

    Recent studies have shown that post-retrieval extinction training attenuates fear and reward-related memories in both humans and rodents. This noninvasive, behavioral approach has the potential to be used in clinical settings to treat maladaptive memories that underlie several psychiatric disorders, including drug addiction. However, few studies to date have used a post-retrieval extinction approach to attenuate addiction-related memories. In the current study, we attempted to disrupt cocaine...

  4. Brucellosis: The Case for Live, Attenuated Vaccines

    OpenAIRE

    Ficht, Thomas A.; Kahl-McDonagh, Melissa M.; Arenas-Gamboa, Angela M.; Rice-Ficht, Allison C.

    2009-01-01

    The successful control of animal brucellosis and associated reduction in human exposure has limited the development of human brucellosis vaccines. However, the potential use of Brucella in bioterrorism or biowarfare suggests that direct intervention strategies are warranted. Although the dominant approach has explored the use of live attenuated vaccines, side-effects associated with their use has prevented widespread use in humans. Development of live, attenuated Brucella vaccines that are sa...

  5. Investigation of photon attenuation coefficients for marble

    International Nuclear Information System (INIS)

    The total linear attenuation coefficients μ (cm-1) have been obtained using the XCOM program at photon energies of 1 keV to 1 GeV for six different natural marbles produced in different places in Turkey. The individual contribution of photon interaction processes to the total linear attenuation coefficients for marble has been investigated. The calculated results were also compared with the measurements. The results obtained for marble were also compared with concrete. (note)

  6. Electron Effective-Attenuation-Length Database

    Science.gov (United States)

    SRD 82 NIST Electron Effective-Attenuation-Length Database (PC database, no charge)   This database provides values of electron effective attenuation lengths (EALs) in solid elements and compounds at selected electron energies between 50 eV and 2,000 eV. The database was designed mainly to provide EALs (to account for effects of elastic-eletron scattering) for applications in surface analysis by Auger-electron spectroscopy (AES) and X-ray photoelectron spectroscopy (XPS).

  7. ATTENUATION AND FLANKING TRANSMISSION IN LIGHTWEIGHT STRUCTURES

    DEFF Research Database (Denmark)

    Brunskog, Jonas; Lhomond, Alice; Ohlrich, Mogens

    2007-01-01

    In this paper the attenuation and flanking transmissions of impact noise in lightweight building structures is studied using a modal approach. The structural field is mainly analysed, putting the main attention to the parts being important in the modelling. The amount of attenuation produced by the...... periodically reinforcing beams used in lightweight building structures is analysed. The consequence of these factors in modelling flanking transmission is also discussed....

  8. Long-acting beta(2)-agonists in management of childhood asthma

    DEFF Research Database (Denmark)

    Bisgaard, H

    2000-01-01

    This review assesses the evidence regarding the use of long-acting beta(2)-agonists in the management of pediatric asthma. Thirty double-blind, randomized, controlled trials on the effects of formoterol and salmeterol on lung function in asthmatic children were identified. Single doses of inhaled...... attempted. The onset of action of formoterol is comparable to salbutamol, while salmeterol has a slower onset of action. Partial tolerance develops when long-acting beta(2)-agonists are used as regular treatment, including cross-tolerance to short-acting beta(2)-agonists. Regular treatment with salmeterol...... long-acting beta(2)-agonists, which is reflected by unchanged or increased bronchial hyperreactivity and no reduction of exacerbation rates. The evidence does not support a recommendation for long-acting beta(2)-agonists as monotherapy, nor does it support their general use as regular add-on therapy...

  9. The GLP-1 agonist, liraglutide, as a pharmacotherapy for obesity.

    Science.gov (United States)

    Crane, James; McGowan, Barbara

    2016-03-01

    There is a global obesity epidemic that will continue to be a financial burden on healthcare systems around the world. Tackling obesity through diet and exercise should always be the first intervention, but this has not proved to be effective for a large number of patients. Pharmacotherapeutic options have been limited and many previously available drugs have been withdrawn due to safety concerns. Currently, only bariatric surgery has the capability to induce both substantial and durable weight loss. This article briefly reviews the history of pharmacotherapy for obesity before focusing on the clinical trial evidence for the use of the GLP-1 agonist liraglutide as a weight loss agent and comparing its efficacy with other emerging drug therapies for obesity. PMID:26977279

  10. Thrombopoietin-receptor agonists in haematological disorders: The Danish experience

    DEFF Research Database (Denmark)

    Gudbrandsdottir, Sif; Frederiksen, Henrik; Hasselbalch, Hans

    2011-01-01

    received TPO-ra from 2009 to 1 May 2011 were available for data collection and included in the study. Of these patients, 15 received TPO-ra for refractory primary ITP, 7 for secondary ITP (chronic lymphatic leukaemia, systemic lupus erythematosus, Evans syndrome, human immunodeficiency virus and celiac......The objective of this study was to investigate the use of thrombopoietin-receptor agonists (TPO-ra) in patients with refractory primary immune thrombocytopenia (ITP) as well as off-label use of TPO-ra in Danish haematology departments. Hospital medical records from 32 of the 39 patients having...... primary ITP patients, 57% of patients with secondary ITP and 40% of patients with non-ITP. There were four deaths in the cohort, three of which were related to pre-existing medical conditions. Otherwise adverse effects were in general mild. This Danish retrospective registration study has demonstrated...

  11. Recent advances in the development of farnesoid X receptor agonists.

    Science.gov (United States)

    Ali, Ahmad H; Carey, Elizabeth J; Lindor, Keith D

    2015-01-01

    Farnesoid X receptors (FXRs) are nuclear hormone receptors expressed in high amounts in body tissues that participate in bilirubin metabolism including the liver, intestines, and kidneys. Bile acids (BAs) are the natural ligands of the FXRs. FXRs regulate the expression of the gene encoding for cholesterol 7 alpha-hydroxylase, which is the rate-limiting enzyme in BA synthesis. In addition, FXRs play a critical role in carbohydrate and lipid metabolism and regulation of insulin sensitivity. FXRs also modulate live growth and regeneration during liver injury. Preclinical studies have shown that FXR activation protects against cholestasis-induced liver injury. Moreover, FXR activation protects against fatty liver injury in animal models of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and improved hyperlipidemia, glucose intolerance, and insulin sensitivity. Obeticholic acid (OCA), a 6α-ethyl derivative of the natural human BA chenodeoxycholic acid (CDCA) is the first-in-class selective FXR agonist that is ~100-fold more potent than CDCA. Preliminary human clinical trials have shown that OCA is safe and effective. In a phase II clinical trial, administration of OCA was well-tolerated, increased insulin sensitivity and reduced markers of liver inflammation and fibrosis in patients with type II diabetes mellitus and NAFLD. In two clinical trials of OCA in patients with primary biliary cirrhosis (PBC), a progressive cholestatic liver disease, OCA significantly reduced serum alkaline phosphatase (ALP) levels, an important disease marker that correlates well with clinical outcomes of patients with PBC. Together, these studies suggest that FXR agonists could potentially be used as therapeutic tools in patients suffering from nonalcoholic fatty and cholestatic liver diseases. Larger and Longer-term studies are currently ongoing. PMID:25705637

  12. Theory of partial agonist activity of steroid hormones

    Directory of Open Access Journals (Sweden)

    Carson C. Chow

    2015-04-01

    Full Text Available The different amounts of residual partial agonist activity (PAA of antisteroids under assorted conditions have long been useful in clinical applications but remain largely unexplained. Not only does a given antagonist often afford unequal induction for multiple genes in the same cell but also the activity of the same antisteroid with the same gene changes with variations in concentration of numerous cofactors. Using glucocorticoid receptors as a model system, we have recently succeeded in constructing from first principles a theory that accurately describes how cofactors can modulate the ability of agonist steroids to regulate both gene induction and gene repression. We now extend this framework to the actions of antisteroids in gene induction. The theory shows why changes in PAA cannot be explained simply by differences in ligand affinity for receptor and requires action at a second step or site in the overall sequence of reactions. The theory also provides a method for locating the position of this second site, relative to a concentration limited step (CLS, which is a previously identified step in glucocorticoid-regulated transactivation that always occurs at the same position in the overall sequence of events of gene induction. Finally, the theory predicts that classes of antagonist ligands may be grouped on the basis of their maximal PAA with excess added cofactor and that the members of each class differ by how they act at the same step in the overall gene induction process. Thus, this theory now makes it possible to predict how different cofactors modulate antisteroid PAA, which should be invaluable in developing more selective antagonists.

  13. Could Dopamine Agonists Aid in Drug Development for Anorexia Nervosa?

    Directory of Open Access Journals (Sweden)

    Guido eFrank

    2014-11-01

    Full Text Available Anorexia nervosa is a severe psychiatric disorder most commonly starting during the teenage years and associated with food refusal and low body weight. Typically there is a loss of menses, intense fear of gaining weight and an often delusional quality of altered body perception. Anorexia nervosa is also associated with a pattern of high cognitive rigidity, which may contribute to treatment resistance and relapse. The complex interplay of state and trait biological, psychological and social factors has complicated identifying neurobiological mechanisms that contribute to the illness. The dopamine D1 and D2 neurotransmitter receptors are involved in motivational aspects of food approach, fear extinction and cognitive flexibility. They could therefore be important targets to improve core and associated behaviors in anorexia nervosa. Treatment with dopamine antagonists has shown little benefit, and it is possible that antagonists over time increase an already hypersensitive dopamine pathway activity in anorexia nervosa. On the contrary, application of dopamine receptor agonists could reduce circuit responsiveness, facilitate fear extinction and improve cognitive flexibility in anorexia nervosa, as they may be particularly effective during underweight and low gonadal hormone states. This article provides evidence that the dopamine receptor system could be a key factor in the pathophysiology of anorexia nervosa and dopamine agonists could be helpful in reducing core symptoms of the disorder. This review is a theoretical approach that primarily focuses on dopamine receptor function as this system has been mechanistically better described than other neurotransmitters that are altered in anorexia nervosa. However, those proposed dopamine mechanisms in anorexia nervosa also warrant further study with respect to their interaction with other neurotransmitter systems, such as serotonin pathways.

  14. Could dopamine agonists aid in drug development for anorexia nervosa?

    Science.gov (United States)

    Frank, Guido K W

    2014-01-01

    Anorexia nervosa is a severe psychiatric disorder most commonly starting during the teenage-years and associated with food refusal and low body weight. Typically there is a loss of menses, intense fear of gaining weight, and an often delusional quality of altered body perception. Anorexia nervosa is also associated with a pattern of high cognitive rigidity, which may contribute to treatment resistance and relapse. The complex interplay of state and trait biological, psychological, and social factors has complicated identifying neurobiological mechanisms that contribute to the illness. The dopamine D1 and D2 neurotransmitter receptors are involved in motivational aspects of food approach, fear extinction, and cognitive flexibility. They could therefore be important targets to improve core and associated behaviors in anorexia nervosa. Treatment with dopamine antagonists has shown little benefit, and it is possible that antagonists over time increase an already hypersensitive dopamine pathway activity in anorexia nervosa. On the contrary, application of dopamine receptor agonists could reduce circuit responsiveness, facilitate fear extinction, and improve cognitive flexibility in anorexia nervosa, as they may be particularly effective during underweight and low gonadal hormone states. This article provides evidence that the dopamine receptor system could be a key factor in the pathophysiology of anorexia nervosa and dopamine agonists could be helpful in reducing core symptoms of the disorder. This review is a theoretical approach that primarily focuses on dopamine receptor function as this system has been mechanistically better described than other neurotransmitters that are altered in anorexia nervosa. However, those proposed dopamine mechanisms in anorexia nervosa also warrant further study with respect to their interaction with other neurotransmitter systems, such as serotonin pathways. PMID:25988121

  15. Allosteric coupling from G protein to the agonist-binding pocket in GPCRs.

    Science.gov (United States)

    DeVree, Brian T; Mahoney, Jacob P; Vélez-Ruiz, Gisselle A; Rasmussen, Soren G F; Kuszak, Adam J; Edwald, Elin; Fung, Juan-Jose; Manglik, Aashish; Masureel, Matthieu; Du, Yang; Matt, Rachel A; Pardon, Els; Steyaert, Jan; Kobilka, Brian K; Sunahara, Roger K

    2016-07-01

    G-protein-coupled receptors (GPCRs) remain the primary conduit by which cells detect environmental stimuli and communicate with each other. Upon activation by extracellular agonists, these seven-transmembrane-domain-containing receptors interact with heterotrimeric G proteins to regulate downstream second messenger and/or protein kinase cascades. Crystallographic evidence from a prototypic GPCR, the β2-adrenergic receptor (β2AR), in complex with its cognate G protein, Gs, has provided a model for how agonist binding promotes conformational changes that propagate through the GPCR and into the nucleotide-binding pocket of the G protein α-subunit to catalyse GDP release, the key step required for GTP binding and activation of G proteins. The structure also offers hints about how G-protein binding may, in turn, allosterically influence ligand binding. Here we provide functional evidence that G-protein coupling to the β2AR stabilizes a ‘closed’ receptor conformation characterized by restricted access to and egress from the hormone-binding site. Surprisingly, the effects of G protein on the hormone-binding site can be observed in the absence of a bound agonist, where G-protein coupling driven by basal receptor activity impedes the association of agonists, partial agonists, antagonists and inverse agonists. The ability of bound ligands to dissociate from the receptor is also hindered, providing a structural explanation for the G-protein-mediated enhancement of agonist affinity, which has been observed for many GPCR–G-protein pairs. Our data also indicate that, in contrast to agonist binding alone, coupling of a G protein in the absence of an agonist stabilizes large structural changes in a GPCR. The effects of nucleotide-free G protein on ligand-binding kinetics are shared by other members of the superfamily of GPCRs, suggesting that a common mechanism may underlie G-protein-mediated enhancement of agonist affinity. PMID:27362234

  16. Mechanisms of geometrical seismic attenuation

    Directory of Open Access Journals (Sweden)

    Igor B. Morozov

    2011-07-01

    Full Text Available In several recent reports, we have explained the frequency dependence of the apparent seismic quality-factor (Q observed in many studies according to the effects of geometrical attenuation, which was defined as the zero-frequency limit of the temporal attenuation coefficient. In particular, geometrical attenuation was found to be positive for most waves traveling within the lithosphere. Here, we present three theoretical models that illustrate the origin of this geometrical attenuation, and we investigate the causes of its preferential positive values. In addition, we discuss the physical basis and limitations of both the conventional and new attenuation models. For waves in media with slowly varying properties, geometrical attenuation is caused by variations in the wavefront curvature, which can be both positive (for defocusing and negative (for focusing. In media with velocity/density contrasts, incoherent reflectivity leads to geometrical-attenuation coefficients which are proportional to the mean squared reflectivity and are always positive. For «coherent» reflectivity, the geometrical attenuation is approximately zero, and the attenuation process can be described according to the concept of «scattering Q». However, the true meaning of this parameter is in describing the mean reflectivity within the medium, and not that of the traditional resonator quality factor known in mechanics. The general conclusion from these models is that non-zero and often positive levels of geometrical attenuation are common in realistic, heterogeneous media, both observationally and theoretically. When transformed into the conventional Q-factor form, this positive geometrical attenuation leads to Q values that quickly increase with frequency. These predictions show that the positive frequency-dependent Q observed in many datasets might represent artifacts of the transformations of the attenuation coefficients into Q.

  1. Structure-Function Basis of Attenuated Inverse Agonism of Angiotensin II Type 1 Receptor Blockers for Active-State Angiotensin II Type 1 Receptor.

    Science.gov (United States)

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

    2015-09-01

    Ligand-independent signaling by the angiotensin II type 1 receptor (AT1R) can be activated in clinical settings by mechanical stretch and autoantibodies as well as receptor mutations. Transition of the AT1R to the activated state is known to lower inverse agonistic efficacy of clinically used AT1R blockers (ARBs). The structure-function basis for reduced efficacy of inverse agonists is a fundamental aspect that has been understudied not only in relation to the AT1R but also regarding other homologous receptors. Here, we demonstrate that the active-state transition in the AT1R indeed attenuates an inverse agonistic effect of four biphenyl-tetrazole ARBs through changes in specific ligand-receptor interactions. In the ground state, tight interactions of four ARBs with a set of residues (Ser109(TM3), Phe182(ECL2), Gln257(TM6), Tyr292(TM7), and Asn295(TM7)) results in potent inverse agonism. In the activated state, the ARB-AT1R interactions shift to a different set of residues (Val108(TM3), Ser109(TM3), Ala163(TM4), Phe182(ECL2), Lys199(TM5), Tyr292(TM7), and Asn295(TM7)), resulting in attenuated inverse agonism. Interestingly, V108I, A163T, N295A, and F182A mutations in the activated state of the AT1R shift the functional response to the ARB binding toward agonism, but in the ground state the same mutations cause inverse agonism. Our data show that the second extracellular loop is an important regulator of the functional states of the AT1R. Our findings suggest that the quest for discovering novel ARBs, and improving current ARBs, fundamentally depends on the knowledge of the unique sets of residues that mediate inverse agonistic potency in the two states of the AT1R. PMID:26121982

  2. Lg Attenuation Modeling in the Middle East

    Science.gov (United States)

    Pasyanos, M. E.; Matzel, E. M.; Walter, W. R.; Rodgers, A. J.

    2008-12-01

    We present a broadband tomographic model of Lg attenuation in the Middle East derived from source- and site-corrected amplitudes. The study region spans from Turkey through the Arabian Peninsula and Iran to Pakistan, Afghanistan, and northwest India. Absolute amplitude measurements are made on hand-selected and carefully windowed seismograms for tens of stations and thousands of crustal earthquakes resulting in excellent coverage of the region. We have modified the standard attenuation tomography technique to more explicitly define the earthquake source expression in terms of the seismic moment. This facilitates the use of the model to predict the expected amplitudes of new events, an important consideration for earthquake hazard or explosion monitoring applications. We will discuss the updated method and implications of this parameterization. A conjugate gradient method is used to tomographically invert the amplitude dataset of over 8000 paths. We solve for Q variation, as well as site and source terms, for a wide range of frequencies ranging from 0.5 -- 10 Hz. The attenuation results have a strong correlation to tectonics. Shields have low attenuation, while tectonic regions have high attenuation, with the highest attenuation at 1 Hz found in eastern Turkey. The results also compare favorably to other studies in the region made using Lg propagation efficiency, Lg/Pg amplitude ratios and two-station methods. We tomographically invert the amplitude measurements for each frequency independently. In doing so, it appears the frequency-dependence of attenuation is not compatible with the power law representation of Q(f). This research was performed under the auspices of the U.S. Department of Energy by the Lawrence Livermore National Laboratory under contract number DE-AC52-07NA27344. This is LLNL contribution LLNL-ABS-406761.

  3. Antitussive profile of the NOP agonist Ro-64-6198 in the guinea pig.

    Science.gov (United States)

    McLeod, Robbie L; Jia, Yanlin; Fernandez, Xiomara; Parra, Leonard E; Wang, Xin; Tulshian, Deen B; Kiselgof, Eugenia J; Tan, Zheng; Fawzi, Ahmad B; Smith-Torhan, April; Zhang, Hongtao; Hey, John A

    2004-07-01

    We have previously shown that N/OFQ, the endogenous peptide ligand for the 'opioid-like' NOP receptor, inhibits cough in guinea pigs and cats. In the present study we sought to continue our characterization of the cough-suppressant effects of NOP stimulation by profiling the pulmonary and antitussive effects of a novel non-peptide NOP agonist, Ro-64-6198, in guinea pigs. In receptor-binding assays, we confirmed that Ro-64-6198 selectively binds to NOP receptors over other opioid receptors. The Ki values for Ro-64-6198 at NOP, MOP, KOP and DOP receptors was 0.3, 36, 214 and 3,787 nmol/l, respectively. In GTPgammaS-binding assays, Ro-64-6198 displayed >900-fold functional selectivity at NOP relative to MOP receptors. We evaluated the effects of Ro-64-6198 (3 and 10 micromol/l) in isolated guinea pig nodose ganglia cells on the increases in intracellular Ca2+ concentration evoked by capsaicin stimulation (1 x 10(-8)-1 x 10(-6) mol/l). Similar to previously reported data with N/OFQ, Ro-64-6198 (3 and 10 micromol/l) significantly attenuated Ca2+ responses in nodose ganglia cells produced by exposure to capsaicin. The effect of Ro-64-6198 (3 micromol/l) on capsaicin-induced intracellular Ca2+ responses was blocked by the NOP antagonist, J113397 (3 micromol/l). In guinea pig in vivo studies, aerosolized capsaicin (10-300 micromol/l) produced a dose-dependent increase in cough number. Ro-64-6198 given i.p. significantly inhibited cough due to capsaicin (300 micromol/l) exposure. In a duration study we found that the maximum antitussive effect (42 +/- 8% inhibition) of Ro-64-6198 (3 mg/kg) was observed at 1 h after i.p. administration. Also at 1 h after administration, Ro-64-6198 (0.003-3.0 mg/kg, i.p.) produced a dose-dependent inhibition of cough. The antitussive effect of Ro-64-6198 (3 mg/kg, i.p.) was blocked by J113397 (12 mg/kg, i.p.) but not by the classical opioid antagonist naltrexone (10 mg/kg, i.p.). Although the antitussive action of Ro-64-6198 may be mediated

  4. Phosphocholine - an agonist of metabotropic but not of ionotropic functions of α9-containing nicotinic acetylcholine receptors.

    Science.gov (United States)

    Richter, K; Mathes, V; Fronius, M; Althaus, M; Hecker, A; Krasteva-Christ, G; Padberg, W; Hone, A J; McIntosh, J M; Zakrzewicz, A; Grau, V

    2016-01-01

    We demonstrated previously that phosphocholine and phosphocholine-modified macromolecules efficiently inhibit ATP-dependent release of interleukin-1β from human and murine monocytes by a mechanism involving nicotinic acetylcholine receptors (nAChR). Interleukin-1β is a potent pro-inflammatory cytokine of innate immunity that plays pivotal roles in host defence. Control of interleukin-1β release is vital as excessively high systemic levels cause life threatening inflammatory diseases. In spite of its structural similarity to acetylcholine, there are no other reports on interactions of phosphocholine with nAChR. In this study, we demonstrate that phosphocholine inhibits ion-channel function of ATP receptor P2X7 in monocytic cells via nAChR containing α9 and α10 subunits. In stark contrast to choline, phosphocholine does not evoke ion current responses in Xenopus laevis oocytes, which heterologously express functional homomeric nAChR composed of α9 subunits or heteromeric receptors containing α9 and α10 subunits. Preincubation of these oocytes with phosphocholine, however, attenuated choline-induced ion current changes, suggesting that phosphocholine may act as a silent agonist. We conclude that phophocholine activates immuno-modulatory nAChR expressed by monocytes but does not stimulate canonical ionotropic receptor functions. PMID:27349288

  5. Effects of dopamine D1 and D2 receptor agonists and antagonists on bombesin-induced behaviors.

    Science.gov (United States)

    Merali, Z; Piggins, H

    1990-12-01

    Central administration of bombesin elicits excessive grooming and locomotor activity in rats. This grooming activity is one characterised by vigorous scratching of the face, nape and body flanks. Pretreatment with the D1 receptor antagonist SCH 23390 inhibited the expression of bombesin-induced activity with grooming being more inhibited than locomotion. Blockade of D2 receptors with eticlopride significantly attenuated the behavioral responses to bombesin. When SCH 23390 and eticlopride were administered concurrently, it was apparent that D1 blockade had a greater effect on grooming and D2 blockade a larger effect on locomotion. Stimulation of D1 receptors by SKF 38393 elicited non-stereotyped locomotor activity and a form of grooming behavior characterised by vigorous washing of the face and ventral body surfaces. Co-administration of bombesin and SKF 38393 resulted in a form of grooming which resembled that elicited by SKF 38393 alone. The specific D2 agonist PPHT elicited a form of locomotion characterised by a downward oriented head posture and slow ambulatory activity around the cage perimeter. Co-administration of PPHT and bombesin resulted in a complete suppression of bombesin-induced behaviors and was largely indistinguishable from activity observed under PPHT alone conditions. These data implicate both D1 and D2 receptor based mechanisms in the modulation/mediation of the behavioral effects of bombesin. Part of the bombesin-induced behavioral effects may be explained by (indirect) activation of (a) dopamine system(s). PMID:2086245

  6. β2-Adrenoceptor agonist-induced RGS2 expression is a genomic mechanism of bronchoprotection that is enhanced by glucocorticoids.

    Science.gov (United States)

    Holden, Neil S; Bell, Matthew J; Rider, Christopher F; King, Elizabeth M; Gaunt, David D; Leigh, Richard; Johnson, Malcolm; Siderovski, David P; Heximer, Scott P; Giembycz, Mark A; Newton, Robert

    2011-12-01

    In asthma and chronic obstructive pulmonary disease, activation of G(q)-protein-coupled receptors causes bronchoconstriction. In each case, the management of moderate-to-severe disease uses inhaled corticosteroid (glucocorticoid)/long-acting β(2)-adrenoceptor agonist (LABA) combination therapies, which are more efficacious than either monotherapy alone. In primary human airway smooth muscle cells, glucocorticoid/LABA combinations synergistically induce the expression of regulator of G-protein signaling 2 (RGS2), a GTPase-activating protein that attenuates G(q) signaling. Functionally, RGS2 reduced intracellular free calcium flux elicited by histamine, methacholine, leukotrienes, and other spasmogens. Furthermore, protection against spasmogen-increased intracellular free calcium, following treatment for 6 h with LABA plus corticosteroid, was dependent on RGS2. Finally, Rgs2-deficient mice revealed enhanced bronchoconstriction to spasmogens and an absence of LABA-induced bronchoprotection. These data identify RGS2 gene expression as a genomic mechanism of bronchoprotection that is induced by glucocorticoids plus LABAs in human airway smooth muscle and provide a rational explanation for the clinical efficacy of inhaled corticosteroid (glucocorticoid)/LABA combinations in obstructive airways diseases. PMID:22080612

  7. Phosphocholine – an agonist of metabotropic but not of ionotropic functions of α9-containing nicotinic acetylcholine receptors

    Science.gov (United States)

    Richter, K.; Mathes, V.; Fronius, M.; Althaus, M.; Hecker, A.; Krasteva-Christ, G.; Padberg, W.; Hone, A. J.; McIntosh, J. M.; Zakrzewicz, A.; Grau, V.

    2016-01-01

    We demonstrated previously that phosphocholine and phosphocholine-modified macromolecules efficiently inhibit ATP-dependent release of interleukin-1β from human and murine monocytes by a mechanism involving nicotinic acetylcholine receptors (nAChR). Interleukin-1β is a potent pro-inflammatory cytokine of innate immunity that plays pivotal roles in host defence. Control of interleukin-1β release is vital as excessively high systemic levels cause life threatening inflammatory diseases. In spite of its structural similarity to acetylcholine, there are no other reports on interactions of phosphocholine with nAChR. In this study, we demonstrate that phosphocholine inhibits ion-channel function of ATP receptor P2X7 in monocytic cells via nAChR containing α9 and α10 subunits. In stark contrast to choline, phosphocholine does not evoke ion current responses in Xenopus laevis oocytes, which heterologously express functional homomeric nAChR composed of α9 subunits or heteromeric receptors containing α9 and α10 subunits. Preincubation of these oocytes with phosphocholine, however, attenuated choline-induced ion current changes, suggesting that phosphocholine may act as a silent agonist. We conclude that phophocholine activates immuno-modulatory nAChR expressed by monocytes but does not stimulate canonical ionotropic receptor functions. PMID:27349288

  8. Environmental Enrichment Attenuated Sevoflurane-Induced Neurotoxicity through the PPAR-γ Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Yupeng Zhao

    2015-01-01

    Full Text Available Sevoflurane is the most widely used inhaled anesthetic. Environmental enrichment (EE can reverse sevoflurane-induced learning and memory impairment in young mice. However, the mechanism by which EE elicits this effect is unclear. The peroxisome proliferator-activated receptor (PPAR regulatory pathway plays a critical role in the regulation of inflammation in central nervous system diseases. In this study, we investigated whether EE attenuates sevoflurane-induced learning and memory disability via the PPAR signaling pathway. Six-day-old mice were treated with 3% sevoflurane for 2 hours daily from postnatal day 6 (P6 to P8. Then, the mice were treated with EE. The effects of sevoflurane on learning and memory function, PPAR-γ expression in the brain, and the numbers of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells and 5-bromodeoxyuridine-positive cells in the hippocampus were determined. Sevoflurane induced neuronal apoptosis and neurogenesis inhibition, which may impair learning and memory in young mice. Furthermore, sevoflurane downregulated PPAR-γ expression. Both EE and the PPAR-γ agonist, rosiglitazone, attenuated sevoflurane-induced neuronal apoptosis, neurogenesis inhibition, and learning and memory impairment. Our findings suggest that EE ameliorated sevoflurane-induced neurotoxicity and learning and memory impairment through the PPAR-γ signaling pathway. PPAR-γ may be a potential therapeutic target for preventing or treating sevoflurane-induced neurotoxicity.

  9. Fat Attenuation at CT in Anorexia Nervosa.

    Science.gov (United States)

    Gill, Corey M; Torriani, Martin; Murphy, Rachel; Harris, Tamara B; Miller, Karen K; Klibanski, Anne; Bredella, Miriam A

    2016-04-01

    Purpose To investigate the composition, cross-sectional area (CSA), and hormonal correlates of different fat depots in women with anorexia nervosa (AN) and control subjects with normal weights to find out whether patients with AN have lower fat CSA but higher attenuation than did control subjects and whether these changes may be mediated by gonadal steroids, cortisol, and thyroid hormones. Materials and Methods This study was institutional review board approved and HIPAA compliant. Written informed consent was obtained. Forty premenopausal women with AN and 40 normal-weight women of comparable age (mean age ± standard deviation, 26 years ± 5) were studied. All individuals underwent computed tomography of the abdomen and thigh with a calibration phantom. Abdominal subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), thigh SAT, and thigh intermuscular adipose tissue CSA and attenuation were quantified. Serum estradiol, thyroid hormones, and urinary free cortisol levels were assessed. Variables were compared by using analysis of variance. Associations were examined by using linear regression analysis. Results Women with AN had higher fat attenuation than did control subjects (-100.1 to -46.7 HU vs -117.6 to -61.8 HU, P < .0001), despite lower fat CSA (2.0-62.8 cm(2) vs 5.5-185.9 cm(2), P < .0001). VAT attenuation but not CSA was inversely associated with lowest prior lifetime body mass index in AN (r = -0.71, P = .006). Serum estradiol levels were inversely associated with fat attenuation (r = -0.34 to -0.61, P = .03 to <.0001) and were positively associated with fat CSA of all compartments (r = 0.42-0.64, P = .007 to <.0001). Thyroxine levels and urinary free cortisol levels were positively associated with thigh SAT attenuation (r = 0.64 [P = .006] and r = 0.68 [P = .0004], respectively) and were inversely associated with abdominal SAT and VAT CSA (r = -0.44 to -0.58, P = .04 to .02). Conclusion Women with AN have differences in fat composition, with

  10. Cine CT for Attenuation Correction in Cardiac PET/CT

    OpenAIRE

    Alessio, Adam M.; Kohlmyer, Steve; Branch, Kelley; Chen, Grace; Caldwell, James; Kinahan, Paul

    2007-01-01

    In dual-modality PET/CT systems, the CT scan provides the attenuation map for PET attenuation correction. The current clinical practice of obtaining a single helical CT scan provides only a snapshot of the respiratory cycle, whereas PET occurs over multiple respiratory cycles. Misalignment of the attenuation map and emission image because of respiratory motion causes errors in the attenuation correction factors and artifacts in the attenuation-corrected PET image. To rectify this problem, we ...

  11. Enabling photon counting detectors with dynamic attenuators

    Science.gov (United States)

    Hsieh, Scott S.; Pelc, Norbert J.

    2014-03-01

    Photon-counting x-ray detectors (PCXDs) are being investigated as a replacement for conventional x-ray detectors because they promise several advantages, including better dose efficiency, higher resolution and spectral imaging. However, many of these advantages disappear when the x-ray flux incident on the detector is too high. We recently proposed a dynamic, piecewise-linear attenuator (or beam shaping filter) that can control the flux incident on the detector. This can restrict the operating range of the PCXD to keep the incident count rate below a given limit. We simulated a system with the piecewise-linear attenuator and a PCXD using raw data generated from forward projected DICOM files. We investigated the classic paralyzable and nonparalyzable PCXD as well as a weighted average of the two, with the weights chosen to mimic an existing PCXD (Taguchi et al, Med Phys 2011). The dynamic attenuator has small synergistic benefits with the nonparalyzable detector and large synergistic benefits with the paralyzable detector. Real PCXDs operate somewhere between these models, and the weighted average model still shows large benefits from the dynamic attenuator. We conclude that dynamic attenuators can reduce the count rate performance necessary for adopting PCXDs.

  12. Inhibition by TRPA1 agonists of compound action potentials in the frog sciatic nerve

    Energy Technology Data Exchange (ETDEWEB)

    Matsushita, Akitomo; Ohtsubo, Sena; Fujita, Tsugumi; Kumamoto, Eiichi, E-mail: kumamote@cc.saga-u.ac.jp

    2013-04-26

    Highlights: •TRPA1 agonists inhibited compound action potentials in frog sciatic nerves. •This inhibition was not mediated by TRPA1 channels. •This efficacy was comparable to those of lidocaine and cocaine. •We found for the first time an ability of TRPA1 agonists to inhibit nerve conduction. -- Abstract: Although TRPV1 and TRPM8 agonists (vanilloid capsaicin and menthol, respectively) at high concentrations inhibit action potential conduction, it remains to be unknown whether TRPA1 agonists have a similar action. The present study examined the actions of TRPA1 agonists, cinnamaldehyde (CA) and allyl isothiocyanate (AITC), which differ in chemical structure from each other, on compound action potentials (CAPs) recorded from the frog sciatic nerve by using the air-gap method. CA and AITC concentration-dependently reduced the peak amplitude of the CAP with the IC{sub 50} values of 1.2 and 1.5 mM, respectively; these activities were resistant to a non-selective TRP antagonist ruthenium red or a selective TRPA1 antagonist HC-030031. The CA and AITC actions were distinct in property; the latter but not former action was delayed in onset and partially reversible, and CA but not AITC increased thresholds to elicit CAPs. A CAP inhibition was seen by hydroxy-α-sanshool (by 60% at 0.05 mM), which activates both TRPA1 and TRPV1 channels, a non-vanilloid TRPV1 agonist piperine (by 20% at 0.07 mM) and tetrahydrolavandulol (where the six-membered ring of menthol is opened; IC{sub 50} = 0.38 mM). It is suggested that TRPA1 agonists as well as TRPV1 and TRPM8 agonists have an ability to inhibit nerve conduction without TRP activation, although their agonists are quite different in chemical structure from each other.

  13. Comparison of human B cell activation by TLR7 and TLR9 agonists

    Directory of Open Access Journals (Sweden)

    Neys Lori

    2008-07-01

    Full Text Available Abstract Background Human B cells and plasmacytoid dendritic cells (pDC are the only cells known to express both TLR7 and TLR9. Plasmacytoid dendritic cells are the primary IFN-α producing cells in response to TLR7 and TLR9 agonists. The direct effects of TLR7 stimulation on human B cells is less understood. The objective of this study was to compare the effects of TLR7 and TLR9 stimulation on human B cell function. Results Gene expression and protein production of cytokines, chemokines, various B cell activation markers, and immunoglobulins were evaluated. Purified human CD19+ B cells (99.9%, containing both naïve and memory populations from peripheral blood were stimulated with a TLR7-selective agonist (852A, TLR7/8 agonist (3M-003, or TLR9 selective agonist CpG ODN (CpG2006. TLR7 and TLR9 agonists similarly modulated the expression of cytokine and chemokine genes (IL-6, MIP1 alpha, MIP1 beta, TNF alpha and LTA, co-stimulatory molecules (CD80, CD40 and CD58, Fc receptors (CD23, CD32, anti-apoptotic genes (BCL2L1, certain transcription factors (MYC, TCFL5, and genes critical for B cell proliferation and differentiation (CD72, IL21R. Both agonists also induced protein expression of the above cytokines and chemokines. Additionally, TLR7 and TLR9 agonists induced the production of IgM and IgG. A TLR8-selective agonist was comparatively ineffective at stimulating purified human B cells. Conclusion These results demonstrate that despite their molecular differences, the TLR7 and TLR9 agonists induce similar genes and proteins in purified human B cells.

  14. Inhibition by TRPA1 agonists of compound action potentials in the frog sciatic nerve

    International Nuclear Information System (INIS)

    Highlights: •TRPA1 agonists inhibited compound action potentials in frog sciatic nerves. •This inhibition was not mediated by TRPA1 channels. •This efficacy was comparable to those of lidocaine and cocaine. •We found for the first time an ability of TRPA1 agonists to inhibit nerve conduction. -- Abstract: Although TRPV1 and TRPM8 agonists (vanilloid capsaicin and menthol, respectively) at high concentrations inhibit action potential conduction, it remains to be unknown whether TRPA1 agonists have a similar action. The present study examined the actions of TRPA1 agonists, cinnamaldehyde (CA) and allyl isothiocyanate (AITC), which differ in chemical structure from each other, on compound action potentials (CAPs) recorded from the frog sciatic nerve by using the air-gap method. CA and AITC concentration-dependently reduced the peak amplitude of the CAP with the IC50 values of 1.2 and 1.5 mM, respectively; these activities were resistant to a non-selective TRP antagonist ruthenium red or a selective TRPA1 antagonist HC-030031. The CA and AITC actions were distinct in property; the latter but not former action was delayed in onset and partially reversible, and CA but not AITC increased thresholds to elicit CAPs. A CAP inhibition was seen by hydroxy-α-sanshool (by 60% at 0.05 mM), which activates both TRPA1 and TRPV1 channels, a non-vanilloid TRPV1 agonist piperine (by 20% at 0.07 mM) and tetrahydrolavandulol (where the six-membered ring of menthol is opened; IC50 = 0.38 mM). It is suggested that TRPA1 agonists as well as TRPV1 and TRPM8 agonists have an ability to inhibit nerve conduction without TRP activation, although their agonists are quite different in chemical structure from each other

  15. Binding Mode of Insulin Receptor and Agonist Peptide

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Insulin is a protein hormone secreted by pancreatic β cells. One of its main functions is to keep the balance of glucose inside the body by regulating the absorption and metabolism of glucose in the periphery tissue, as well as the production and storage of hepatic glycogen. The insulin receptor is a transmembrane glycoprotein in which two α subunits with a molecular weight of 135 kD and twoβ subunits with a molecular weight of 95 kD are joined by a disulfide bond to form a β-α-α-β structure. The extracellular α subunit, especially, its three domains near the N-terminal are partially responsible for signal transduction or ligand-binding, as indicated by the experiments. The extracellular α subunits are involved in binding the ligands. The experimental results indicate that the three domains of the N-terminal of the α subunits are the main determinative parts of the insulin receptor to bind the insulin or mimetic peptide.We employed the extracellular domain (PDBID: 1IGR) of the insulin-like growth factor-1 receptor (IGF-1 R ) as the template to simulate and optimize the spatial structures of the three domains in the extracellular domain of the insulin receptor, which includes 468 residues. The work was accomplished by making use of the homology program in the Insight Ⅱ package on an Origin3800 server. The docking calculations of the insulin receptor obtained by homology with hexapeptides were carried out by means of the program Affinity. The analysis indicated that there were hydrogen bonding, and electrostatic and hydrophobic effects in the docking complex of the insulin receptor with hexapeptides.Moreover, we described the spatial orientation of a mimetic peptide with agonist activity in the docking complex. We obtained a rough model of binding of DLAPSQ or STIVYS with the insulin receptor, which provides the powerful theoretical support for designing the minimal insulin mimetic peptide with agonist activity, making it possible to develop oral small

  16. Major drawbacks and additional benefits of agonist trigger-not ovarian hyperstimulation syndrome related

    DEFF Research Database (Denmark)

    Shapiro, Bruce S; Andersen, Claus Yding

    2015-01-01

    optimal luteal support. The agonist trigger option also allows continued stimulation and subsequent trigger of high responders with reasonable safety, potentially leading to retrievals of larger cohorts of mature oocytes. It may also reduce the number of retrievals needed to achieve a large family. The...... agonist trigger might alter other paradigms as well, such as making oocyte donation more efficient per stimulation by virtually eliminating follicular-phase cycle cancellation, coasting, and premature triggering. There are both corresponding potential benefits and drawbacks of using the agonist trigger...

  17. A protease-activated receptor 2 agonist (AC-264613) suppresses interferon regulatory factor 5 and decreases interleukin-12p40 production by lipopolysaccharide-stimulated macrophages: Role of p53.

    Science.gov (United States)

    Yamaguchi, Rui; Yamamoto, Takatoshi; Sakamoto, Arisa; Ishimaru, Yasuji; Narahara, Shinji; Sugiuchi, Hiroyuki; Yamaguchi, Yasuo

    2016-06-01

    The transcription factor interferon regulatory factor 5 (IRF5) has a key role in the production of interleukin (IL)-12 by macrophages. IRF5 is also a central mediator of toll-like receptor signaling and is a direct target of p53. Activation of protease-activated receptor 2 (PAR-2) upregulates p53 and suppresses apoptosis. This study investigated the influence of human neutrophil elastase (HNE) and PAR-2 agonists on expression of IRF5 and IL-12p40 by macrophages stimulated with lipopolysaccharide. Granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent macrophages showed upregulation of IRF5 expression, while HNE reduced expression of p53 and IRF5 in a concentration-dependent manner. HNE also caused a concentration-dependent decrease of IRF5 in macrophages transfected with small interfering RNA to silence p53, while silencing of β-arrestin 2 blunted the reduction of p53 or IRF5 by HNE. Incubation of macrophages with a PAR-2 agonist, AC-264613, caused a decrease of IRF5 expression and also significantly reduced p53 protein expression. HNE upregulated the expression of tumor necrosis factor receptor-associated factor 6 (TRAF6) and caused transactivation of TLR4, while AC-264613 did not promote TLR4 transactivation. In conclusion, the PAR-2 agonist AC-264613 attenuated IRF5-associated IL-12p40 production by macrophages. PMID:26833899

  18. Finite Element Analysis of Honeycomb Impact Attenuator

    Science.gov (United States)

    Yang, Seung-Yong; Choi, Seung-Kyu; Kim, Nohyu

    To participate in Student Formula Society of Automotive Engineers (SAE) competitions, it is necessary to build an impact attenuator that would give an average deceleration not to exceed 20g when it runs into a rigid wall. Students can use numerical simulations or experimental test data to show that their car satisfies this safety requirement. A student group to study formula cars at the Korea University of Technology and Education has designed a vehicle to take part in a SAE competition, and a honeycomb structure was adopted as the impact attenuator. In this paper, finite element calculations were carried out to investigate the dynamic behavior of the honeycomb attenuator. Deceleration and deformation behaviors were studied. Effect of the yield strength was checked by comparing the numerical results. ABAQUS/Explicit finite element code was used.

  19. Attenuation of the gamma rays in tissues

    International Nuclear Information System (INIS)

    The mass and lineal attenuation coefficient and of hepatic tissue, muscular, osseous and of brain before gamma rays of 10-3 to 105 MeV were calculated. For the case of the osseous tissue the calculation was made for the cartilage, the cortical tissue and the bone marrow. During the calculations the elementary composition of the tissues of human origin was used. The calculations include by separate the Photoelectric effect, the Compton scattering and the Pair production, as well as the total. For to establish a comparison with the attenuation capacities, the coefficients of the water, the aluminum and the lead also were calculated. The study was complemented measuring the attenuation coefficient of hepatic tissue of bovine before gamma rays of 0.662 MeV of a source of 137 Cs. The measurement was made through of an experiment of photons transmission through samples frozen of hepatic tissue and with a Geiger-Mueller detector. (Author)

  20. Graphene-Based Waveguide Terahertz Wave Attenuator

    Science.gov (United States)

    Jian-rong, Hu; Jiu-sheng, Li; Guo-hua, Qiu

    2016-07-01

    We design an electrically controllable terahertz wave attenuator by using graphene. We show that terahertz wave can be confined and propagate on S-shaped graphene waveguide with little radiation losses, and the confined terahertz wave is further manipulated and controlled via external applied voltage bias. The simulated results show that, when chemical potential changes from 0.03 into 0.05 eV, the extinction ratio of the terahertz wave attenuator can be tuned from 1.28 to 39.42 dB. Besides the simplicity, this novel terahertz wave attenuator has advantages of small size (24 × 30 μm2), a low insertion loss, and good controllability. It has a potential application for forthcoming planar terahertz wave integrated circuit fields.

  1. Attenuation of ear muffs in Canadian mines

    Energy Technology Data Exchange (ETDEWEB)

    Savich, M.U.

    1979-12-01

    The main characteristics of eleven commercially available ear muffs were investigated in the laboratory and analyzed by a psychophysical and a physical method. Nine ear muffs were tested in mines. The three best muffs had bands passing behind the head. The ear muff with a support strap, which improves comfort and maintains a good fit during wear, showed the best attenuation. Causes of poor attenuation are listed. None of the ear muffs tested had all the characteristics desirable in an ideal unit. Because of unsatisfactory attenuation in working conditions, it should be a mandatory requirement that workers wear both ear muffs and ear plugs if the noise level is higher than 105 dBA.

  2. Extensible chip of optofluidic variable optical attenuator.

    Science.gov (United States)

    Wan, J; Xue, F L; Wu, L X; Fu, Y J; Hu, J; Zhang, W; Hu, F R

    2016-05-01

    A core chip of optofluidic variable optical attenuator (VOA) is reported. The chip, with a simple structure, utilizes microfluid and compressed air to regulate the optical attenuation, and it can be expanded to form a number of VOAs by using different microfluidic driving technologies. Three VOAs based on this chip and different driving technologies are introduced. The theoretical and experimental results show that the proposed chip possesses the advantages of large optical attenuation range (> 50dB) and low insertion loss (0.55 dB). Moreover it is a broadband optical device which can be operated in visible and near infrared wavelengths. The proposed chip provides a new method for seeking miniaturized VOAs with good performances, and it is promising to develop a number of different VOAs. PMID:27137582

  3. Research on Nanosecond Pulse Corona Discharge Attenuation

    International Nuclear Information System (INIS)

    A line-to-plate reactor was set-up in the experimental study on the application of nanosecond pulsed corona discharge plasma technology in environmental pollution control. Investigation on the attenuation and distortion of the amplitude of the pulse wave front and the discharge image as well as the waveform along the corona wire was conducted. The results show that the wave front decreases sharply during the corona discharge along the corona wire. The higher the amplitude of the applied pulse is, the more the amplitude of the wave front decreased. The wave attenuation responds in a lower corona discharge inversely. To get a higher efficiency of the line-to-plate reactor a sharp attenuation of the corona has to be considered in practical design

  4. Research on Nanosecond Pulse Corona Discharge Attenuation

    Institute of Scientific and Technical Information of China (English)

    HE Zheng-hao; XU Huai-li; BAI Jing; YU Fu-sheng; HU Feng; LI Jin

    2007-01-01

    A line-to-plate reactor was set-up in the experimental study on the application of nanosecond pulsed corona discharge plasma technology in environmental pollution control.Investigation on the attenuation and distortion of the amplitude of the pulse wave front and the discharge image as well as the waveform along the corona wire was conducted.The results show that the wave front decreases sharply during the corona discharge along the corona wire.The higher the amplitude of the applied pulse is,the more the amplitude of the wave front decreased.The wave attenuation responds in a lower corona discharge inversely.To get a higher efficiency of the line-to-plate reactor a sharp attenuation of the corona has to be considered in practical design.

  5. Development of PPAR-agonist GW0742 as antidiabetic drug: study in animals

    Directory of Open Access Journals (Sweden)

    Niu HS

    2015-10-01

    Full Text Available Ho-Shan Niu,1 Po-Ming Ku,2,3 Chiang-Shan Niu,1 Juei-Tang Cheng,3,4 Kung-Shing Lee5–71Department of Nursing, Tzu Chi College of Technology, Hualien City, 2Department of Cardiology, 3Department of Medical Research, Chi-Mei Medical Center, Yong Kang, Tainan City, 4Institute of Medical Sciences, Chang Jung Christian University, Guiren, Tainan City, 5Department of Surgery, Division of Neurosurgery, Pingtung Hospital, 6Department of Surgery, Kaohsiung Medical University, 7School of Medicine, Chung-Ho Memorial Hospital, Kaohsiung Medical University, Kaohsiung City, TaiwanBackground: The development of new drugs for the treatment of diabetes mellitus (DM is critically important. Insulin resistance (IR is one of the main problems associated with type-2 DM (T2DM seen in clinics. GW0742, a selective peroxisome proliferator-activated receptor (PPAR-δ agonist, has been shown to ameliorate metabolic abnormalities including IR in skeletal muscle in mice fed high-fructose corn syrup. However, the influence of GW0742 on systemic insulin sensitivity has still not been elucidated. Therefore, it is important to investigate the effect of GW0742 on systemic IR in diabetic rats for the development of new drugs.Methods: The present study used a T2DM animal model to compare the effect of GW0742 on IR using homeostasis model assessment-IR (HOMA-IR and hyperinsulinemic euglycemic clamping. Additionally, the insulinotropic action of GW0742 was investigated in type-1 DM (T1DM rats. Changes in the protein expression of glucose transporter 4 (GLUT4 and phosphoenolpyruvate carboxykinase (PEPCK in skeletal muscle and in liver, respectively, were also identified by Western blots.Results: GW0742 attenuated the increased HOMA-IR in diabetic rats fed a fructose-rich diet. This action was blocked by GSK0660 at the dose sufficient to inhibit PPAR-δ. Improvement of IR by GW0742 was also characterized in diabetic rats using hyperinsulinemic euglycemic clamping. Additionally, an

  6. Brazilin isolated from Caesalpinia sappan L. acts as a novel collagen receptor agonist in human platelets

    Directory of Open Access Journals (Sweden)

    Chang Yi

    2013-01-01

    Full Text Available Abstract Background Brazilin, isolated from the heartwood of Caesalpinia sappan L., has been shown to possess multiple pharmacological properties. Methods In this study, platelet aggregation, flow cytometry, immunoblotting analysis, and electron spin resonance (ESR spectrometry were used to investigate the effects of brazilin on platelet activation ex vivo. Moreover, fluorescein sodium-induced platelet thrombi of mesenteric microvessels was also used in in vivo study. Results We demonstrated that relatively low concentrations of brazilin (1 to 10 μM potentiated platelet aggregation induced by collagen (0.1 μg/ml in washed human platelets. Higher concentrations of brazilin (20 to 50 μM directly triggered platelet aggregation. Brazilin-mediated platelet aggregation was slightly inhibited by ATP (an antagonist of ADP. It was not inhibited by yohimbine (an antagonist of epinephrine, by SCH79797 (an antagonist of thrombin protease-activated receptor [PAR] 1, or by tcY-NH2 (an antagonist of PAR 4. Brazilin did not significantly affect FITC-triflavin binding to the integrin αIIbβ3 in platelet suspensions. Pretreatment of the platelets with caffeic acid phenethyl ester (an antagonist of collagen receptors or JAQ1 and Sam.G4 monoclonal antibodies raised against collagen receptor glycoprotein VI and integrin α2β1, respectively, abolished platelet aggregation stimulated by collagen or brazilin. The immunoblotting analysis showed that brazilin stimulated the phosphorylation of phospholipase C (PLCγ2 and Lyn, which were significantly attenuated in the presence of JAQ1 and Sam.G4. In addition, brazilin did not significantly trigger hydroxyl radical formation in ESR analysis. An in vivo mouse study showed that brazilin treatment (2 and 4 mg/kg significantly shortened the occlusion time for platelet plug formation in mesenteric venules. Conclusion To the best of our knowledge, this study provides the first evidence that brazilin acts a novel collagen

  7. Des-Aspartate-Angiotensin I Attenuates Mortality of Mice Exposed to Gamma Radiation via a Novel Mechanism of Action.

    Directory of Open Access Journals (Sweden)

    Hong Wang

    Full Text Available ACE inhibitors and ARBs (angiotensin receptor blockers have been shown to attenuate radiation injuries in animal models of lethal gamma irradiation. These two classes of drug act by curtailing the actions of angiotensin II-linked inflammatory pathways that are up-regulated during gamma radiation in organ systems such as the brain, lung, kidney, and bone marrow. ACE inhibitors inhibit ACE and attenuate the formation of angiotensin II from angiotensin I; ARBs block the angiotensin AT1 receptor and attenuate the actions of angiotensin II that are elicited through the receptor. DAA-I (des-aspartate-angiotensin I, an orally active angiotensin peptide, also attenuates the deleterious actions of angiotensin II. It acts as an agonist on the angiotensin AT1 receptor and elicits responses that oppose those of angiotensn II. Thus, DAA-I was investigated for its anticipated radioprotection in gamma irradiated mice. DAA-I administered orally at 800 nmole/kg/day for 30 days post exposure (6.4 Gy attenuated the death of mice during the 30-day period. The attenuation was blocked by losartan (50 nmole/kg/day, i.p. that was administered sequential to DAA-I administration. This shows that the radioprotection was mediated via the angiotensin AT1 receptor. Furthermore, the radioprotection correlated to an increase in circulating PGE2 of surviving animals, and this suggests that PGE2 is involved in the radioprotection in DAA-I-treated mice. At the hematopoietic level, DAA-I significantly improved two syndromes of myelosuppression (leucopenia and lymphocytopenia, and mice pre-treated with DAA-I prior to gamma irradiation showed significant improvement in the four myelodysplastic syndromes that were investigated, namely leucopenia, lymphocytopenia, monocytopenia and thrombocytopenia. Based on the known ability of PGE2 to attenuate the loss of functional hematopoietic stem and progenitor cells in radiation injury, we hypothesize that PGE2 mediated the action of DAA

  8. Des-Aspartate-Angiotensin I Attenuates Mortality of Mice Exposed to Gamma Radiation via a Novel Mechanism of Action

    Science.gov (United States)

    Wang, Hong; Sethi, Gautam; Loke, Weng-Keong; Sim, Meng-Kwoon

    2015-01-01

    ACE inhibitors and ARBs (angiotensin receptor blockers) have been shown to attenuate radiation injuries in animal models of lethal gamma irradiation. These two classes of drug act by curtailing the actions of angiotensin II-linked inflammatory pathways that are up-regulated during gamma radiation in organ systems such as the brain, lung, kidney, and bone marrow. ACE inhibitors inhibit ACE and attenuate the formation of angiotensin II from angiotensin I; ARBs block the angiotensin AT1 receptor and attenuate the actions of angiotensin II that are elicited through the receptor. DAA-I (des-aspartate-angiotensin I), an orally active angiotensin peptide, also attenuates the deleterious actions of angiotensin II. It acts as an agonist on the angiotensin AT1 receptor and elicits responses that oppose those of angiotensn II. Thus, DAA-I was investigated for its anticipated radioprotection in gamma irradiated mice. DAA-I administered orally at 800 nmole/kg/day for 30 days post exposure (6.4 Gy) attenuated the death of mice during the 30-day period. The attenuation was blocked by losartan (50 nmole/kg/day, i.p.) that was administered sequential to DAA-I administration. This shows that the radioprotection was mediated via the angiotensin AT1 receptor. Furthermore, the radioprotection correlated to an increase in circulating PGE2 of surviving animals, and this suggests that PGE2 is involved in the radioprotection in DAA-I-treated mice. At the hematopoietic level, DAA-I significantly improved two syndromes of myelosuppression (leucopenia and lymphocytopenia), and mice pre-treated with DAA-I prior to gamma irradiation showed significant improvement in the four myelodysplastic syndromes that were investigated, namely leucopenia, lymphocytopenia, monocytopenia and thrombocytopenia. Based on the known ability of PGE2 to attenuate the loss of functional hematopoietic stem and progenitor cells in radiation injury, we hypothesize that PGE2 mediated the action of DAA-I. DAA-I completely

  9. Is there seismic attenuation in the mantle?

    Science.gov (United States)

    Ricard, Y.; Durand, S.; Montagner, J.-P.; Chambat, F.

    2014-02-01

    The small scale heterogeneity of the mantle is mostly due to the mixing of petrological heterogeneities by a smooth but chaotic convection and should consist in a laminated structure (marble cake) with a power spectrum S(k) varying as 1/k, where k is the wavenumber of the anomalies. This distribution of heterogeneities during convective stirring with negligible diffusion, called Batchelor regime is documented by fluid dynamic experiments and corresponds to what can be inferred from geochemistry and seismic tomography. This laminated structure imposes density, seismic velocity and potentially, anisotropic heterogeneities with similar 1/k spectra. A seismic wave of wavenumber k0 crossing such a medium is partly reflected by the heterogeneities and we show that the scattered energy is proportional to k0S(2k0). The reduction of energy for the propagating wave appears therefore equivalent to a quality factor 1/Q∝k0S(2k0). With the specific 1/k spectrum of the mantle, the resulting apparent attenuation should therefore be frequency independent. We show that the total contribution of 6-9% RMS density, velocity and anisotropy would explain the observed S and P attenuation of the mantle. Although these values are large, they are not unreasonable and we discuss how they depend on the range of frequencies over which the attenuation is explained. If such a level of heterogeneity were present, most of the attenuation of the Earth would be due to small scale scattering by laminations, not by intrinsic dissipation. Intrinsic dissipation must certainly exist but might correspond to a larger, yet unobserved Q. This provocative result would explain the very weak frequency dependence of the attenuation, and the fact that bulk attenuation seems negligible, two observations that have been difficult to explain for 50 years.

  10. The mGlu2/3 Receptor Agonists LY354740 and LY379268 Differentially Regulate Restraint-Stress-Induced Expression of c-Fos in Rat Cerebral Cortex

    Directory of Open Access Journals (Sweden)

    M. M. Menezes

    2013-01-01

    Full Text Available Metabotropic glutamate 2/3 (mGlu2/3 receptors have emerged as potential therapeutic targets due to the ability of mGlu2/3 receptor agonists to modulate excitatory transmission at specific synapses. LY354740 and LY379268 are selective and potent mGlu2/3 receptor agonists that show both anxiolytic- and antipsychotic-like effects in animal models. We compared the efficacy of LY354740 and LY379268 in attenuating restraint-stress-induced expression of the immediate early gene c-Fos in the rat prelimbic (PrL and infralimbic (IL cortex. LY354740 (10 and 30 mg/kg, i.p. showed statistically significant and dose-related attenuation of stress-induced increase in c-Fos expression, in the rat cortex. By contrast, LY379268 had no effect on restraint-stress-induced c-Fos upregulation (0.3–10 mg/kg, i.p.. Because both compounds inhibit serotonin 2A receptor (5-HT2AR-induced c-Fos expression, we hypothesize that LY354740 and LY379268 have different in vivo properties and that 5-HT2AR activation and restraint stress induce c-Fos through distinct mechanisms.

  11. Therapeutic applications of TRAIL receptor agonists in cancer and beyond.

    Science.gov (United States)

    Amarante-Mendes, Gustavo P; Griffith, Thomas S

    2015-11-01

    TRAIL/Apo-2L is a member of the TNF superfamily first described as an apoptosis-inducing cytokine in 1995. Similar to TNF and Fas ligand, TRAIL induces apoptosis in caspase-dependent manner following TRAIL death receptor trimerization. Because tumor cells were shown to be particularly sensitive to this cytokine while normal cells/tissues proved to be resistant along with being able to synthesize and release TRAIL, it was rapidly appreciated that TRAIL likely served as one of our major physiologic weapons against cancer. In line with this, a number of research laboratories and pharmaceutical companies have attempted to exploit the ability of TRAIL to kill cancer cells by developing recombinant forms of TRAIL or TRAIL receptor agonists (e.g., receptor-specific mAb) for therapeutic purposes. In this review article we will describe the biochemical pathways used by TRAIL to induce different cell death programs. We will also summarize the clinical trials related to this pathway and discuss possible novel uses of TRAIL-related therapies. In recent years, the physiological importance of TRAIL has expanded beyond being a tumoricidal molecule to one critical for a number of clinical settings - ranging from infectious disease and autoimmunity to cardiovascular anomalies. We will also highlight some of these conditions where modulation of the TRAIL/TRAIL receptor system may be targeted in the future. PMID:26343199

  12. Agouti signalling protein is an inverse agonist to the wildtype and agonist to the melanic variant of the melanocortin-1 receptor in the grey squirrel (Sciurus carolinensis).

    Science.gov (United States)

    McRobie, Helen R; King, Linda M; Fanutti, Cristina; Symmons, Martyn F; Coussons, Peter J

    2014-06-27

    The melanocortin-1 receptor (MC1R) is a key regulator of mammalian pigmentation. Melanism in the grey squirrel is associated with an eight amino acid deletion in the mutant melanocortin-1 receptor with 24 base pair deletion (MC1RΔ24) variant. We demonstrate that the MC1RΔ24 exhibits a higher basal activity than the wildtype MC1R (MC1R-wt). We demonstrate that agouti signalling protein (ASIP) is an inverse agonist to the MC1R-wt but is an agonist to the MC1RΔ24. We conclude that the deletion in the MC1RΔ24 leads to a receptor with a high basal activity which is further activated by ASIP. This is the first report of ASIP acting as an agonist to MC1R. PMID:24879893

  13. Acute and Chronic Effects of ß2-Adrenoceptor Agonists in Relation to Exercise Performance and Doping with Emphasis on Terbutaline

    DEFF Research Database (Denmark)

    Hostrup, Morten

    This thesis addresses the performance enhancing effects of β2-agonists (asthma medication) with emphasis on terbutaline in the context of doping. Given the high prevalence of asthma in the athletic population, β2-agonists are among the most used drugs in competitive sport. While there is consensus...... that therapeutic inhalation of β2-agonists is without performance enhancing effects, oral β2-agonists are considered performance-enhancing. Since the systemic uptake of inhaled β2-agonists is higher than after oral intake, it may be that high dose inhalation of β2-agonists is performance enhancing. Moreover......, the underlying mechanisms by which β2-agonists affect performance in humans are inadequately explored. The purpose of this PhD was to investigate acute and chronic effects of high dose administration of terbutaline and to examine underlying mechanisms by which terbutaline affects performance....

  14. Ultrasound transmission attenuation tomography using energy-scaled amplitude ratios

    Science.gov (United States)

    Chen, Ting; Shin, Junseob; Huang, Lianjie

    2016-04-01

    Ultrasound attenuation of breast tumors is related to their types and pathological states, and can be used to detect and characterize breast cancer. Particularly, ultrasound scattering attenuation can infer the margin properties of breast tumors. Ultrasound attenuation tomography quantitatively reconstructs the attenuation properties of the breast. Our synthetic-aperture breast ultrasound tomography system with two parallel transducer arrays records both ultrasound reflection and transmission signals. We develop an ultrasound attenuation tomography method using ultrasound energy-scaled amplitude decays of ultrasound transmission signals and conduct ultrasound attenuation tomography using a known sound-speed model. We apply our ultrasound transmission attenuation tomography method to a breast phantom dataset, and compare the ultrasound attenuation tomography results with conventional beamforming ultrasound images obtained using reflection signals. We show that ultrasound transmission attenuation tomography complements beamforming images in identifying breast lesions.

  15. Structure and function of an irreversible agonist-β(2) adrenoceptor complex

    DEFF Research Database (Denmark)

    Rosenbaum, Daniel M; Zhang, Cheng; Lyons, Joseph A; Holl, Ralph; Aragao, David; Arlow, Daniel H; Rasmussen, Søren Gøgsig Faarup; Choi, Hee-Jung; Devree, Brian T; Sunahara, Roger K; Chae, Pil Seok; Gellman, Samuel H; Dror, Ron O; Shaw, David E; Weis, William I; Caffrey, Martin; Gmeiner, Peter; Kobilka, Brian K

    2011-01-01

    modest affinities and rapid off-rates of available agonists. Using the inactive structure of the human β(2) adrenergic receptor (β(2)AR) as a guide, we designed a β(2)AR agonist that can be covalently tethered to a specific site on the receptor through a disulphide bond. The covalent β(2)AR......-agonist complex forms efficiently, and is capable of activating a heterotrimeric G protein. We crystallized a covalent agonist-bound β(2)AR-T4L fusion protein in lipid bilayers through the use of the lipidic mesophase method, and determined its structure at 3.5 Å resolution. A comparison to the inactive structure...

  16. Lepidozenolide from the liverwort Lepidozia fauriana acts as a farnesoid X receptor agonist.

    Science.gov (United States)

    Lin, Hsiang-Ru

    2015-01-01

    Lepidozenolide is a sesquiterpenoid isolated from the liverwort Lepidozia fauriana and its possible bioactivity is unclear. The farnesoid X receptor (FXR) is a member of nuclear receptor superfamily that has been widely targeted for developing treatments for chronic liver disease and hyperglycemia. In this study, whether lepidozenolide may act as a FXR agonist was determined. Indeed, in mammalian one-hybrid and transient transfection reporter assays, lepidozenolide transactivated FXR to modulate promoter action including GAL4, CYP7A1, and PLTP promoters in a dose-dependent manner, while it exhibited slightly less agonistic activity than chenodeoxycholic acid, an endogenous FXR agonist. Through the molecular modeling docking studies lepidozenolide was shown to bind to FXR ligand binding pocket fairly well. All these results indicate that lepidozenolide acts as a FXR agonist. PMID:25315435

  17. Agonists of fibroblast growth factor receptor induce neurite outgrowth and survival of cerebellar granule neurons

    DEFF Research Database (Denmark)

    Li, Shizhong; Christensen, Claus; Køhler, Lene B; Kiselyov, Vladislav V; Berezin, Vladimir; Bock, Elisabeth

    2009-01-01

    Fibroblast growth factor receptor (FGFR) signaling is pivotal in the regulation of neurogenesis, neuronal differentiation and survival, and synaptic plasticity both during development and in adulthood. In order to develop low molecular weight agonists of FGFR, seven peptides, termed hexafins...

  18. Synthesis of 2-(Benzodioxol-2-yl)acetic Acids as PPARδ Agonists

    Institute of Scientific and Technical Information of China (English)

    Jian Lei KANG; Zhi Bing ZHENG; Dan QIN; Li Li WANG; Song LI

    2006-01-01

    A new series of compounds, 2-(benzodioxol-2-yl)acetic acids, have been synthesized. Their structures were confirmed by MS and 1H-NMR. The preliminary pharmacological screening showed that these compounds exhibited potent human PPARδ agonist activities.

  19. Immunotherapy with Agonistic Anti-CD137: Two Sides of a Coin

    Institute of Scientific and Technical Information of China (English)

    YonglianSun; JonathanH.Chen; YangxinFu

    2004-01-01

    CD137 (4-1BB), a member of the TNF receptor superfamily, is an inducible T cell costimulatory receptor primarily expressed on activated CD4+ and CD8+ T cells. Agonistic monoclonal antibodies (mAbs) against CD137 greatly enhance T cell-mediated immune responses against many types of tumors and viruses. Surprisingly, these agonists also showed therapeutic effects in several autoimmune diseases. These findings suggest that in different disease environments, CD137 engagement with agonist mAb in vivo can diametrically modulate immune response outcomes. Therefore, CD137 agonists represent a promising immunotherapeutic approach to a wide array of disparate immune disorders. However, CD137's potency in modulating immune response necessitates caution when targeting CD137 clinically. Cellular & Molecular Immunology. 2004;1(1):31-36.

  20. Immunotherapy with Agonistic Anti-CD137: Two Sides of a Coin

    Institute of Scientific and Technical Information of China (English)

    Yonglian Sun; Jonathan H.Chen; Yangxin Fu

    2004-01-01

    CD137 (4-1BB), a member of the TNF receptor superfamily, is an inducible T cell costimulatory receptor primarily expressed on activated CD4+ and CD8+ T cells. Agonistic monoclonal antibodies (mAbs) against CD137 greatly enhance T cell-mediated immune responses against many types of tumors and viruses. Surprisingly, these agonists also showed therapeutic effects in several autoimmune diseases. These findings suggest that in different disease environments, CD137 engagement with agonist mAb in vivo can diametrically modulate immune response outcomes. Therefore, CD137 agonists represent a promising immunotherapeutic approach to a wide array of disparate immune disorders. However, CD137's potency in modulating immune response necessitates caution when targeting CD137 clinically. Cellular & Molecular Immunology. 2004;1(1):31-36.

  1. Clinical use of GnRH agonists in canine and feline species.

    Science.gov (United States)

    Fontaine, E; Fontbonne, A

    2011-04-01

    GnRH (gonadotrophin releasing hormone) is a key hormone of reproductive function in mammals; agonist forms have been largely developed, and data concerning their use in small animal reproduction are now abundant. GnRH agonists act by a two-step mechanism. First, their agonist properties on the pituitary will cause marked LH (luteinizing hormone) and FSH (follicle-stimulating hormone) secretion into the bloodstream, accompanied by an increase in the concentrations of sex steroid hormones. Then, in case of constant administration, GnRH agonists will lead to pituitary desensitization, and FSH and LH levels will collapse. These two effects have been widely documented, and these compounds have many potential benefits in a clinical context, capitalizing both on their stimulating and sterilizing effects. PMID:20964727

  2. Determination of beta-agonists in swine hair by μFIA and chemiluminescence.

    Science.gov (United States)

    Chen, Xu; Luo, Yong; Shi, Bo; Gao, Zhigang; Du, Yuguang; Liu, Xianming; Zhao, Weijie; Lin, Bingcheng

    2015-04-01

    β-Agonists are a group of illegal feed additives. In this paper, it was found that the light emission produced by the oxidation of luminol by potassium ferricyanide was enhanced by the β-agonists (ractopamine, salbutamol, and terbutaline). Based on chemiluminescence phenomenon, a novel, rapid, and sensitive microflow injection analysis system on a microfluidic glass chip was established for determination of the β-agonists. The chip was fabricated from two glass plates (64 mm × 32 mm) with microchannels of 200 μm width and 100 μm depth. The detection limits were achieved at 2.0 × 10(-8) mol/L of ractopamine, 1.0 × 10(-8) mol/L of terbutaline and 5.0 × 10(-7) mol/L of salbutamol. In this report, our method was applied for determination of the β-agonists in swine hair from three different sources with satisfactory results. PMID:25546131

  3. INFLAMMATORY AGONIST STIMULATION AND SIGNAL PATHWAY OF OXIDATIVE BURST IN NEONATAL CHICKEN HETEROPHILS

    Science.gov (United States)

    A fluorescence microplate assay was adapted to examine the oxidative response by heterophils from neonatal chicks following in vitro stimulation with various inflammatory agonists. Both nonopsonized formalin-killed Salmonella enteritidis and Staphylococcus aureus stimulated significant heterophil o...

  4. Dopamine Agonist in Treatment of ADHD with Restless Legs Syndrome and ODD

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2005-05-01

    Full Text Available A 6-year-old male with attention deficit hyperactivity disorder who responded poorly to methylphenidate (MPH was benefited following treatment with the dopamine agonist ropinirole, in a report from the Hopital Robert Debre, Paris, France.

  5. PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) AGONISTS AS PROMISING NEW MEDICATIONS FOR DRUG ADDICTION: PRECLINICAL EVIDENCE

    Science.gov (United States)

    Foll, Bernard Le; Ciano, Patricia Di; Panlilio, Leigh V.; Goldberg, Steven R.; Ciccocioppo, Roberto

    2013-01-01

    This review examines the growing literature on the role of peroxisome proliferator-activated receptors (PPARs) in addiction. There are two subtypes of PPAR receptors that have been studied in addiction: PPAR-α and PPAR-γ. The role of each PPAR subtype in common models of addictive behavior, mainly pre-clinical models, is summarized. In particular, studies are reviewed that investigated the effects of PPAR-α agonists on relapse, sensitization, conditioned place preference, withdrawal and drug intake, and effects of PPAR-γ agonists on relapse, withdrawal and drug intake. Finally, studies that investigated the effects of PPAR agonists on neural pathways of addiction are reviewed. Taken together this preclinical data indicates that PPAR agonists are promising new medications for drug addiction treatment. PMID:23614675

  6. FSL-1, a Toll-like Receptor 2/6 Agonist, Induces Expression of Interleukin-1α in the Presence of 27-hydroxycholesterol

    Science.gov (United States)

    Heo, Weon; Kim, Sun-Mi; Eo, Seong-Kug; Rhim, Byung-Yong

    2014-01-01

    We investigated the question of whether cholesterol catabolite can influence expression of inflammatory cytokines via Toll-like receptors (TLR) in monocytic cells. Treatment of THP-1 monocytic cells with 27-hydroxycholesterol (27OHChol) resulted in induction of gene transcription of TLR6 and elevated level of cell surface TLR6. Addition of FSL-1, a TLR6 agonist, to 27OHChol-treated cells resulted in transcription of the IL-1α gene and enhanced secretion of the corresponding gene product. However, cholesterol did not affect TLR6 expression, and addition of FSL-1 to cholesterol-treated cells did not induce expression of IL-1α. Using pharmacological inhibitors, we investigated molecular mechanisms underlying the expression of TLR6 and IL-1α. Treatment with Akt inhibitor IV or U0126 resulted in significantly attenuated expression of TLR6 and IL-1α induced by 27OHChol and 27OHChol plus FSL-1, respectively. In addition, treatment with LY294002, SB202190, or SP600125 resulted in significantly attenuated secretion of IL-1α. These results indicate that 27OHChol can induce inflammation by augmentation of TLR6-mediated production of IL-1α in monocytic cells via multiple signaling pathways. PMID:25598661

  7. The GPR 55 agonist, L-α-lysophosphatidylinositol, mediates ovarian carcinoma cell-induced angiogenesis

    OpenAIRE

    Nicole A. Hofmann; Yang, Jiang; Trauger, Sunia A.; Nakayama, Hironao; Huang, Lan; Strunk, Dirk; Moses, Marsha A.; Klagsbrun, Michael; Bischoff, Joyce; Graier, Wolfgang F

    2015-01-01

    Background and Purpose Highly vascularized ovarian carcinoma secretes the putative endocannabinoid and GPR55 agonist, L-α-lysophosphatidylinositol (LPI), into the circulation. We aimed to assess the involvement of this agonist and its receptor in ovarian cancer angiogenesis. Experimental Approach Secretion of LPI by three ovarian cancer cell lines (OVCAR-3, OVCAR-5 and COV-362) was tested by mass spectrometry. Involvement of cancer cell-derived LPI on angiogenesis was tested in the in vivo ch...

  8. Lack of Cocaine-Like Discriminative-Stimulus Effects of σ Receptor Agonists in Rats

    OpenAIRE

    Hiranita, Takato; Soto, Paul L; Tanda, Gianluigi; Katz, Jonathan L.

    2011-01-01

    Previous studies demonstrated effectiveness of selective sigma-receptor (σR) agonists (DTG, PRE-084) as reinforcers in rats trained to self-administer cocaine. Like cocaine, these drugs increased nucleus accumbens shell dopamine levels, and effects of DTG, but not PRE-084, on dopamine appeared to be mediated by σRs. Additionally, σR antagonists blocked self-administration of σR agonists, but were inactive against reinforcing and neurochemical effects of cocaine. Thus pharmacologically distinc...

  9. Radiolabeled somatostatin receptor antagonists are preferable to agonists for in vivo peptide receptor targeting of tumors

    OpenAIRE

    Ginj, Mihaela; Zhang, Hanwen; Waser, Beatrice; Cescato, Renzo; Wild, Damian; Wang, Xuejuan; Erchegyi, Judit; Rivier, Jean; Mäcke, Helmut R.; Reubi, Jean Claude

    2006-01-01

    Targeting neuroendocrine tumors expressing somatostatin receptor subtypes (sst) with radiolabeled somatostatin agonists is an established diagnostic and therapeutic approach in oncology. While agonists readily internalize into tumor cells, permitting accumulation of radioactivity, radiolabeled antagonists do not, and they have not been considered for tumor targeting. The macrocyclic chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was coupled to two potent somatostatin...

  10. Serotonin(4) (5-HT(4)) receptor agonists are putative antidepressants with a rapid onset of action

    DEFF Research Database (Denmark)

    Lucas, Guillaume; Rymar, Vladimir V; Du, Jenny;

    2007-01-01

    Current antidepressants are clinically effective only after several weeks of administration. Here, we show that serotonin(4) (5-HT(4)) agonists reduce immobility in the forced swimming test, displaying an antidepressant potential. Moreover, a 3 day regimen with such compounds modifies rat brain p...... intake consecutive to a chronic mild stress. These findings point out 5-HT(4) receptor agonists as a putative class of antidepressants with a rapid onset of action. Udgivelsesdato: 2007-Sep-6...

  11. Dopamine Agonist Increases Risk Taking but Blunts Reward-Related Brain Activity

    OpenAIRE

    Jordi Riba; Krämer, Ulrike M.; Marcus Heldmann; Sylvia Richter; Münte, Thomas F.

    2008-01-01

    The use of D2/D3 dopaminergic agonists in Parkinson's disease (PD) may lead to pathological gambling. In a placebo-controlled double-blind study in healthy volunteers, we observed riskier choices in a lottery task after administration of the D3 receptor-preferring agonist pramipexole thus mimicking risk-taking behavior in PD. Moreover, we demonstrate decreased activation in the rostral basal ganglia and midbrain, key structures of the reward system, following unexpected high gains and therefo...

  12. Biphasic Effect of Melanocortin Agonists on Metabolic Rate and Body Temperature

    OpenAIRE

    Lute, Beth; Jou, William; Lateef, Dalya M.; Goldgof, Margalit; Xiao, Cuiying; Piñol, Ramón A.; Kravitz, Alexxai V.; Miller, Nicole R.; Huang, Yuning George; Girardet, Clemence; Butler, Andrew A.; Gavrilova, Oksana; Reitman, Marc L.

    2014-01-01

    The melanocortin system regulates metabolic homeostasis and inflammation. Melanocortin agonists have contradictorily been reported to both increase and decrease metabolic rate and body temperature. We find two distinct physiologic responses occurring at similar doses. Intraperitoneal administration of the nonselective melanocortin agonist MTII causes a melanocortin-4 receptor (Mc4r) mediated hypermetabolism/hyperthermia. This is preceded by a profound, transient hypometabolism/hypothermia tha...

  13. Inhibition of the production of endothelium-derived hyperpolarizing factor by cannabinoid receptor agonists

    OpenAIRE

    Fleming, I.; Schermer, B; Popp, R; Busse, R.

    1999-01-01

    The endogenous cannabinoid, anandamide, has been reported to induce an 'endothelium-derived hyperpolarizing factor (EDHF)-like' relaxation in vitro. We therefore investigated the effects of cannabinoid CB1 receptor agonists; HU 210, Δ9-tetrahydrocannabinol (Δ9-THC) and anandamide, and a CB1 antagonist/inverse agonist, SR 141716A, on nitric oxide (NO) and EDHF-mediated relaxation in precontracted rings of porcine coronary, rabbit carotid and mesenteric arteries.In rings of mesenteric artery HU...

  14. PPARα-Independent Arterial Smooth Muscle Relaxant Effects of PPARα Agonists

    OpenAIRE

    Silswal, Neerupma; Parelkar, Nikhil K; Michael J. Wacker; Badr, Mostafa; Andresen, Jon

    2012-01-01

    We sought to determine direct vascular effects of peroxisome proliferator-activated receptor alpha (PPAR α ) agonists using isolated mouse aortas and middle cerebral arteries (MCAs). The PPAR α agonists GW7647, WY14643, and gemfibrozil acutely relaxed aortas held under isometric tension and dilated pressurized MCAs with the following order of potency: GW7647≫WY14643>gemfibrozil. Responses were endothelium-independent, and the use of PPAR α deficient mice demonstrated that responses were also ...

  15. Perioperative use of selective alpha-2 agonists and antagonists in small animals

    OpenAIRE

    Lemke, Kip A.

    2004-01-01

    Alpha-2 agonists are the only single class of anesthetic drugs that induce reliable, dose-dependent sedation, analgesia, and muscle relaxation in dogs and cats. Used at low doses, as adjuncts to injectable and inhalational anesthetics, selective alpha-2 agonists dramatically reduce the amount of anesthetic drug required to induce and maintain anesthesia. This reduction in anesthetic requirements is achieved without significant depression of pulmonary function and with limited effects on cardi...

  16. PPAR agonists regulate brain gene expression: Relationship to their effects on ethanol consumption

    OpenAIRE

    Ferguson, Laura B.; Most, Dana; Yuri A Blednov; Harris, R. Adron

    2014-01-01

    Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that act as ligand-activated transcription factors. Although prescribed for dyslipidemia and type-II diabetes, PPAR agonists also possess anti-addictive characteristics. PPAR agonists decrease ethanol consumption and reduce withdrawal severity and susceptibility to stress-induced relapse in rodents. However, the cellular and molecular mechanisms facilitating these properties have yet to be investigated. We teste...

  17. Evaluation of the beta 2 adrenoceptor agonist/antagonist activity of formoterol and salmeterol.

    OpenAIRE

    Grove, A.; Lipworth, B J

    1996-01-01

    BACKGROUND: Salmeterol and formoterol have a lower intrinsic activity at beta 2 receptors than isoprenaline in human bronchus in vitro. The aim of the present study was to evaluate in vivo the beta 2 agonist/antagonist activity of salmeterol and formoterol at rest with low endogenous adrenergic tone, on exercise with raised endogenous adrenergic tone, and in the presence of fenoterol, an exogenous full beta 2 receptor agonist. METHODS: Eight normal subjects were randomised to receive single d...

  18. Tolerance to bronchodilation during treatment with long-acting beta-agonists, a randomised controlled trial

    Directory of Open Access Journals (Sweden)

    Hancox Robert J

    2005-09-01

    Full Text Available Abstract Background Regular use of beta-agonists leads to tolerance to their bronchodilator effects. This can be demonstrated by measuring the response to beta-agonist following bronchoconstriction using methacholine. However most studies have demonstrated tolerance after a period of beta-agonist withdrawal, which is not typical of their use in clinical practice. This study assessed tolerance to the bronchodilator action of salbutamol during ongoing treatment with long-acting beta-agonist. Methods Random-order, double-blind, placebo-controlled, crossover trial. After 1 week without beta-agonists, 13 asthmatic subjects inhaled formoterol 12 μg twice daily or matching placebo for 1 week. Eight hours after the first and last doses subjects inhaled methacholine to produce a 20% fall in FEV1. Salbutamol 100, 200 and 400 μg (cumulative dose was then given at 5-minute intervals and FEV1 was measured 5 minutes after each dose. After a 1 week washout subjects crossed over to the other treatment. Unscheduled use of beta-agonists was not allowed during the study. The main outcome variable was the area under the salbutamol response curve. Results The analysis showed a significant time by treatment interaction indicating that the response to salbutamol fell during formoterol therapy compared to placebo. After 1 week of formoterol the area under the salbutamol response curve was 48% (95% confidence interval 28 to 68% lower than placebo. This reduction in response remained significant when the analyses were adjusted for changes in the pre-challenge FEV1 and dose of methacholine given (p = 0.001. Conclusion The bronchodilator response to salbutamol is significantly reduced in patients taking formoterol. Clinically relevant tolerance to rescue beta-agonist treatment is likely to occur in patients treated with long-acting beta-agonists.

  19. Recurrence of hyperprolactinemia after withdrawal of dopamine agonists: systematic review and meta-analysis.

    OpenAIRE

    Dekkers, O. M.; Lagro, J.; Burman, P; J. O. Jorgensen; Romijn, J.A.; A M Pereira

    2010-01-01

    CONTEXT: Dopamine agonists are the treatment of choice for prolactinomas and symptomatic idiopathic hyperprolactinemia. However, the optimal treatment strategy and treatment duration is not clear in all details. OBJECTIVE: The aim of the study was to assess the effect of dopamine agonist withdrawal in patients with idiopathic hyperprolactinemia and prolactinomas. DATA SOURCES: PubMed, the Cochrane Library, the Web of Science, and EMBASE were searched electronically. No restriction was made wi...

  20. Organelle selection determines agonist-specific Ca2+ signals in pancreatic acinar and beta cells

    OpenAIRE

    Yamasaki, M.; Masgrau, R.; Morgan, A. J.; Churchill, G. C.; Patel, S.; Ashcroft, S. J. H.; Galione, A

    2004-01-01

    How different extracellular stimuli can evoke different spatiotemporal Ca2+ signals is uncertain. We have elucidated a novel paradigm whereby different agonists use different Ca2+-storing organelles ("organelle seleetion") to evoke unique responses. Some agonists select the endoplasmic reticulum (ER), and others select lysosome-related (acidic) organelles, evoking spatial Ca2+ responses that mirror the organellar distribution. In pancreatic acinar cells, acetylcholine and bombesin exclusively...

  1. Agonists, antagonists and modulators of excitatory amino acid receptors in the guinea-pig myenteric plexus.

    OpenAIRE

    Luzzi, S; Zilletti, L.; S.Franchi-Micheli; Gori, A M; Moroni, F

    1988-01-01

    1. The receptors for glutamic acid (L-Glu) present in the guinea-pig myenteric plexus-ileal longitudinal muscle preparation have been studied by measuring the muscle contraction induced by numerous putative endogenous agonists acting at these receptors. Furthermore, the actions of different concentrations of antagonists, glycine, Mg2+ and Ca2+ on the ileal contractions induced by L-Glu have been evaluated. 2. The EC50 values of the most common putative endogenous agonists of these receptors w...

  2. A TRβ-selective agonist confers resistance to diet-induced obesity

    OpenAIRE

    Amorim, Beatriz S; Ueta, Cintia B; Freitas, Beatriz C. G.; Nassif, Renata J; de Azevedo Gouveia, Cecília Helena; Christoffolete, Marcelo A.; Moriscot, Anselmo S.; Lancelloti, Carmen Lucia; Llimona, Flávia; Barbeiro, Hermes Vieira; de Souza, Heraldo Possolo; Catanozi, Sergio; Passarelli, Marisa; Marcelo S. Aoki; Bianco, Antonio C.

    2009-01-01

    Thyroid hormone receptor β (TRβ also listed as THRB on the MGI Database)-selective agonists activate brown adipose tissue (BAT) thermogenesis, while only minimally affecting cardiac activity or lean body mass. Here, we tested the hypothesis that daily administration of the TRβ agonist GC-24 prevents the metabolic alterations associated with a hypercaloric diet. Rats were placed on a high-fat diet and after a month exhibited increased body weight (BW) and adiposity, fasting hyperglycemia and g...

  3. A comparison of agonist-specific coupling of cloned human α2-adrenoceptor subtypes

    OpenAIRE

    Rudling, Jane E; Richardson, Jo; Evans, Peter D.

    2000-01-01

    The agonist-specific coupling properties of the three cloned human α2-adrenoceptor subtypes have been compared, when expressed at similar levels in Chinese hamster ovary (CHO) cell lines, using noradrenaline and (±)-meta-octopamine as agonists.Noradrenaline can couple the receptor to both the inhibition and stimulation of forskolin-stimulated cyclic AMP production in all three receptor subtypes, with the relative strength of the coupling to the pathways varying for each of the receptor subtyp...

  4. Hadron attenuation at HERMES and JLab

    OpenAIRE

    Falter, T.; Cassing, W.; Gallmeister, K.; Mosel, U.

    2005-01-01

    We investigate the attenuation of hadrons in deep inelastic lepton-nucleus scattering in the kinematical regime of the HERMES and Jefferson Lab experiments. The calculation is carried out in the framework of a BUU transport model. Our results indicate a strong influence of (pre)hadronic final state interactions on the observed multiplicity ratios.

  5. Microwave attenuation with composite of copper microwires

    Energy Technology Data Exchange (ETDEWEB)

    Gorriti, A.G.; Marin, P. [Instituto de Magnetismo Aplicado, (UCM-ADIF-CSIC) and Departamento de Fisica de Materiales (UCM). P.O. Box 155, Las Rozas, Madrid 28230 (Spain); Cortina, D. [Micromag S.L., Las Rozas, Madrid 28230 (Spain); Hernando, A., E-mail: antonio.hernando@adif.e [Instituto de Magnetismo Aplicado, (UCM-ADIF-CSIC) and Departamento de Fisica de Materiales (UCM). P.O. Box 155, Las Rozas, Madrid 28230 (Spain); Micromag S.L., Las Rozas, Madrid 28230 (Spain)

    2010-05-15

    It is shown that copper microwires composite media attenuates microwave reflection of metallic surfaces. We show how the distance to the metallic surface, as well as the length and volume fraction of microwires, determine the frequency of maximum absorption and the return loss level. Furthermore, we were able to fit the experimental results with a theoretical model based on Maxwell-Garnett mixing formula.

  6. Switching Control for Adaptive Disturbance Attenuation

    NARCIS (Netherlands)

    Battistelli, Giorgio; Mari, Daniele; Selvi, Daniela; Tesi, Alberto; Tesi, Pietro

    2014-01-01

    The problem of adaptive disturbance attenuation is addressed in this paper using a switching control approach. A finite family of stabilizing controllers is pre-designed, with the assumption that, for any possible operating condition, at least one controller is able to achieve a prescribed level of

  7. Attenuation correction for small animal PET tomographs

    Energy Technology Data Exchange (ETDEWEB)

    Chow, Patrick L [David Geffen School of Medicine at UCLA, Crump Institute for Molecular Imaging, University of California, 700 Westwood Plaza, Los Angeles, CA 90095 (United States); Rannou, Fernando R [Departamento de Ingenieria Informatica, Universidad de Santiago de Chile (USACH), Av. Ecuador 3659, Santiago (Chile); Chatziioannou, Arion F [David Geffen School of Medicine at UCLA, Crump Institute for Molecular Imaging, University of California, 700 Westwood Plaza, Los Angeles, CA 90095 (United States)

    2005-04-21

    Attenuation correction is one of the important corrections required for quantitative positron emission tomography (PET). This work will compare the quantitative accuracy of attenuation correction using a simple global scale factor with traditional transmission-based methods acquired either with a small animal PET or a small animal x-ray computed tomography (CT) scanner. Two phantoms (one mouse-sized and one rat-sized) and two animal subjects (one mouse and one rat) were scanned in CTI Concorde Microsystem's microPET (registered) Focus{sup TM} for emission and transmission data and in ImTek's MicroCAT{sup TM} II for transmission data. PET emission image values were calibrated against a scintillation well counter. Results indicate that the scale factor method of attenuation correction places the average measured activity concentration about the expected value, without correcting for the cupping artefact from attenuation. Noise analysis in the phantom studies with the PET-based method shows that noise in the transmission data increases the noise in the corrected emission data. The CT-based method was accurate and delivered low-noise images suitable for both PET data correction and PET tracer localization.

  8. The Coriolis attenuation problem in 235U

    International Nuclear Information System (INIS)

    A new version of the particle-rotor model, featuring diagonalization of a state-dependent pairing force and the full recoil term, has been applied to 235U. A significant improvement is obtained in the description of the Coriolis coupled K=5/2, 7/2 and 9/2 rotational bands. No ad hoc Coriolis attenuation factors are used. (orig.)

  9. Attenuation of PRRSV by chimera construction

    Science.gov (United States)

    Two genetically distinct infectious recombinant virus clones (pMLV, constructed from Ingelvac® PRRS MLV and pMN184, constructed from virulent strain MN184) were developed to study attenuation of contemporary PRRSV. Two reciprocal chimeric clones (pMLVORF1/MN184 and pMN184ORF1/MLV) were then constru...

  10. Electrically tunable hot-silicon terahertz attenuator

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Minjie [Department of Electrical and Computer Engineering, Rice University, Houston, Texas 77005 (United States); Vajtai, Robert; Ajayan, Pulickel M. [Department of Materials Science and NanoEngineering, Rice University, Houston, Texas 77005 (United States); Kono, Junichiro, E-mail: kono@rice.edu [Department of Electrical and Computer Engineering, Rice University, Houston, Texas 77005 (United States); Department of Materials Science and NanoEngineering, Rice University, Houston, Texas 77005 (United States); Department of Physics and Astronomy, Rice University, Houston, Texas 77005 (United States)

    2014-10-06

    We have developed a continuously tunable, broadband terahertz attenuator with a transmission tuning range greater than 10{sup 3}. Attenuation tuning is achieved electrically, by simply changing the DC voltage applied to a heating wire attached to a bulk silicon wafer, which controls its temperature between room temperature and ∼550 K, with the corresponding free-carrier density adjusted between ∼10{sup 11 }cm{sup −3} and ∼10{sup 17 }cm{sup −3}. This “hot-silicon”-based terahertz attenuator works most effectively at 450–550 K (corresponding to a DC voltage variation of only ∼7 V) and completely shields terahertz radiation above 550 K in a frequency range of 0.1–2.5 THz. Both intrinsic and doped silicon wafers were tested and demonstrated to work well as a continuously tunable attenuator. All behaviors can be understood quantitatively via the free-carrier Drude model taking into account thermally activated intrinsic carriers.

  11. Electrically tunable hot-silicon terahertz attenuator

    International Nuclear Information System (INIS)

    We have developed a continuously tunable, broadband terahertz attenuator with a transmission tuning range greater than 103. Attenuation tuning is achieved electrically, by simply changing the DC voltage applied to a heating wire attached to a bulk silicon wafer, which controls its temperature between room temperature and ∼550 K, with the corresponding free-carrier density adjusted between ∼1011 cm−3 and ∼1017 cm−3. This “hot-silicon”-based terahertz attenuator works most effectively at 450–550 K (corresponding to a DC voltage variation of only ∼7 V) and completely shields terahertz radiation above 550 K in a frequency range of 0.1–2.5 THz. Both intrinsic and doped silicon wafers were tested and demonstrated to work well as a continuously tunable attenuator. All behaviors can be understood quantitatively via the free-carrier Drude model taking into account thermally activated intrinsic carriers.

  12. GPR measurements of attenuation in concrete

    International Nuclear Information System (INIS)

    Ground-penetrating radar (GPR) signals from concrete structures are affected by several phenomenon, including: (1) transmission and reflection coefficients at interfaces; (2) the radiation patterns of the antenna(s) being used; and (3) the material properties of concrete and any embedded objects. In this paper we investigate different schemes for determining the electromagnetic (EM) attenuation of concrete from measured signals obtained using commercially-available GPR equipment. We adapt procedures commonly used in ultrasonic inspections where one compares the relative strengths of two or more signals having different travel paths through the material of interest. After correcting for beam spread (i.e., diffraction), interface phenomena, and equipment amplification settings, any remaining signal differences are assumed to be due to attenuation thus allowing the attenuation coefficient (say, in dB of loss per inch of travel) to be estimated. We begin with a brief overview of our approach, and then discuss how diffraction corrections were determined for our two 1.6 GHz GPR antennas. We then present results of attenuation measurements for two types of concrete using both pulse/echo and pitch/catch measurement setups

  13. ULTRASONIC ATTENUATION IN MIXED STATE OF NIOBIUM

    OpenAIRE

    Dominec, J.; MÍŠek, K.

    1987-01-01

    We have investigated the attenuation of ultrasonic waves in the mixed state of niobium, where a remarkable dip appears near the lower critical field . The measurement has been performed on one sample for various orientations of the wave vector and of the principal crystallographic axes of the sample with respect to external magnetic field.

  14. Alpha1 receptor coupling events initiated by methoxy-substituted tolazoline partial agonists

    International Nuclear Information System (INIS)

    A series of mono- and dimethyoxy substituted tolazoline derivatives, known to be partial agonists at the alpha1 receptor, were compared with the α1 selective full agonist phenylephrine (PE) on isolated strips of rabbit aorta Agonist activity was evaluated in contraction, 45Ca influx, 45Ca efflux, and 32P-Phospholipid labelling studies. Maximum contractile responses for the 2-, 3-, and 3, 5- methoxy substituted tolazoline derivatives (10-5M) were 53.8, 67.6 and 99.7% of the PE (10-5M) response respectively. These same partial agonists caused a stimulation of 45Ca influx to the extent of 64, 86, and 95% of the PE response respectively. In 45Ca efflux studies, (a measure of the intracellular Ca+2 release) the tolazolines caused: 30%, 63%, and 78% of the PE stimulated level. 32P-Phosphatidic acid (PA) labelling was measured as an index of PI turnover after α1 receptor stimulation. Compared to PE, the 2-, 3-, and 3,5- methoxy substituted tolazoline derivatives caused 22, 46, and 72% PA labelling. The above values are all in reasonable accord with the rank order or agonist activity shown in maximum contractile responses. The results of this investigation suggest that partial agonists stimulate α receptor coupling events at a level which is quantitatively comparable to their potencies in causing contraction of arterial smooth muscle

  15. Alpha/sub 1/ receptor coupling events initiated by methoxy-substituted tolazoline partial agonists

    Energy Technology Data Exchange (ETDEWEB)

    Wick, P.; Keung, A.; Deth, R.

    1986-03-01

    A series of mono- and dimethyoxy substituted tolazoline derivatives, known to be partial agonists at the alpha/sub 1/ receptor, were compared with the ..cap alpha../sub 1/ selective full agonist phenylephrine (PE) on isolated strips of rabbit aorta Agonist activity was evaluated in contraction, /sup 45/Ca influx, /sup 45/Ca efflux, and /sup 32/P-Phospholipid labelling studies. Maximum contractile responses for the 2-, 3-, and 3, 5- methoxy substituted tolazoline derivatives (10/sup -5/M) were 53.8, 67.6 and 99.7% of the PE (10/sup -5/M) response respectively. These same partial agonists caused a stimulation of /sup 45/Ca influx to the extent of 64, 86, and 95% of the PE response respectively. In /sup 45/Ca efflux studies, (a measure of the intracellular Ca/sup +2/ release) the tolazolines caused: 30%, 63%, and 78% of the PE stimulated level. /sup 32/P-Phosphatidic acid (PA) labelling was measured as an index of PI turnover after ..cap alpha../sub 1/ receptor stimulation. Compared to PE, the 2-, 3-, and 3,5- methoxy substituted tolazoline derivatives caused 22, 46, and 72% PA labelling. The above values are all in reasonable accord with the rank order or agonist activity shown in maximum contractile responses. The results of this investigation suggest that partial agonists stimulate ..cap alpha.. receptor coupling events at a level which is quantitatively comparable to their potencies in causing contraction of arterial smooth muscle.

  16. Targeted Delivery of LXR Agonist Using a Site-Specific Antibody-Drug Conjugate.

    Science.gov (United States)

    Lim, Reyna K V; Yu, Shan; Cheng, Bo; Li, Sijia; Kim, Nam-Jung; Cao, Yu; Chi, Victor; Kim, Ji Young; Chatterjee, Arnab K; Schultz, Peter G; Tremblay, Matthew S; Kazane, Stephanie A

    2015-11-18

    Liver X receptor (LXR) agonists have been explored as potential treatments for atherosclerosis and other diseases based on their ability to induce reverse cholesterol transport and suppress inflammation. However, this therapeutic potential has been hindered by on-target adverse effects in the liver mediated by excessive lipogenesis. Herein, we report a novel site-specific antibody-drug conjugate (ADC) that selectively delivers a LXR agonist to monocytes/macrophages while sparing hepatocytes. The unnatural amino acid para-acetylphenylalanine (pAcF) was site-specifically incorporated into anti-CD11a IgG, which binds the α-chain component of the lymphocyte function-associated antigen 1 (LFA-1) expressed on nearly all monocytes and macrophages. An aminooxy-modified LXR agonist was conjugated to anti-CD11a IgG through a stable, cathepsin B cleavable oxime linkage to afford a chemically defined ADC. The anti-CD11a IgG-LXR agonist ADC induced LXR activation specifically in human THP-1 monocyte/macrophage cells in vitro (EC50-27 nM), but had no significant effect in hepatocytes, indicating that payload delivery is CD11a-mediated. Moreover, the ADC exhibited higher-fold activation compared to a conventional synthetic LXR agonist T0901317 (Tularik) (3-fold). This novel ADC represents a fundamentally different strategy that uses tissue targeting to overcome the limitations of LXR agonists for potential use in treating atherosclerosis. PMID:25945727

  17. Is there a problem with inhaled long-acting beta-adrenergic agonists?

    Science.gov (United States)

    Nelson, Harold S

    2006-01-01

    Short-acting beta(2)-agonists are effective in relieving acute symptoms of asthma and in the short-term prevention of symptoms from stimuli, such as exercise. They are ineffective when used on a regular schedule to improve asthma control. Long-acting beta(2)-agonists, on the other hand, provide sustained bronchodilation and improve asthma control. Regular use of long-acting beta(2)-agonists is not associated with significant tolerance to their bronchodilator action, impairment in the response to albuterol, decreased baseline pulmonary function, increased response to methacholine, or increased risk of adverse cardiac events. Case-control studies do not suggest an increased risk for death or intensive care unit admissions with use of long-acting beta(2)-agonists. In prospective studies in which there has been an increase in asthma deaths or serious asthma exacerbations, this increased risk has not been observed in subjects using inhaled corticosteroids. Where increased deaths have occurred in relation to either short- or long-acting beta(2)-agonists, the events have not occurred equally throughout the exposed population. This suggests that these outcomes were not a direct toxic effect of the drugs and increases the possibility that they resulted from an interaction between relief of symptoms by beta(2)-agonists and delay in seeking medical care. PMID:16387577

  18. Identification of Ecdysone Hormone Receptor Agonists as a Therapeutic Approach for Treating Filarial Infections

    Science.gov (United States)

    Mhashilkar, Amruta S.; Vankayala, Sai L.; Liu, Canhui; Kearns, Fiona; Mehrotra, Priyanka; Tzertzinis, George; Palli, Subba R.; Woodcock, H. Lee; Unnasch, Thomas R.

    2016-01-01

    Background A homologue of the ecdysone receptor has previously been identified in human filarial parasites. As the ecdysone receptor is not found in vertebrates, it and the regulatory pathways it controls represent attractive potential chemotherapeutic targets. Methodology/ Principal Findings Administration of 20-hydroxyecdysone to gerbils infected with B. malayi infective larvae disrupted their development to adult stage parasites. A stable mammalian cell line was created incorporating the B. malayi ecdysone receptor ligand-binding domain, its heterodimer partner and a secreted luciferase reporter in HEK293 cells. This was employed to screen a series of ecdysone agonist, identifying seven agonists active at sub-micromolar concentrations. A B. malayi ecdysone receptor ligand-binding domain was developed and used to study the ligand-receptor interactions of these agonists. An excellent correlation between the virtual screening results and the screening assay was observed. Based on both of these approaches, steroidal ecdysone agonists and the diacylhydrazine family of compounds were identified as a fruitful source of potential receptor agonists. In further confirmation of the modeling and screening results, Ponasterone A and Muristerone A, two compounds predicted to be strong ecdysone agonists stimulated expulsion of microfilaria and immature stages from adult parasites. Conclusions The studies validate the potential of the B. malayi ecdysone receptor as a drug target and provide a means to rapidly evaluate compounds for development of a new class of drugs against the human filarial parasites. PMID:27300294

  19. Structural Requirements of N-Substituted Spiropiperidine Analogues as Agonists of Nociceptin/Orphanin FQ Receptor

    Directory of Open Access Journals (Sweden)

    Ling Yang

    2011-12-01

    Full Text Available The nociceptin/orphanin FQ (NOP receptor is involved in a wide range of biological functions, including pain, anxiety, depression and drug abuse. Especially, its agonists have great potential to be developed into anxiolytics. In this work, both the ligand- and receptor-based three-dimensional quantitative structure–activity relationship (3D-QSAR studies were carried out using comparative molecular field analysis (CoMFA and comparative molecular similarity indices analysis (CoMSIA techniques on 103 N-substituted spiropiperidine analogues as NOP agonists. The resultant optimal ligand-based CoMSIA model exhibited Q2 of 0.501, R2ncv of 0.912 and its predictive ability was validated by using an independent test set of 26 compounds which gave R2pred value of 0.818. In addition, docking analysis and molecular dynamics simulation (MD were also applied to elucidate the probable binding modes of these agonists. Interpretation of the 3D contour maps, in the context of the topology of the active site of NOP, provided insight into the NOP-agonist interactions. The information obtained from this work can be used to accurately predict the binding affinity of related agonists and also facilitate the future rational design of novel agonists with improved activity.

  20. Beta-1 adrenergic agonist treatment mitigates negative changes in cancellous bone microarchitecture and inhibits osteocyte apoptosis during disuse.

    Science.gov (United States)

    Swift, Joshua M; Swift, Sibyl N; Allen, Matthew R; Bloomfield, Susan A

    2014-01-01

    The sympathetic nervous system (SNS) plays an important role in mediating bone remodeling. However, the exact role that beta-1 adrenergic receptors (beta1AR) have in this process has not been elucidated. We have previously demonstrated the ability of dobutamine (DOB), primarily a beta1AR agonist, to inhibit reductions in cancellous bone formation and mitigate disuse-induced loss of bone mass. The purpose of this study was to characterize the independent and combined effects of DOB and hindlimb unloading (HU) on cancellous bone microarchitecture, tissue-level bone cell activity, and osteocyte apoptosis. Male Sprague-Dawley rats, aged 6-mos, were assigned to either normal cage activity (CC) or HU (n = 18/group) for 28 days. Animals were administered either daily DOB (4 mg/kg BW/d) or an equal volume of saline (VEH) (n = 9/gp). Unloading resulted in significantly lower distal femur cancellous BV/TV (-33%), Tb.Th (-11%), and Tb.N (-25%) compared to ambulatory controls (CC-VEH). DOB treatment during HU attenuated these changes in cancellous bone microarchitecture, resulting in greater BV/TV (+29%), Tb.Th (+7%), and Tb.N (+21%) vs. HU-VEH. Distal femur cancellous vBMD (+11%) and total BMC (+8%) were significantly greater in DOB- vs. VEH-treated unloaded rats. Administration of DOB during HU resulted in significantly greater osteoid surface (+158%) and osteoblast surface (+110%) vs. HU-VEH group. Furthermore, Oc.S/BS was significantly greater in HU-DOB (+55%) vs. CC-DOB group. DOB treatment during unloading fully restored bone formation, resulting in significantly greater bone formation rate (+200%) than in HU-VEH rats. HU resulted in an increased percentage of apoptotic cancellous osteocytes (+85%), reduced osteocyte number (-16%), lower percentage of occupied osteocytic lacunae (-30%) as compared to CC-VEH, these parameters were all normalized with DOB treatment. Altogether, these data indicate that beta1AR agonist treatment during disuse mitigates negative

  1. Beta-1 adrenergic agonist treatment mitigates negative changes in cancellous bone microarchitecture and inhibits osteocyte apoptosis during disuse.

    Directory of Open Access Journals (Sweden)

    Joshua M Swift

    Full Text Available The sympathetic nervous system (SNS plays an important role in mediating bone remodeling. However, the exact role that beta-1 adrenergic receptors (beta1AR have in this process has not been elucidated. We have previously demonstrated the ability of dobutamine (DOB, primarily a beta1AR agonist, to inhibit reductions in cancellous bone formation and mitigate disuse-induced loss of bone mass. The purpose of this study was to characterize the independent and combined effects of DOB and hindlimb unloading (HU on cancellous bone microarchitecture, tissue-level bone cell activity, and osteocyte apoptosis. Male Sprague-Dawley rats, aged 6-mos, were assigned to either normal cage activity (CC or HU (n = 18/group for 28 days. Animals were administered either daily DOB (4 mg/kg BW/d or an equal volume of saline (VEH (n = 9/gp. Unloading resulted in significantly lower distal femur cancellous BV/TV (-33%, Tb.Th (-11%, and Tb.N (-25% compared to ambulatory controls (CC-VEH. DOB treatment during HU attenuated these changes in cancellous bone microarchitecture, resulting in greater BV/TV (+29%, Tb.Th (+7%, and Tb.N (+21% vs. HU-VEH. Distal femur cancellous vBMD (+11% and total BMC (+8% were significantly greater in DOB- vs. VEH-treated unloaded rats. Administration of DOB during HU resulted in significantly greater osteoid surface (+158% and osteoblast surface (+110% vs. HU-VEH group. Furthermore, Oc.S/BS was significantly greater in HU-DOB (+55% vs. CC-DOB group. DOB treatment during unloading fully restored bone formation, resulting in significantly greater bone formation rate (+200% than in HU-VEH rats. HU resulted in an increased percentage of apoptotic cancellous osteocytes (+85%, reduced osteocyte number (-16%, lower percentage of occupied osteocytic lacunae (-30% as compared to CC-VEH, these parameters were all normalized with DOB treatment. Altogether, these data indicate that beta1AR agonist treatment during disuse mitigates negative changes

  2. Investigation of cyclooxygenase and signaling pathways involved in human platelet aggregation mediated by synergistic interaction of various agonists.

    Science.gov (United States)

    Khan, Nadia; Farooq, Ahsana Dar; Sadek, Bassem

    2015-01-01

    In the present study, the mechanism(s) of synergistic interaction of various platelet mediators such as arachidonic acid (AA) when combined with 5-hydroxytryptamine (5-HT) or adenosine diphosphate (ADP) on human platelet aggregation were examined. The results demonstrated that 5-HT had no or negligible effect on aggregation but it did potentiate the aggregation response of AA. Similarly, the combination of subeffective concentrations of ADP and AA exhibited noticeable rise in platelet aggregation. Moreover, the observed synergistic effect of AA with 5-HT on platelets was inhibited by different cyclooxygenase (COX) inhibitors, namely ibuprofen and celecoxib, with half maximal inhibitory effect (IC50) values of 18.0 ± 1.8 and 15.6 ± 3.4 μmol/L, respectively. Interestingly, the synergistic effect observed for AA with 5-HT was, also, blocked by the 5-HT receptor blockers cyproheptadine (IC50=22.0 ± 7 μmol/L), ketanserin (IC50=152 ± 23 μmol/L), phospholipase C (PLC) inhibitor (U73122; IC50=6.1 ± 0.8 μmol/L), and mitogen activated protein kinase (MAPK) inhibitor (PD98059; IC50=3.8 ± 0.5 μmol/L). Likewise, the synergism of AA and ADP was, also, attenuated by COX inhibitors (ibuprofen; IC50=20 ± 4 μmol/L and celecoxib; IC50=24 ± 7 μmol/L), PLC inhibitor (U73122; IC50=3.7 ± 0.3 μmol/L), and MAPK inhibitor (PD98059; IC50=2.8 ± 1.1 μmol/L). Our observed data demonstrate that the combination of subthreshold concentrations of agonists amplifies platelet aggregation and that these synergistic effects largely depend on activation of COX/thromboxane A2, receptor-operated Ca(2+) channels, Gq/PLC, and MAPK signaling pathways. Moreover, our data revealed that inhibition of COX pathways by using both selective and/or non-selective COX inhibitors blocks not only AA metabolism and thromboxane A2 formation, but also its binding to Gq receptors and activation of receptor-operated Ca(2+) channels in platelets. Overall, our results show that PLC and MAPK inhibitors proved

  3. Radiolabelled D2 agonists as prolactinoma imaging agents

    Energy Technology Data Exchange (ETDEWEB)

    Otto, C.A.

    1989-08-01

    During the past year, further studies on mAChR were conducted. These studies included verification of the difference in pituitary distribution based on ligand charge. The pituitary localization of TRB. A neutral mAChR ligand, was verified. The lack of QNB blockade of TRB uptake was tested by blockage with scopolamine, another mAChR antagonist and by testing the effect in a different strain of rat. Neither scopolamine or change of rat strain had any effect. We concluded that TRB uptake in pituitary is not a receptor-mediated process. Further studies were conducted with an additional quaternized mAChR ligand: MQNB. Pituitary localization of MQNB, like MTRB, could be blocked by pretreatment with QNB. We have tentatively concluded that permanent charge on a mAChR antagonist changes the mechanism of uptake in the pituitary. Time course studies and the effects of DES on myocardial uptake are reported. A brief report on preliminary results of evaluation of quaternized mAChR ligands in the heart is included. In a limited series of such ligands, we have observed a single binding site and a difference in B{sub max} values: QNB competition studies yield larger B{sub max} values than studies with {sup 3}H-NMS. Progress in the synthesis of D{sub 2} agonists includes solving a synthetic problem and preparation of the cold'' analogue of N-0437 using procedures applicable to eventual synthesis with {sup 11}C-CH{sub 3}I. 2 refs., 5 figs., 1 tab.

  4. Cardiovascular Effects of Glucagon-Like Peptide-1 Receptor Agonists.

    Science.gov (United States)

    Kang, Yu Mi; Jung, Chang Hee

    2016-06-01

    Glucagon-like peptide-1 (GLP-1) is a member of the proglucagon incretin family, and GLP-1 receptor agonists (RAs) have been introduced as a new class of antidiabetic medications in the past decade. The benefits of GLP-1 RAs are derived from their pleiotropic effects, which include glucose-dependent insulin secretion, suppressed glucagon secretion, and reduced appetite. Moreover, GLP-1 RAs also exert beneficial roles on multiple organ systems in which the GLP-1 receptors exist, including the cardiovascular system. Cardiovascular effects of GLP-1 RAs have been of great interest since the burden from cardiovascular diseases (CVD) has been unbearably increasing in a diabetic population worldwide, despite strict glycemic control and advanced therapeutic techniques to treat CVD. Preclinical studies have already demonstrated the beneficial effects of GLP-1 on myocardium and vascular endothelium, and many clinical studies evaluating changes in surrogate markers of CVD have suggested potential benefits from the use of GLP-1 RAs. Data from numerous clinical trials primarily evaluating the antihyperglycemic effects of multiple GLP-1 RAs have also revealed that changes in most CVD risk markers reported as secondary outcomes have been in favor of GLP-1 RAs treatment. However, to date, there is only one randomized clinical trial of GLP-1 RAs (the ELIXA study) evaluating major cardiovascular events as their primary outcomes, and in this study, a neutral cardiovascular effect of lixisenatide was observed in high-risk diabetic subjects. Therefore, the results of ongoing CVD outcome trials with the use of GLP-1 RAs should be awaited to elucidate the translation of benefits previously seen in CVD risk marker studies into large clinical trials with primary cardiovascular outcomes. PMID:27118277

  5. Evaluation of satellite derived spectral diffuse attenuation coefficients

    Digital Repository Service at National Institute of Oceanography (India)

    Suresh, T.; Talaulikar, M.; Desa, E.; Mascarenhas, A.A.M.Q.; Matondkar, S.G.P.

    Spectral diffuse attenuation K sub(d)(lambda) is an important apparent optical property that provide information about the attenuation of the spectral downwelling solar irradiance with depth in water. The spectral K sub(d)(lambda) at lambda = 412...

  6. Photon attenuation characteristics of radiation shielding materials

    International Nuclear Information System (INIS)

    In the design and construction of installation housing high intensity radiation sources and other radiation generating equipment, a variety of shielding materials are used to minimise exposure to individual. Among the materials, lead is best known for radiation shielding characteristics due to their high density and atomic number. Commercial and barium enriched cement, apart from better compressive strength, smoother surface finish and high abrasion resistance, offers adequate shielding to gamma radiations. Although photon attenuation data are available in literature, it is necessary to test these commercially available material experimentally for their radiation shielding efficiency before putting them in to regular use. In the present work, attenuation characteristics of lead. commercial cement and barium enriched cement supplied by a manufacturing firm have been studied for photons of 662 and 1250keV from Cs-137 and Co-60. The radiographic sources of Cs-137 and Co-60 of radioactive strength of 260 and 30 mCi respectively were utilised in the present investigation. Experimental measurements were done with gamma radiography survey meter MR 4500A placed at a distance of 2 meters from the source. Attenuation coefficients for photons in commercial cement, barite and lead were determined experimentally through photon transmission measurements performed under broad beam counting geometry. The absorbers used were in form of thin sheets of lead, commercial cements and barite of uniform thicknesses. These thin sheets were weighed accurately on an analytical balance and from their measured area, thicknesses proportional to area density in gram.cm-2 were determined. The average thickness of each absorber varied from a few milligram to several gram per cm-2. Higher thicknesses were obtained by stacking the absorbers with each other. Each absorber of specified thickness was interposed between the source and detector such that the primary beam is incident normally on its

  7. Breath-hold CT attenuation correction for quantitative cardiac SPECT

    OpenAIRE

    Koshino, Kazuhiro; Fukushima, Kazuhito; Fukumoto, Masaji; Sasaki, Kazunari; Moriguchi, Tetsuaki; Hori, Yuki; Zeniya, Tsutomu; Nishimura, Yoshihiro; Kiso, Keisuke; Iida, Hidehiro

    2012-01-01

    Background Attenuation correction of a single photon emission computed tomography (SPECT) image is possible using computed tomography (CT)-based attenuation maps with hybrid SPECT/CT. CT attenuation maps acquired during breath holding can be misaligned with SPECT, generating artifacts in the reconstructed images. The purpose of this study was to investigate the effects of respiratory phase during breath-hold CT acquisition on attenuation correction of cardiac SPECT imaging. Methods A series o...

  8. Antimitogenic effect of bitter taste receptor agonists on airway smooth muscle cells.

    Science.gov (United States)

    Sharma, Pawan; Panebra, Alfredo; Pera, Tonio; Tiegs, Brian C; Hershfeld, Alena; Kenyon, Lawrence C; Deshpande, Deepak A

    2016-02-15

    Airway remodeling is a hallmark feature of asthma and chronic obstructive pulmonary disease. Clinical studies and animal models have demonstrated increased airway smooth muscle (ASM) mass, and ASM thickness is correlated with severity of the disease. Current medications control inflammation and reverse airway obstruction effectively but have limited effect on remodeling. Recently we identified the expression of bitter taste receptors (TAS2R) on ASM cells, and activation with known TAS2R agonists resulted in ASM relaxation and bronchodilation. These studies suggest that TAS2R can be used as new therapeutic targets in the treatment of obstructive lung diseases. To further establish their effectiveness, in this study we aimed to determine the effects of TAS2R agonists on ASM growth and promitogenic signaling. Pretreatment of healthy and asthmatic human ASM cells with TAS2R agonists resulted in a dose-dependent inhibition of ASM proliferation. The antimitogenic effect of TAS2R ligands was not dependent on activation of protein kinase A, protein kinase C, or high/intermediate-conductance calcium-activated K(+) channels. Immunoblot analyses revealed that TAS2R agonists inhibit growth factor-activated protein kinase B phosphorylation without affecting the availability of phosphatidylinositol 3,4,5-trisphosphate, suggesting TAS2R agonists block signaling downstream of phosphatidylinositol 3-kinase. Furthermore, the antimitogenic effect of TAS2R agonists involved inhibition of induced transcription factors (activator protein-1, signal transducer and activator of transcription-3, E2 factor, nuclear factor of activated T cells) and inhibition of expression of multiple cell cycle regulatory genes, suggesting a direct inhibition of cell cycle progression. Collectively, these findings establish the antimitogenic effect of TAS2R agonists and identify a novel class of receptors and signaling pathways that can be targeted to reduce or prevent airway remodeling as well as

  9. Metabotropic glutamate receptor agonists modify the pyloric output of the crustacean stomatogastric ganglion.

    Science.gov (United States)

    Pérez-Acevedo, Nivia L; Krenz, Wulf D

    2005-11-16

    We have studied the effects of groups I, II, and III metabotropic glutamate receptor (mGluR) agonists and antagonists on pyloric activity in the stomatogastric ganglion (STG) of the Caribbean spiny lobster Panulirus argus. We have found that agonists for all three groups of mGluRs modify the pyloric output. The group I agonist, l-quisqualic acid (l-QA), activated the pyloric central pattern generator (CPG). When the pyloric rhythm was partially suppressed by sucrose-block of input fibers in the stomatogastric nerve (stn), l-QA accelerated the rhythmic activity. In addition, the number of spike discharges was increased in pyloric motoneurons: pyloric (PY), and lateral pyloric (LP). In completely blocked preparations, a slow pyloric rhythm was initiated by l-QA. Groups II and III agonists exerted an inhibitory effect on pyloric activity. The group II agonist, (2S,1'S,2'S)-2-(Carboxycyclopropyl)glycine (L-CCG-I), decreased both the frequency of the pyloric rhythm and the number of spike discharges in the motoneurons: ventricular dilator (VD), PY, and LP. The effects of L-CCG-I were dose-dependent. The group III agonist, l-(+)-2-Amino-4-phosphonobutyric acid (l-AP4), slightly decreased the frequency of the pyloric rhythm and suppressed spike discharges in the VD neuron. All effects of mGluR agonists were reversible. The effect of l-QA was blocked by the broad spectrum mGluR antagonist (S)-Methyl-4-carboxyphenylglycine (MCPG). The inhibitory effect of L-CCG-I was prevented by MCPG and by the group II/III mGluR antagonist (RS)-alpha-Methyl-4-phosphonophenylglycine (MPPG), and was partially blocked by the group II mGluR antagonist (RS)-1-amino-5-phosphonoindan-1-carboxylic acid (APICA). The inhibitory effect of l-AP4 was blocked by MPPG and partially blocked by APICA. PMID:16256086

  10. Ascorbic acid enables reversible dopamine receptor /sup 3/H-agonist binding

    Energy Technology Data Exchange (ETDEWEB)

    Leff, S.; Sibley, D.R.; Hamblin, M.; Creese, I.

    1981-11-16

    The effects of ascorbic acid on dopaminergic /sup 3/H-agonist receptor binding were studied in membrane homogenates of bovine anterior pituitary and caudate, and rat striatum. In all tissues virtually no stereospecific binding (defined using 1uM (+)butaclamol) of the /sup 3/H-agonists N-propylnorapomorphine (NPA), apomorphine, or dopamine could be demonstrated in the absence of ascorbic acid. Although levels of total /sup 3/H-agonist binding were three to five times greater in the absence than in the presence of 0.1% ascorbic acid, the increased binding was entirely non-stereospecific. Greater amounts of dopamine-inhibitable /sup 3/H-NPA binding could be demonstrated in the absence of 0.1% ascorbic acid, but this measure of ''specific binding'' was demonstrated not to represent dopamine receptor binding since several other catecholamines and catechol were equipotent with dopamine and more potent than the dopamine agonist (+/-)amino-6,7-dihydroxy-1,2,3,4-tetrahydronapthalene (ADTN) in inhibiting this binding. High levels of dopamine-displaceable /sup 3/H-agonist binding were detected in fresh and boiled homogenates of cerebellum, an area of brain which receives no dopaminergic innervation, further demonstrating the non-specific nature of /sup 3/H-agonist binding in the absence of ascorbic acid. These studies emphasize that under typical assay conditions ascorbic acid is required in order to demonstrate reversible and specific /sup 3/H-agonist binding to dopamine receptors.

  11. PPAR agonists regulate brain gene expression: relationship to their effects on ethanol consumption.

    Science.gov (United States)

    Ferguson, Laura B; Most, Dana; Blednov, Yuri A; Harris, R Adron

    2014-11-01

    Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that act as ligand-activated transcription factors. Although prescribed for dyslipidemia and type-II diabetes, PPAR agonists also possess anti-addictive characteristics. PPAR agonists decrease ethanol consumption and reduce withdrawal severity and susceptibility to stress-induced relapse in rodents. However, the cellular and molecular mechanisms facilitating these properties have yet to be investigated. We tested three PPAR agonists in a continuous access two-bottle choice (2BC) drinking paradigm and found that tesaglitazar (PPARα/γ; 1.5 mg/kg) and fenofibrate (PPARα; 150 mg/kg) decreased ethanol consumption in male C57BL/6J mice while bezafibrate (PPARα/γ/β; 75 mg/kg) did not. We hypothesized that changes in brain gene expression following fenofibrate and tesaglitazar treatment lead to reduced ethanol drinking. We studied unbiased genomic profiles in areas of the brain known to be important for ethanol dependence, the prefrontal cortex (PFC) and amygdala, and also profiled gene expression in liver. Genomic profiles from the non-effective bezafibrate treatment were used to filter out genes not associated with ethanol consumption. Because PPAR agonists are anti-inflammatory, they would be expected to target microglia and astrocytes. Surprisingly, PPAR agonists produced a strong neuronal signature in mouse brain, and fenofibrate and tesaglitazar (but not bezafibrate) targeted a subset of GABAergic interneurons in the amygdala. Weighted gene co-expression network analysis (WGCNA) revealed co-expression of treatment-significant genes. Functional annotation of these gene networks suggested that PPAR agonists might act via neuropeptide and dopaminergic signaling pathways in the amygdala. Our results reveal gene targets through which PPAR agonists can affect alcohol consumption behavior. PMID:25036611

  12. Simple Scheme for Variable High Power Laser Beam Attenuation

    OpenAIRE

    Bialkowski, Stephen E.

    1987-01-01

    A venetian style infrared attenuator placed prior to a pinhole spatial filter results in variable high‐power laser attenuation. This attenuation scheme has a wide dynamic range, results in high‐quality Gaussian beams, does not introduce beam walk‐off error, and is independent of polarization.

  13. Frequency Dependence of Attenuation Constant of Dielectric Materials

    Directory of Open Access Journals (Sweden)

    A. S. Zadgaonkar

    1975-01-01

    Full Text Available Different dielectric materials have been studied for frequency dependence of attenuation constant. The sensitive cathode ray oscillograph method has been used to evaluate to the dielectric constant and loss factor, and from these attenuation constants have been calculated. The temperature remaining constant, a regular increase has been observed in attenuation constant, at higher frequencies of electro-magnetic propagating wave.

  14. Attenuation of gamma radiation in concrete shields

    International Nuclear Information System (INIS)

    The attenuation characteristics of γ radiation in concrete layers considering their mechanical resistence and densities were determined. A 137Cs source was used in a 'good geometry' arrangement to eliminate the effects of the buildup factor. The ordinary and the heavy concrete were irradiated and for the latter it was used as additives iron ore and Fe2O3 pellets in various grain sizes. The detection system consisted of a 2' x 2' NaI (Tl) crystal coupled to a photomultiplier tube and the associated electronic equipment. FORTRAN programs were used for determining the absorption coefficients and the attenuation factors. These programs calculate photopeak areas eliminating all contributions due to Compton effect and background. (Author)

  15. Implicit temporal expectation attenuates auditory attentional blink.

    Directory of Open Access Journals (Sweden)

    Dawei Shen

    Full Text Available Attentional blink (AB describes a phenomenon whereby correct identification of a first target impairs the processing of a second target (i.e., probe nearby in time. Evidence suggests that explicit attention orienting in the time domain can attenuate the AB. Here, we used scalp-recorded, event-related potentials to examine whether auditory AB is also sensitive to implicit temporal attention orienting. Expectations were set up implicitly by varying the probability (i.e., 80% or 20% that the probe would occur at the +2 or +8 position following target presentation. Participants showed a significant AB, which was reduced with the increased probe probability at the +2 position. The probe probability effect was paralleled by an increase in P3b amplitude elicited by the probe. The results suggest that implicit temporal attention orienting can facilitate short-term consolidation of the probe and attenuate auditory AB.

  16. Particle size characterization by ultrasonic attenuation spectra

    Institute of Scientific and Technical Information of China (English)

    Mingxu Su; Minghua Xue; Xiaoshu Cai; Zhitao Shang; Feng Xu

    2008-01-01

    This paper contributes to extracting information from signals of broadband ultrasonic attenuation spectrum for effective utilization in particle size characterization. The single particle scattering model and the coupled-phase model are formulated simultaneously, the relationship between particle size distribution and ultrasonic spectrum is established, and a convergence criterion for calculation is quantified. Demonsa'ation inversion by the optimum regularization factor method is carded out to yield typical numerical results for discussion. With the experimental set-up developed by the Institute of Particle and Two-Phase Flow Measurement (IPTFM) at the University of Shanghai for Science and Technology, sand sediment particle size is measured by attenuation spectrum and analyzed using the above inversion algorithm and theoretical models. To validate the proposed ultrasonic spectrum particle sizing method, results are compared with those obtained by microscopy.

  17. Decreased B and T lymphocyte attenuator in Behcet's disease may trigger abnormal Th17 and Th1 immune responses.

    Science.gov (United States)

    Ye, Zi; Deng, Bolin; Wang, Chaokui; Zhang, Dike; Kijlstra, Aize; Yang, Peizeng

    2016-01-01

    Behcet's disease (BD) is a chronic, systemic and recurrent inflammatory disease associated with hyperactive Th17 and Th1 immune responses. Recent studies have shown that B and T lymphocyte attenuator (BTLA) negatively regulates the immune response. In this study, we investigated whether BTLA activation could be exploited to inhibit the development of abnormal immune responses in BD patients. BTLA expression in PBMCs and CD4(+) T cells was significantly decreased in active BD patients. Decreased BTLA level was associated with increased Th17 and Th1 responses. Activation of BTLA inhibited the abnormal Th17 and Th1 responses and IL-22 expression in both patients and controls. Addition of an agonistic anti-BTLA antibody remarkably inhibited DC-induced Th17 and Th1 cell responses, resulted in decreased production of the Th17 and Th1-related cytokines IL-1beta, IL-6, IL-23 and IL-12p70 and reduced CD40 expression in DCs. In conclusion, decreased BTLA expression in ocular BD may lead to inappropriate control of the Th17 and Th1 immune responses and DC functions. Therefore, BTLA may be involved in the development and recurrence of this disease. Agonistic agents of BTLA may represent a potential therapeutic approach for the treatment of BD and other inflammatory diseases mediated by abnormal Th17 and Th1 immune responses. PMID:26841832

  18. Activation of the adenosine A2A receptor attenuates experimental autoimmune encephalomyelitis and is associated with increased intracellular calcium levels.

    Science.gov (United States)

    Liu, Yumei; Zou, Haifeng; Zhao, Ping; Sun, Bo; Wang, Jinghua; Kong, Qingfei; Mu, Lili; Zhao, Sihan; Wang, Guangyou; Wang, Dandan; Zhang, Yao; Zhao, Jiaying; Yin, Pengqi; Liu, Lei; Zhao, Xiuli; Li, Hulun

    2016-08-25

    Multiple sclerosis (MS) is a common autoimmune disease that inevitably causes inflammatory nerve demyelination. However, an effective approach to prevent its course is still lacking and urgently needed. Recently, the adenosine A2A receptor (A2AR) has emerged as a novel inflammation regulator. Manipulation of A2AR activity may suppress the MS process and protect against nerve damage. To test this hypothesis, we treated murine experimental autoimmune encephalomyelitis (EAE), a model for MS, with the selective A2AR agonist, CGS21680 (CGS). We evaluated the effects of CGS on the pathological features of EAE progression, including CNS cellular infiltration, inflammatory cytokine expression, lymphocyte proliferation, and cell surface markers. Treatment with CGS significantly suppressed specific lymphocyte proliferation, reduced infiltration of CD4(+) T lymphocytes, and attenuated the expression of inflammatory cytokines, which in turn inhibited the EAE progression. For the first time, we demonstrate that CGS can increase the intracellular calcium concentration ([Ca(2+)]i) in murine lymphocytes, which may be the mechanism underlying the suppressive effects of CGS-induced A2AR activation on EAE progression. Our findings strongly suggest that A2AR is a potential therapeutic target for MS and provide insight into the mechanism of action of A2AR agonists, which may offer a therapeutic option for this disease. PMID:27217214

  19. Conopeptide-Derived κ-Opioid Agonists (Conorphins): Potent, Selective, and Metabolic Stable Dynorphin A Mimetics with Antinociceptive Properties.

    Science.gov (United States)

    Brust, Andreas; Croker, Daniel E; Colless, Barbara; Ragnarsson, Lotten; Andersson, Åsa; Jain, Kapil; Garcia-Caraballo, Sonia; Castro, Joel; Brierley, Stuart M; Alewood, Paul F; Lewis, Richard J

    2016-03-24

    Opioid receptor screening of a conopeptide library led to a novel selective κ-opioid agonist peptide (conorphin T). Intensive medicinal chemistry, guided by potency, selectivity, and stability assays generated a pharmacophore model supporting rational design of highly potent and selective κ-opioid receptor (KOR) agonists (conorphins) with exceptional plasma stability. Conorphins are defined by a hydrophobic benzoprolyl moiety, a double arginine sequence, a spacer amino acid followed by a hydrophobic residue and a C-terminal vicinal disulfide moiety. The pharmacophore model was supported by computational docking studies, revealing receptor-ligand interactions similar to KOR agonist dynorphin A (1-8). A conorphin agonist inhibited colonic nociceptors in a mouse tissue model of chronic visceral hypersensitivity, suggesting the potential of KOR agonists for the treatment of chronic abdominal pain. This new conorphine KOR agonist class and pharmacophore model provide opportunities for future rational drug development and probes for exploring the role of the κ-opioid receptor. PMID:26859603

  20. Dipeptidyl peptidase-4 (DPP-4) inhibitors are favourable to glucagon-like peptide-1 (GLP-1) agonists

    DEFF Research Database (Denmark)

    Madsbad, Sten

    2012-01-01

    Incretin-based therapies, which include the GLP-1 receptor agonists and DPP-4 inhibitors, use the antidiabetic properties of potentiating the GLP-1 receptor signalling via the regulation of insulin and glucagon secretion, inhibition of gastric emptying and suppression of appetite. Most physicians...... will start antidiabetic treatment with metformin, but adding a GLP-1 receptor agonist as the second drug seems to be optimal since more patients will reach an HbA1c below 7% than with a DPP-4 inhibitor or another oral antidiabetic agents and with minimal risk of hypoglycaemia. The GLP-1 receptor...... agonists are also more effective in weight and systolic blood pressure control than DPP-4 inhibitors. The side effects of the GLP-1 receptor agonists are primarily nausea and vomiting, which is less pronounced with the long acting agonists and often transient. A GLP-1 receptor agonist can be recommended...

  1. Narrow terahertz attenuation signatures in Bacillus thuringiensis.

    Science.gov (United States)

    Zhang, Weidong; Brown, Elliott R; Viveros, Leamon; Burris, Kellie P; Stewart, C Neal

    2014-10-01

    Terahertz absorption signatures from culture-cultivated Bacillus thuringiensis were measured with a THz photomixing spectrometer operating from 400 to 1200 GHz. We observe two distinct signatures centered at ∼955 and 1015 GHz, and attribute them to the optically coupled particle vibrational resonance (surface phonon-polariton) of Bacillus spores. This demonstrates the potential of the THz attenuation signatures as "fingerprints" for label-free biomolecular detection. PMID:23821459

  2. Attenuated Measles Virus as a Vaccine Vector

    OpenAIRE

    Zuniga, Armando; Wang, Zili; Liniger, Matthias; Hangartner, Lars; Caballero, Michael; Pavlovic, Jovan; Wild, Peter; Viret, Jean Francois; Glueck, Reinhard; Billeter, Martin A.; Naim, Hussein Y.

    2007-01-01

    Live attenuated measles virus (MV) vaccines have an impressive record of safety, efficacy and ability to induce life-long immunity against measles infection. Using reverse genetics technology, such negative-strand RNA viruses can now be rescued from cloned DNA. This technology allows the insertion of exogenous genes encoding foreign antigens into the MV genome in such a way that they can be expressed by the MV vaccine strain, without affecting virus structure, propagation and cell targeting. ...

  3. Wave attenuation charcteristics of tethered float system

    Digital Repository Service at National Institute of Oceanography (India)

    Vethamony, P.

    and transmitted wave powers, transmission coefficients are computed. The results show that transmission coefficient does not vary with changes in wave height or water depth. When depth of submergence of float increases, wave attenuation decreases, showing... incident wave height transmitted wave height G wave number float mass number of rows of floats drag power transmitted wave power incident wave power 111 112 P. Vethamony float radius wave period time velocity and acceleration of fluid...

  4. Bubbles attenuate elastic waves at seismic frequencies

    Science.gov (United States)

    Tisato, Nicola; Quintal, Beatriz; Chapman, Samuel; Podladchikov, Yury; Burg, Jean-Pierre

    2016-04-01

    The vertical migration of multiphase fluids in the crust can cause hazardous events such as eruptions, explosions, pollution and earthquakes. Although seismic tomography could potentially provide a detailed image of such fluid-saturated regions, the interpretation of the tomographic signals is often controversial and fails in providing a conclusive map of the subsurface saturation. Seismic tomography should be improved considering seismic wave attenuation (1/Q) and the dispersive elastic moduli which allow accounting for the energy lost by the propagating elastic wave. In particular, in saturated media a significant portion of the energy carried by the propagating wave is dissipated by the wave-induced-fluid-flow and the wave-induced-gas-exsolution-dissolution (WIGED) mechanisms. The WIGED mechanism describes how a propagating wave modifies the thermodynamic equillibrium between different fluid phases causing the exsolution and the dissolution of the gas in the liquid, which in turn causes a significant frequency dependent 1/Q and moduli dispersion. The WIGED theory was initially postulated for bubbly magmas but only recently was extended to bubbly water and experimentally demonstrated. Here we report these theory and laboratory experiments. Specifically, we present i) attenuation measurements performed by means of the Broad Band Attenuation Vessel on porous media saturated with water and different gases, and ii) numerical experiments validating the laboratory observations. Finally, we will extend the theory to fluids and to pressure-temperature conditions which are typical of phreatomagmatic and hydrocarbon domains and we will compare the propagation of seismic waves in bubble-free and bubble-bearing subsurface domains. With the present contribution we extend the knowledge about attenuation in rocks which are saturated with multiphase fluid demonstrating that the WIGED mechanism could be extremely important to image subsurface gas plumes.

  5. Implicit Temporal Expectation Attenuates Auditory Attentional Blink

    OpenAIRE

    Shen, Dawei; Alain, Claude

    2012-01-01

    Attentional blink (AB) describes a phenomenon whereby correct identification of a first target impairs the processing of a second target (i.e., probe) nearby in time. Evidence suggests that explicit attention orienting in the time domain can attenuate the AB. Here, we used scalp-recorded, event-related potentials to examine whether auditory AB is also sensitive to implicit temporal attention orienting. Expectations were set up implicitly by varying the probability (i.e., 80% or 20%) that the ...

  6. The attenuation of the periodic table

    International Nuclear Information System (INIS)

    Unique among models of nuclear structure, the face-centered-cubic (FCC) lattice model predicts the attenuation of the periodic table at Z < 110 and the impossibility of superheavy nuclei. The total binding energies of superheavy nuclei in the FCC model (109 < Z < 127) were calculated on the basis of parameters obtained from a least-squares best-fit for 914 nuclei (Z < 99). No indication of increased stability is found for any of the transuranic elements

  7. Lg Attenuation of the Western United States

    Science.gov (United States)

    Gallegos, A. C.; Ranasinghe, N. R.; Ni, J.; Sandvol, E. A.

    2014-12-01

    Lg waveforms recorded by EarthScope's Transportable Array (TA) are used to estimate Lg Q in the Western United States (WUS). Attenuation is calculated based on Lg spectral amplitudes filtered at a narrow band from 0.5 to 1.5 Hz with a central frequency of 1 Hz. The two-station and reverse two-station techniques were used to calculate Qo values. 398 events occurring from 2005 to 2009 and ranging from magnitude 3 to magnitude 6 were used in this study. The geometric spreading term can be determined by using a three-dimensional linear fit of the amplitude ratios versus epicentral distances to two stations. The slope of this line provides the geometric spreading term we use to calculate Lg Qo values of WUS. The results show high Q regions (low attenuation) corresponding to the Colorado Plateau (CP), the Rocky Mountains (RM), the Columbia Plateau (COP), and the Sierra Nevada Mountains (SNM). Regions of low Q (high attenuation) are seen along the Snake River Plain (SRP), the Rio Grande Rift (RGR), the Cascade Mountains (CM), and in east and west of the Basin and Range (BR) where tectonic activity is more active than the central part of the BR. A positive correlation between high heat flow, recent tectonic activity and Q was observed. Areas with low heat flow, thin sediment cover, and no recent tectonic activity were observed to have consistently high Q. These new models use two-station and reversed two-station methods and provide a comparison with previous studies and better constrain regions with high attenuation. This increase in detail can improve high frequency ground motion predictions of future large earthquakes for more accurate hazard assessment and improve overall understanding of the structure and assemblage of the WUS.

  8. Natural attenuation of biogas in landfill covers

    International Nuclear Information System (INIS)

    In the risk evaluation of uncontrolled biogas emissions from landfills, the process of natural attenuation in landfill covers assumes a very important role. The capacity of biogas oxidation in the cover soils seems to be the most important control to mitigate the biogas emission during the aftercare period when the biogas collection system might fail. In the present paper laboratory experiences on lab columns to study the biogas oxidation are discussed

  9. Live-Attenuated Respiratory Syncytial Virus Vaccines

    OpenAIRE

    Karron, Ruth A.; Buchholz, Ursula J.; Collins, Peter L.

    2013-01-01

    Live-attenuated respiratory syncytial virus (RSV) vaccines offer several advantages for immunization of infants and young children: (1) they do not cause vaccine-associated enhanced RSV disease; (2) they broadly stimulate innate, humoral, and cellular immunity, both systemically and locally in the respiratory tract; (3) they are delivered intranasally; and (4) they replicate in the upper respiratory tract of young infants despite the presence of passively acquired maternally derived RSV neutr...

  10. Phonic Attenuation due to Screen-Barriers

    OpenAIRE

    Vasile Bacria; Nicolae Herişanu

    2011-01-01

    The technique of noise decreasing admits two basic approaches: an active approach and a passive one. In the frame of passive method one can count the employment of screen-barriers. In this paper we present some considerations on sound attenuation due to screen-barriers emphasizing the elements which influence it. The elucidation of these elements is made by measurements. The obtained results can be applied in every other practical situation concerning the protection against ...

  11. Chiral Seismic Attenuation with Acoustic Metamaterials

    OpenAIRE

    Hector Torres-Silva; Diego Torres Cabezas

    2013-01-01

    We study the analogy between the linear elasticity theory equations and classical Maxwell equation with chiral effects and we propose a new method of an earthquake-resistant design to support conventional aseismic designs using acoustic metamaterials. We suggest a simple and practical method to reduce the amplitude of a seismic wave exponentially. Our device is like an attenuator of a chiral seismic wave. Constructing a cylindrical shell-type waveguide that creates a stop-band for the chiral...

  12. The attenuation coefficients in CT: Didactic review

    International Nuclear Information System (INIS)

    The review article refers details about the derivation of the Attenuation coefficient of the CT-Number, the electron density and physical density, the effective atomic number, dual KV scanning, the performance of different scanners, furtheron the CT-numbers of intracranial structures, the attempts of characterization of tissue by CT, measurements of effective atomic number and electron density, distribution and probability of occurance of CT-numbers, and distribution of CT-numbers in space. (AJ)

  13. Two-dimensional dynamic fluid bowtie attenuators.

    Science.gov (United States)

    Hermus, James R; Szczykutowicz, Timothy P

    2016-01-01

    Fluence field modulated (FFM) CT allows for improvements in image quality and dose reduction. To date, only one-dimensional modulators have been proposed, as the extension to two-dimensional (2-D) modulation is difficult with solid-metal attenuation-based fluence field modulated designs. This work proposes to use liquid and gas to attenuate the x-ray beam, as unlike solids, these materials can be arranged allowing for 2-D fluence modulation. The thickness of liquid and the pressure for a given path length of gas were determined that provided the same attenuation as 30 cm of soft tissue at 80, 100, 120, and 140 kV. Liquid iodine, zinc chloride, cerium chloride, erbium oxide, iron oxide, and gadolinium chloride were studied. Gaseous xenon, uranium hexafluoride, tungsten hexafluoride, and nickel tetracarbonyl were also studied. Additionally, we performed a proof-of-concept experiment using a 96 cell array in which the liquid thickness in each cell was adjusted manually. Liquid thickness varied as a function of kV and chemical composition, with erbium oxide allowing for the smallest thickness. For the gases, tungsten hexaflouride required the smallest pressure to compensate for 30 cm of soft tissue. The 96 cell iodine attenuator allowed for a reduction in both dynamic range to the detector and scatter-to-primary ratio. For both liquids and gases, when k-edges were located within the diagnostic energy range used for imaging, the mean beam energy exhibited the smallest change with compensation amount. The thickness of liquids and the gas pressure seem logistically implementable within the space constraints of C-arm-based cone beam CT (CBCT) and diagnostic CT systems. The gas pressures also seem logistically implementable within the space and tube loading constraints of CBCT and diagnostic CT systems. PMID:26835499

  14. Pharmacological activation of cannabinoid 2 receptor attenuates inflammation, fibrogenesis, and promotes re-epithelialization during skin wound healing.

    Science.gov (United States)

    Wang, Lin-Lin; Zhao, Rui; Li, Jiao-Yong; Li, Shan-Shan; Liu, Min; Wang, Meng; Zhang, Meng-Zhou; Dong, Wen-Wen; Jiang, Shu-Kun; Zhang, Miao; Tian, Zhi-Ling; Liu, Chang-Sheng; Guan, Da-Wei

    2016-09-01

    Previous studies showed that cannabinoid 2 (CB2) receptor is expressed in multiple effector cells during skin wound healing. Meanwhile, its functional involvement in inflammation, fibrosis, and cell proliferation in other organs and skin diseases implied CB2 receptor might also regulate skin wound healing. To verify this hypothesis, mice excisional wounds were created and treated with highly selective CB2 receptor agonist GP1a (1-(2,4-dichlorophenyl)-6-methyl- N-piperidin-1-yl-4H-indeno[1,2-c]pyrazole-3-carboxamide) and antagonist AM630 ([6-iodo-2- methyl-1-(2-morpholin-4-ylethyl)indol-3-yl]-(4-methoxyphenyl)methanone) respectively. The inflammatory infiltration, cytokine expression, fibrogenesis, and wound re-epithelialization were analyzed. After CB2 receptor activation, neutrophil and macrophage infiltrations were reduced, and expressions of monocyte chemotactic protein (MCP)-1, stromal cell-derived factor (SDF)-1, Interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β1 and vascular endothelial growth factor (VEGF)-A were decreased. Keratinocyte proliferation and migration were enhanced. Wound re-epithelialization was accelerated. Fibroblast accumulation and fibroblast-to-myofibroblast transformation were attenuated, and expression of pro-collagen I was decreased. Furthermore, HaCaT cells in vitro were treated with GP1a or AM630, which revealed that CB2 receptor activation promoted keratinocyte migration by inducing the epithelial to mesenchymal transition. These results, taken together, indicate that activating CB2 receptor could ameliorate wound healing by reducing inflammation, accelerating re-epithelialization, and attenuating scar formation. Thus, CB2 receptor agonist might be a novel perspective for skin wound therapy. PMID:27268717

  15. Natural Biological Attenuation of Benzene in Groundwater

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Benzene has been found in subsurface unsaturated soil and groundwater beneath a petro-chemical plant. Although the groundwater contained several mg/L of benzene in the area immediately beneath the source, benzene was not detected in monitoring wells approximately 800m down stream. All kinds of physical processes such as adsorption and advection/dispersion are considered to account for the observed attenuation. The results indicated that the attenuation was primarily due to natural biological processes occurring within the aquifer. The evidence for the natural bioremediation of benzene from the groundwater included: (1) analysis of groundwater chemistry, (2) laboratory studies demonstrating benzene biodegradation in aquifer samples, and (3) computer simulations examining benzene transport. Laboratory experiments indicated that for conditions similar to those in the plume, the aerobic degradation of benzene by the naturally occurring microorganisms in the polluted groundwater samples was quite rapid with a half-life time of from 5 to 15 days. In situ analyses indicated the level of dissolved oxygen in the groundwater was over 2mg/L. Thus, oxygen should not limit the biodegradation. In fact, the benzene was also shown to degrade under anaerobic conditions. The results from the modeling simulations indicate that biodegradation is the dominant process influencing attenuation of the benzene.

  16. Soil mass attenuation coefficient: Analysis and evaluation

    International Nuclear Information System (INIS)

    Highlights: • Experimental mass attenuation coefficient is affected by sample size. • Sample thickness larger than 9 cm presents the best results for 137Cs. • Sample thickness smaller than 5 cm presents the best results for 241Am. - Abstract: The mass attenuation coefficient (μ) is an important parameter to characterize the penetration and interaction of gamma-rays in the soil. Accurate determinations of μ are important to obtain representative values of soil physical properties by gamma-ray attenuation technique. In this study, the effect of collimator size (2–4 mm diameters) and absorber thickness (2–15 cm) on the experimental μ values of water and soils with different textures were investigated for 59.54 keV (241Am) and 661.1 keV (137Cs) gamma-ray sources. Theoretical results were calculated using the program XCOM. Experimental results were compared with theoretical ones showing a good correlation between methods. It was observed that for the 137Cs the best agreements between theoretical and experimental μ were obtained for sample thickness ⩾10 cm while for the 241Am were those obtained for thickness <5 cm for small collimators

  17. Novel Intriguing Strategies Attenuating to Sarcopenia

    Directory of Open Access Journals (Sweden)

    Kunihiro Sakuma

    2012-01-01

    Full Text Available Sarcopenia, the age-related loss of skeletal muscle mass, is characterized by a deterioration of muscle quantity and quality leading to a gradual slowing of movement, a decline in strength and power, increased risk of fall-related injury, and, often, frailty. Since sarcopenia is largely attributed to various molecular mediators affecting fiber size, mitochondrial homeostasis, and apoptosis, the mechanisms responsible for these deleterious changes present numerous therapeutic targets for drug discovery. Resistance training combined with amino acid-containing supplements is often utilized to prevent age-related muscle wasting and weakness. In this review, we summarize more recent therapeutic strategies (myostatin or proteasome inhibition, supplementation with eicosapentaenoic acid (EPA or ursolic acid, etc. for counteracting sarcopenia. Myostatin inhibitor is the most advanced research with a Phase I/II trial in muscular dystrophy but does not try the possibility for attenuating sarcopenia. EPA and ursolic acid seem to be effective as therapeutic agents, because they attenuate the degenerative symptoms of muscular dystrophy and cachexic muscle. The activation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α in skeletal muscle by exercise and/or unknown supplementation would be an intriguing approach to attenuating sarcopenia. In contrast, muscle loss with age may not be influenced positively by treatment with a proteasome inhibitor or antioxidant.

  18. Anti-Atherosclerotic Effects of A Novel Synthetic Tissue-Selective Steroidal LXR Agonist in LDLR−/− Mice

    OpenAIRE

    Peng, Dacheng; Hiipakka, Richard A.; Dai, Qing; Guo, Jian; Reardon, Catherine A.; Getz, Godfrey S; Liao, Shutsung

    2008-01-01

    Liver X receptor (LXR) agonists have the potential to treat atherosclerosis based on their ability to enhance reverse cholesterol transport. However, their side effects, such as induction of liver lipogenesis and triglyceridemia, may limit their pharmaceutical development. In contrast to the non-steroidal LXR agonist T0901317, 3α, 6α, 24-trihydroxy-24, 24-di(trifluoromethyl)-5β-cholane (ATI-829), a novel potent synthetic steroidal LXR agonist, was a poor inducer of SREBP-1c expression in hepa...

  19. Exercise as an Adjunct Treatment for Opiate Agonist Treatment: Review of the Current Research and Implementation Strategies

    OpenAIRE

    Weinstock, Jeremiah; Wadeson, Heather K.; VanHeest, Jaci L.

    2012-01-01

    Opiate dependence is a significant public health concern linked to poor quality of life, co-morbid psychiatric disorders, and high costs to society. Current opiate agonist treatments are an effective but limited intervention. Adjunctive interventions could improve and augment opiate agonist treatment outcomes, including drug abstinence, quality of life, and physical health. This article reviews exercise as an adjunctive intervention for opiate agonist treatment, especially in regards to impro...

  20. Inhibitory effects of sigma-2 receptor agonists on T lymphocyte activation

    Directory of Open Access Journals (Sweden)

    MANUELFRESNO

    2013-03-01

    Full Text Available Sigma (σ receptor ligands are essentially known for their effects on the nervous system although recent studies have shown their potential effects modulating some other pathophysiological processes as cell proliferation, cancer and the immune response. Here, we have analyzed the actions of σ-1 and σ-2 receptors ligands on T cell activation. Our results show that treatment of Jurkat T cells with σ-2 agonists decreased the induction of the expression of Interleukin (IL-2, Tumor necrosis factor (TNF-α and Cyclooxygenase (COX-2 by activated T cells in a dose–dependent manner. These effects take place at the transcriptional level since σ-2 agonists BD-737 and CB-184 diminished the activity of the promoters of those genes. Those immunosuppressive effects could be attributable to interference with transcription factor activation. Induced transcription mediated by Nuclear factor (NF-κB or Nuclear Factor of Activated T cells (NFAT was inhibited by σ-2 agonists. These effects seem to be specific for σ-2 agonists as no significant effects on T cell activation by σ-1 ligands PRE-084 and BD-1063 were found. Our results provide new insights into the immunomodulatory actions of σ ligands and describe a new property of σ-2 agonists, through inhibition of activation of transcription factors as NFAT by which these compounds are regulating gene expression. This may have important consequences on the possible therapeutic use of those compounds.

  1. Evaluation of direct and indirect effects of the PPARγ agonist troglitazone on mouse endothelial cell proliferation.

    Science.gov (United States)

    Kakiuchi-Kiyota, Satoko; Arnold, Lora L; Yokohira, Masanao; Koza-Taylor, Petra; Suzuki, Shugo; Varney, Michelle; Pennington, Karen L; Cohen, Samuel M

    2011-12-01

    Peroxisome proliferator-activated receptor gamma (PPARγ) agonists and PPARγ/α dual agonists are used in the treatment of type 2 diabetes mellitus and hyperlipidemias. In carcinogenicity studies, some of these agonists induced hemangiomas/hemangiosarcomas in mice, but not in rats. We hypothesized that increased endothelial cell (EC) proliferation may be involved in the mechanism of PPAR agonist-induced vascular tumors in mice. We previously showed that the sarcomagenic PPARγ agonist troglitazone (TG) increased EC proliferation in brown and white adipose tissue and liver in mice at sarcomagenic doses (400 and 800 mg/kg) after four weeks of treatment. In vitro, TG had a mitogenic effect on mouse microvascular mouse ECs by increasing cell proliferation and survival. The current studies showed that treatment of mouse ECs in vitro induced alterations in proliferation pathway gene expression, especially the expression of insulin-like growth factor-1, but had no effect on mouse oxidative stress pathways. In vivo, treatment with vitamin E did not inhibit TG-induced EC proliferation in liver and adipose tissue. In addition, no hypoxic effect was detected in adipose tissue of TG-treated mice; however, TG had a minor effect on hepatocellular hypoxia. These results provide additional evidence supporting a direct mitogenic effect in the mode of action of TG-induced hemangiosarcomas in mice. PMID:21937740

  2. Rat Urinary Bladder Carcinogenesis by Dual-Acting PPARα+γ Agonists

    Directory of Open Access Journals (Sweden)

    Martin B. Oleksiewicz

    2008-01-01

    Full Text Available Despite clinical promise, dual-acting activators of PPARα and γ (here termed PPARα+γ agonists have experienced high attrition rates in preclinical and early clinical development, due to toxicity. In some cases, discontinuation was due to carcinogenic effect in the rat urothelium, the epithelial layer lining the urinary bladder, ureters, and kidney pelvis. Chronic pharmacological activation of PPARα is invariably associated with cancer in rats and mice. Chronic pharmacological activation of PPARγ can in some cases also cause cancer in rats and mice. Urothelial cells coexpress PPARα as well as PPARγ, making it plausible that the urothelial carcinogenicity of PPARα+γ agonists may be caused by receptor-mediated effects (exaggerated pharmacology. Based on previously published mode of action data for the PPARα+γ agonist ragaglitazar, and the available literature about the role of PPARα and γ in rodent carcinogenesis, we propose a mode of action hypothesis for the carcinogenic effect of PPARα+γ agonists in the rat urothelium, which combines receptor-mediated and off-target cytotoxic effects. The proposed mode of action hypothesis is being explored in our laboratories, towards understanding the human relevance of the rat cancer findings, and developing rapid in vitro or short-term in vivo screening approaches to faciliate development of new dual-acting PPAR agonist compounds.

  3. Dissociated nonsteroidal glucocorticoid receptor modulators; discovery of the agonist trigger in a tetrahydronaphthalene-benzoxazine series.

    Science.gov (United States)

    Barker, Mike; Clackers, Margaret; Copley, Royston; Demaine, Derek A; Humphreys, Davina; Inglis, Graham G A; Johnston, Michael J; Jones, Haydn T; Haase, Michael V; House, David; Loiseau, Richard; Nisbet, Lesley; Pacquet, Francois; Skone, Philip A; Shanahan, Stephen E; Tape, Dan; Vinader, Victoria M; Washington, Melanie; Uings, Iain; Upton, Richard; McLay, Iain M; Macdonald, Simon J F

    2006-07-13

    The tetrahydronaphthalene-benzoxazine glucocorticoid receptor (GR) partial agonist 4b was optimized to produce potent full agonists of GR. Aromatic ring substitution of the tetrahydronaphthalene leads to weak GR antagonists. Discovery of an "agonist trigger" substituent on the saturated ring of the tetrahydronaphthalene leads to increased potency and efficacious GR agonism. These compounds are efficacy selective in an NFkB GR agonist assay (representing transrepression effects) over an MMTV GR agonist assay (representing transactivation effects). 52 and 60 have NFkB pIC(50) = 8.92 (105%) and 8.69 (92%) and MMTV pEC(50) = 8.20 (47%) and 7.75 (39%), respectively. The impact of the trigger substituent on agonism is modeled within GR and discussed. 36, 52, and 60 have anti-inflammatory activity in a mouse model of inflammation after topical dosing with 52 and 60, having an effect similar to that of dexamethasone. The original lead was discovered by a manual agreement docking method, and automation of this method is also described. PMID:16821781

  4. Evidence for air movement signals in the agonistic behaviour of a nocturnal arachnid (order Amblypygi.

    Directory of Open Access Journals (Sweden)

    Roger D Santer

    Full Text Available Many arthropods possess filiform hair sensilla (termed trichobothria in arachnids, which are extremely sensitive detectors of medium particle displacement. Electrophysiological evidence in some taxa suggests that these sensilla can detect air particle displacements resulting from intraspecific communication signals. However, it has not yet been shown for any species that the air particle displacements detected by the filiform hairs are themselves perceived as a 'signal' (i.e. that individuals make behavioural decisions based upon the responses of these organs to the displays of conspecifics. We investigate the agonistic behaviour of the whip spider Phrynus marginemaculatus and the role of its trichobothria in receiving agonistic signals. Whip spiders have extremely elongated 'antenniform' first legs, which they vibrate close to their opponents during agonistic interactions, inducing air movements that excite their opponents' trichobothria. We find that ablation of the trichobothria causes significant increases in: (I contest duration, and (II the probability of contest escalation past aggressive displays to physical fighting. Therefore, in the absence of air movement-sensitive sensilla, contest assessment is impaired. This suggests that whip spiders exploit true air movement signals during agonistic interactions, and that these are received by the trichobothria. Furthermore, these results indicate that, in whip spiders, such signals help mitigate the cost of agonistic interaction.

  5. Effects of glucagon-like peptide-1 receptor agonists on renal function

    Institute of Scientific and Technical Information of China (English)

    Theodosios; D; Filippatos; Moses; S; Elisaf

    2013-01-01

    Glucagon-like peptide-1(GLP-1)receptor agonists result in greater improvements in glycemic control than placebo and promote weight loss with minimal hypoglycemia in patients with type 2 diabetes mellitus.A number of case reports show an association of GLP-1receptor agonists,mainly exenatide,with the development of acute kidney injury.The present review aims to present the available data regarding the effects of GLP-1 receptor agonists on renal function,their use in subjects with chronic renal failure and their possible association with acute kidney injury.Based on the current evidence,exenatide is eliminated by renal mechanisms and should not be given in patients with severe renal impairment or end stage renal disease.Liraglutide is not eliminated by renal or hepatic mechanisms,but it should be used with caution since there are only limited data in patients with renal or hepatic impairment.There is evidence from animal studies that GLP-1 receptor agonists exert protective role in diabetic nephropathy with mechanisms that seem to be independent of their glucose-lowering effect.Additionally,there is evidence that GLP-1 receptor agonists influence water and electrolyte balance.These effects may represent new ways to improve or even prevent diabetic nephropathy.

  6. Identification of adiponectin receptor agonist utilizing a fluorescence polarization based high throughput assay.

    Science.gov (United States)

    Sun, Yiyi; Zang, Zhihe; Zhong, Ling; Wu, Min; Su, Qing; Gao, Xiurong; Zan, Wang; Lin, Dong; Zhao, Yan; Zhang, Zhonglin

    2013-01-01

    Adiponectin, the adipose-derived hormone, plays an important role in the suppression of metabolic disorders that can result in type 2 diabetes, obesity, and atherosclerosis. It has been shown that up-regulation of adiponectin or adiponectin receptor has a number of therapeutic benefits. Given that it is hard to convert the full size adiponectin protein into a viable drug, adiponectin receptor agonists could be designed or identified using high-throughput screening. Here, we report on the development of a two-step screening process to identify adiponectin agonists. First step, we developed a high throughput screening assay based on fluorescence polarization to identify adiponectin ligands. The fluorescence polarization assay reported here could be adapted to screening against larger small molecular compound libraries. A natural product library containing 10,000 compounds was screened and 9 hits were selected for validation. These compounds have been taken for the second-step in vitro tests to confirm their agonistic activity. The most active adiponectin receptor 1 agonists are matairesinol, arctiin, (-)-arctigenin and gramine. The most active adiponectin receptor 2 agonists are parthenolide, taxifoliol, deoxyschizandrin, and syringin. These compounds may be useful drug candidates for hypoadiponectin related diseases. PMID:23691032

  7. Identification of adiponectin receptor agonist utilizing a fluorescence polarization based high throughput assay.

    Directory of Open Access Journals (Sweden)

    Yiyi Sun

    Full Text Available Adiponectin, the adipose-derived hormone, plays an important role in the suppression of metabolic disorders that can result in type 2 diabetes, obesity, and atherosclerosis. It has been shown that up-regulation of adiponectin or adiponectin receptor has a number of therapeutic benefits. Given that it is hard to convert the full size adiponectin protein into a viable drug, adiponectin receptor agonists could be designed or identified using high-throughput screening. Here, we report on the development of a two-step screening process to identify adiponectin agonists. First step, we developed a high throughput screening assay based on fluorescence polarization to identify adiponectin ligands. The fluorescence polarization assay reported here could be adapted to screening against larger small molecular compound libraries. A natural product library containing 10,000 compounds was screened and 9 hits were selected for validation. These compounds have been taken for the second-step in vitro tests to confirm their agonistic activity. The most active adiponectin receptor 1 agonists are matairesinol, arctiin, (--arctigenin and gramine. The most active adiponectin receptor 2 agonists are parthenolide, taxifoliol, deoxyschizandrin, and syringin. These compounds may be useful drug candidates for hypoadiponectin related diseases.

  8. G-protein-coupled estrogen receptor agonist suppresses airway inflammation in a mouse model of asthma through IL-10.

    Science.gov (United States)

    Itoga, Masamichi; Konno, Yasunori; Moritoki, Yuki; Saito, Yukiko; Ito, Wataru; Tamaki, Mami; Kobayashi, Yoshiki; Kayaba, Hiroyuki; Kikuchi, Yuta; Chihara, Junichi; Takeda, Masahide; Ueki, Shigeharu; Hirokawa, Makoto

    2015-01-01

    Estrogen influences the disease severity and sexual dimorphism in asthma, which is caused by complex mechanisms. Besides classical nuclear estrogen receptors (ERαβ), G-protein-coupled estrogen receptor (GPER) was recently established as an estrogen receptor on the cell membrane. Although GPER is associated with immunoregulatory functions of estrogen, the pathophysiological role of GPER in allergic inflammatory lung disease has not been examined. We investigated the effect of GPER-specific agonist G-1 in asthmatic mice. GPER expression in asthmatic lung was confirmed by immunofluorescent staining. OVA-sensitized BALB/c and C57BL/6 mice were treated with G-1 by daily subcutaneous injections during an airway challenge phase, followed by histological and biochemical examination. Strikingly, administration of G-1 attenuated airway hyperresponsiveness, accumulation of inflammatory cells, and levels of Th2 cytokines (IL-5 and IL-13) in BAL fluid. G-1 treatment also decreased serum levels of anti-OVA IgE antibodies. The frequency of splenic Foxp3+CD4+ regulatory T cells and IL-10-producing GPER+CD4+ T cells was significantly increased in G-1-treated mice. Additionally, splenocytes isolated from G-1-treated mice showed greater IL-10 production. G-1-induced amelioration of airway inflammation and IgE production were abolished in IL-10-deficient mice. Taken together, these results indicate that extended GPER activation negatively regulates the acute asthmatic condition by altering the IL-10-producing lymphocyte population. The current results have potential importance for understanding the mechanistic aspects of function of estrogen in allergic inflammatory response. PMID:25826377

  9. G-protein-coupled estrogen receptor agonist suppresses airway inflammation in a mouse model of asthma through IL-10.

    Directory of Open Access Journals (Sweden)

    Masamichi Itoga

    Full Text Available Estrogen influences the disease severity and sexual dimorphism in asthma, which is caused by complex mechanisms. Besides classical nuclear estrogen receptors (ERαβ, G-protein-coupled estrogen receptor (GPER was recently established as an estrogen receptor on the cell membrane. Although GPER is associated with immunoregulatory functions of estrogen, the pathophysiological role of GPER in allergic inflammatory lung disease has not been examined. We investigated the effect of GPER-specific agonist G-1 in asthmatic mice. GPER expression in asthmatic lung was confirmed by immunofluorescent staining. OVA-sensitized BALB/c and C57BL/6 mice were treated with G-1 by daily subcutaneous injections during an airway challenge phase, followed by histological and biochemical examination. Strikingly, administration of G-1 attenuated airway hyperresponsiveness, accumulation of inflammatory cells, and levels of Th2 cytokines (IL-5 and IL-13 in BAL fluid. G-1 treatment also decreased serum levels of anti-OVA IgE antibodies. The frequency of splenic Foxp3+CD4+ regulatory T cells and IL-10-producing GPER+CD4+ T cells was significantly increased in G-1-treated mice. Additionally, splenocytes isolated from G-1-treated mice showed greater IL-10 production. G-1-induced amelioration of airway inflammation and IgE production were abolished in IL-10-deficient mice. Taken together, these results indicate that extended GPER activation negatively regulates the acute asthmatic condition by altering the IL-10-producing lymphocyte population. The current results have potential importance for understanding the mechanistic aspects of function of estrogen in allergic inflammatory response.

  10. Seismic Attenuation Inversion with t* Using tstarTomog.

    Energy Technology Data Exchange (ETDEWEB)

    Preston, Leiph

    2014-09-01

    Seismic attenuation is defined as the loss of the seismic wave amplitude as the wave propagates excluding losses strictly due to geometric spreading. Information gleaned from seismic waves can be utilized to solve for the attenuation properties of the earth. One method of solving for earth attenuation properties is called t*. This report will start by introducing the basic theory behind t* and delve into inverse theory as it pertains to how the algorithm called tstarTomog inverts for attenuation properties using t* observations. This report also describes how to use the tstarTomog package to go from observed data to a 3-D model of attenuation structure in the earth.

  11. Design and synthesis of silicon-containing fatty acid amide derivatives as novel peroxisome proliferator-activated receptor (PPAR) agonists.

    Science.gov (United States)

    Kajita, Daisuke; Nakamura, Masaharu; Matsumoto, Yotaro; Ishikawa, Minoru; Hashimoto, Yuichi; Fujii, Shinya

    2015-08-15

    We recently reported that diphenylsilane structure can function as a cis-stilbene mimetic. Here, we investigate whether silyl functionality can also serve as a mimetic of aliphatic cis-olefin. We designed and synthesized various silyl derivatives of oleoylethanolamide (OEA: 8), an endogenous cis-olefin-containing PPARα agonist, and evaluated their PPARα/δ/γ agonistic activity. We found that diethylsilyl derivative 20 exhibited PPARα/δ agonistic activity, and we also obtained a PPARδ-selective agonist, 32. Our results suggest that incorporation of silyl functionality is a useful option for structural development of biologically active compounds. PMID:26071639

  12. Determination of the attenuation map in emission tomography

    CERN Document Server

    Zaidi, H

    2002-01-01

    Reliable attenuation correction methods for quantitative emission computed tomography (ECT) require accurate delineation of the body contour and often necessitate knowledge of internal anatomical structure. Two broad classes of methods have been used to calculate the attenuation map referred to as "transmissionless" and transmission-based attenuation correction techniques. While calculated attenuation correction belonging to the first class of methods is appropriate for brain studies, more adequate methods must be performed in clinical applications where the attenuation coefficient distribution is not known a priori, and for areas of inhomogeneous attenuation such as the chest. Measured attenuation correction overcomes this problem and utilizes different approaches to determine this map including transmission scanning, segmented magnetic resonance images or appropriately scaled X-ray CT scans acquired either independently on separate or simultaneously on multimodality imaging systems. Combination of data acqu...

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

    Science.gov (United States)

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

    2014-01-01

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

  14. Epoxyeicosatrienoic acid agonist regulates human mesenchymal stem cell-derived adipocytes through activation of HO-1-pAKT signaling and a decrease in PPARγ.

    Science.gov (United States)

    Kim, Dong Hyun; Vanella, Luca; Inoue, Kazuyoshi; Burgess, Angela; Gotlinger, Katherine; Manthati, Vijaya Lingam; Koduru, Sreenivasulu Reddy; Zeldin, Darryl C; Falck, John R; Schwartzman, Michal L; Abraham, Nader G

    2010-12-01

    Human mesenchymal stem cells (MSCs) expressed substantial levels of CYP2J2, a major CYP450 involved in epoxyeicosatrienoic acid (EET) formation. MSCs synthesized significant levels of EETs (65.8 ± 5.8 pg/mg protein) and dihydroxyeicosatrienoic acids (DHETs) (15.83 ± 1.62 pg/mg protein), suggesting the presence of soluble epoxide hydrolase (sEH). The addition of an sEH inhibitor to MSC culture decreased adipogenesis. EETs decreased MSC-derived adipocytes in a concentration-dependent manner, 8,9- and 14,15-EET having the maximum reductive effect on adipogenesis. We examined the effect of 12-(3-hexylureido)dodec-8(Z)-enoic acid, an EET agonist, on MSC-derived adipocytes and demonstrated an increased number of healthy small adipocytes, attenuated fatty acid synthase (FAS) levels (P SnMP) and LY2940002, respectively, reversed EET-induced inhibition of adipogenesis, suggesting that activation of the HO-1-adiponectin axis underlies EET effect in MSCs. These findings indicate that EETs decrease MSC-derived adipocyte stem cell differentiation by upregulation of HO-1-adiponectin-AKT signaling and play essential roles in the regulation of adipocyte differentiation by inhibiting PPARγ, C/EBPα, and FAS and in stem cell development. These novel observations highlight the seminal role of arachidonic acid metabolism in MSCs and suggest that an EET agonist may have potential therapeutic use in the treatment of dyslipidemia, diabetes, and the metabolic syndrome. PMID:20412023

  15. Effects of combined PPAR-γ and PPAR-α agonist therapy on fructose induced NASH in rats: Modulation of gene expression.

    Science.gov (United States)

    Abd El-Haleim, Enas A; Bahgat, Ashraf K; Saleh, Samira

    2016-02-15

    Peroxisome proliferator-activated receptors (PPARs) gamma and alpha have been shown to play key roles in maintaining glucose and lipid homeostasis by acting as insulin sensitizers and lipid-lowering agents respectively, which would make them potential candidates for the treatment of non-alcoholic steatohepatitis (NASH) characterized by insulin resistance, hyperglycemia, and hypertriglyceridemia. The effects of pioglitazone, a PPAR-γ agonist, and fenofibrate, a PPAR-α agonist, as monotherapy and in combination on the expressions of key genes linked to the development of NASH were studied in rats with fructose-induced NASH. Fructose-enriched diet was given to rats for 12 weeks. Fenofibrate (100mg/kg), pioglitazone (4 mg/kg) and combined treatment with both in half doses were given. Body weight, liver index, insulin resistance indices, triglycerides, oxidative stress markers, AST/ALT ratio and TNF-α were measured. Additionally, hepatic genes expressions of SOCS-3, sterol regulatory element binding protein-1c, fatty acid synthase, malonyl CoA decarboxylase, TGF-β1, and adipose tissue genes expressions of leptin and adiponectin were investigated. The combination of both drugs, in half doses, improved NASH-related disturbances similar to, or even better than, a full dose of fenofibrate alone possibly due to attenuating effects of pioglitazone on expression of genes responsible for insulin resistance, fatty acid synthesis and fibrosis in addition to correcting the balance between leptin and adiponectin. Histopathology confirmed the ability of this combination to decrease steatosis area and to normalize hepatic tissue structure. In Conclusion, dual activation of PPAR-γ and PPAR-α has remarkable effect in ameliorating NASH by modulation of some hepatic and adipose tissue genes expressions. PMID:26825546

  16. Structure-guided development of dual β2 adrenergic/dopamine D2 receptor agonists.

    Science.gov (United States)

    Weichert, Dietmar; Stanek, Markus; Hübner, Harald; Gmeiner, Peter

    2016-06-15

    Aiming to discover dual-acting β2 adrenergic/dopamine D2 receptor ligands, a structure-guided approach for the evolution of GPCR agonists that address multiple targets was elaborated. Starting from GPCR crystal structures, we describe the design, synthesis and biological investigation of a defined set of compounds leading to the identification of the benzoxazinone (R)-3, which shows agonist properties at the adrenergic β2 receptor and substantial G protein-promoted activation at the D2 receptor. This directed approach yielded molecular probes with tuned dual activity. The congener desOH-3 devoid of the benzylic hydroxyl function was shown to be a β2 adrenergic antagonist/D2 receptor agonist with Ki values in the low nanomolar range. The compounds may serve as a promising starting point for the investigation and treatment of neurological disorders. PMID:27132867

  17. Oxidation of nutrients in bull calves treated with beta-adrenergic agonists

    DEFF Research Database (Denmark)

    Chwalibog, André; Jensen, K; Thorbek, G

    1996-01-01

    Oxidation of protein (OXP), carbohydrate (OXCHO) and fat (OXF) was investigated with 12 growing bulls treated with beta-agonist (L-644, 969) during two 6 weeks trials (Section A and B) at a mean live weight of 195 and 335 kg. Heat production and nutrient oxidation was calculated from gas exchange......, with CO2 reduced for CO2 from fermentation processes, and nitrogen excretion in urine. The beta-agonist had no effect on the level of rumen fermentation as indicated by the same methane production for control and treated animals. Heat Production (HE, RQx) increased by the treatment of beta......-agonist corresponding to the increment in the protein retention. OXP/HE,RQx was reduced to about 10% in treated animals, indicating that in order to supply amino acids for an increased protein deposition oxidation of protein is decreased. OXF/HE,RQx were markedly higher in treated animals, but as indicated by the same...

  18. Diverging mechanisms of activation of chemokine receptors revealed by novel chemokine agonists.

    Directory of Open Access Journals (Sweden)

    Jose Sarmiento

    Full Text Available CXCL8/interleukin-8 is a pro-inflammatory chemokine that triggers pleiotropic responses, including inflammation, angiogenesis, wound healing and tumorigenesis. We engineered the first selective CXCR1 agonists on the basis of residue substitutions in the conserved ELR triad and CXC motif of CXCL8. Our data reveal that the molecular mechanisms of activation of CXCR1 and CXCR2 are distinct: the N-loop of CXCL8 is the major determinant for CXCR1 activation, whereas the N-terminus of CXCL8 (ELR and CXC is essential for CXCR2 activation. We also found that activation of CXCR1 cross-desensitized CXCR2 responses in human neutrophils co-expressing both receptors, indicating that these novel CXCR1 agonists represent a new class of anti-inflammatory agents. Further, these selective CXCR1 agonists will aid at elucidating the functional significance of CXCR1 in vivo under pathophysiological conditions.

  19. Search for new type of PPARγ agonist-like anti-diabetic compounds from medicinal plants.

    Science.gov (United States)

    Matsuda, Hisashi; Nakamura, Seikou; Yoshikawa, Masayuki

    2014-01-01

    Potent ligands of peroxisome proliferator-activated receptor γ (PPARγ) such as thiazolidinediones (pioglitazone, troglitazone, etc.) improve insulin sensitivity by increasing the levels of adiponectin, an important adipocytokine associated with insulin sensitivity in adipose tissue. Several constituents from medicinal plants were recently reported to show PPARγ agonist-like activity in 3T3-L1 cells, but did not show agonistic activity at the receptor site different from thiazolidinediones. Our recent studies on PPARγ agonist-like constituents, such as hydrangenol and hydrangeic acid from the processed leaves of Hydrangea macrophylla var. thunbergii, piperlonguminine and retrofractamide A from the fruit of Piper chaba, and tetramethylkaempferol and pentamethylquercetin from the rhizomes of Kaempferia parviflora, are reviewed. PMID:24882400

  20. Metabotropic glutamate receptor agonists potentiate a slow afterdepolarization in CNS neurons

    Science.gov (United States)

    Zheng, F.; Gallagher, J. P.

    1992-01-01

    We have previously reported that, in the rat dorsolateral septal nucleus (DLSN), metabotropic glutamate receptor (met-GluR) agonists evoked a slow depolarization accompanied by an increase in membrane conductance and burst firing. We have speculated that the burst firing elicited by met-GluR agonists may be due to activation or enhancement of a non-specific cation current, which exists in some DLSN neurons. Now we report that a slow afterdepolarization (sADP) mediated by a non-specific cation current was potentiated by both 1S,3R-ACPD and quisqualate. In addition, met-GluR agonists unmask a sADP in DLSN neurons which did not show a sADP under control conditions. Our data suggest that a non-specific cation current can be potentiated by activation of the met-GluR.

  1. PPARα agonists up-regulate organic cation transporters in rat liver cells

    International Nuclear Information System (INIS)

    It has been shown that clofibrate treatment increases the carnitine concentration in the liver of rats. However, the molecular mechanism is still unknown. In this study, we observed for the first time that treatment of rats with the peroxisome proliferator activated receptor (PPAR)-α agonist clofibrate increases hepatic mRNA concentrations of organic cation transporters (OCTNs)-1 and -2 which act as transporters of carnitine into the cell. In rat hepatoma (Fao) cells, treatment with WY-14,643 also increased the mRNA concentration of OCTN-2. mRNA concentrations of enzymes involved in carnitine biosynthesis were not altered by treatment with the PPARα agonists in livers of rats and in Fao cells. We conclude that PPARα agonists increase carnitine concentrations in livers of rats and cells by an increased uptake of carnitine into the cell but not by an increased carnitine biosynthesis

  2. Chronic exposure to a beta 2-adrenoceptor agonist increases the airway response to methacholine.

    Science.gov (United States)

    Witt-Enderby, P A; Yamamura, H I; Halonen, M; Palmer, J D; Bloom, J W

    1993-09-01

    Scheduled chronic administration of beta 2-adrenoceptor agonist bronchodilators in patients with asthma recently has been reported to be associated with a worsening of symptoms and an increase in bronchial responsiveness. We wanted to determine whether a 28-day in vivo exposure to albuterol (beta 2-adrenoceptor agonist) altered the response of rabbit airways to the cholinergic agonist methacholine. We found, using in vitro tissue bath techniques, that in mainstem bronchi from rabbits given a 28-day exposure to albuterol, maximum contraction to methacholine was increased in the albuterol-treated group (control group = 1.10 +/- 0.11 g vs. treated group = 1.50 +/- 0.13 g, P airway smooth muscle to methacholine.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7901034

  3. Discovery of novel indazole derivatives as dual angiotensin II antagonists and partial PPARγ agonists.

    Science.gov (United States)

    Lamotte, Yann; Faucher, Nicolas; Sançon, Julien; Pineau, Olivier; Sautet, Stéphane; Fouchet, Marie-Hélène; Beneton, Véronique; Tousaint, Jean-Jacques; Saintillan, Yannick; Ancellin, Nicolas; Nicodeme, Edwige; Grillot, Didier; Martres, Paul

    2014-02-15

    Identification of indazole derivatives acting as dual angiotensin II type 1 (AT1) receptor antagonists and partial peroxisome proliferator-activated receptor-γ (PPARγ) agonists is described. Starting from Telmisartan, we previously described that indole derivatives were very potent partial PPARγ agonists with loss of AT1 receptor antagonist activity. Design, synthesis and evaluation of new central scaffolds led us to the discovery of pyrrazolopyridine then indazole derivatives provided novel series possessing the desired dual activity. Among the new compounds, 38 was identified as a potent AT1 receptor antagonist (IC50=0.006 μM) and partial PPARγ agonist (EC50=0.25 μM, 40% max) with good oral bioavailability in rat. The dual pharmacology of compound 38 was demonstrated in two preclinical models of hypertension (SHR) and insulin resistance (Zucker fa/fa rat). PMID:24462665

  4. Inhibiting TNF-α signaling does not attenuate induction of endotoxin tolerance

    Directory of Open Access Journals (Sweden)

    Loosbroock C

    2014-12-01

    Full Text Available Christopher Loosbroock, Kenneth W Hunter Department of Microbiology and Immunology, University of Nevada School of Medicine, Reno, NV, USA Abstract: Tumor necrosis factor-alpha (TNF-α is a central mediator of inflammatory responses elicited by Toll-like receptor agonists, such as the Gram-negative bacterial outer membrane antigen lipopolysaccharide (LPS. TNF-α is responsible for altering vascular permeability and activating infiltrating inflammatory cells, such as monocytes and neutrophils. Interestingly, TNF-α has also demonstrated the ability to induce tolerance to subsequent challenges with TNF-α or LPS in monocyte and macrophage cell populations. Tolerance is characterized by the inability to mount a typical inflammatory response during subsequent challenges following the initial exposure to an inflammatory mediator such as LPS. The ability of TNF-α to induce a tolerant-like state with regard to LPS is most likely a regulatory mechanism to prevent excessive inflammation. We hypothesized that the induction of tolerance or the degree of tolerance is dependent upon the production of TNF-α during the primary response to LPS. To investigate TNF-α-dependent tolerance, human monocytic THP-1 cells were treated with TNF-α-neutralizing antibodies or antagonistic TNF-α receptor antibodies before primary LPS stimulation and then monitored for the production of TNF-α during the primary and challenge stimulation. During the primary stimulation, anti-TNF-α treatment effectively attenuated the production of TNF-α and interleukin-1β; however, this reduced production did not impact the induction of endotoxin tolerance. These results demonstrate that interfering with TNF-α signaling attenuates production of inflammatory cytokines without affecting the induction of tolerance. Keywords: endotoxin tolerance, lipopolysaccharide, tumor necrosis factor-alpha, anti-tumor necrosis factor-alpha, THP-1 cells

  5. Arginase attenuates inhibitory nonadrenergic noncholinergic nerve-induced nitric oxide generation and airway smooth muscle relaxation

    Directory of Open Access Journals (Sweden)

    Meurs Herman

    2005-03-01

    Full Text Available Abstract Background Recent evidence suggests that endogenous arginase activity potentiates airway responsiveness to methacholine by attenuation of agonist-induced nitric oxide (NO production, presumably by competition with epithelial constitutive NO synthase for the common substrate, L-arginine. Using guinea pig tracheal open-ring preparations, we now investigated the involvement of arginase in the modulation of neuronal nitric oxide synthase (nNOS-mediated relaxation induced by inhibitory nonadrenergic noncholinergic (iNANC nerve stimulation. Methods Electrical field stimulation (EFS; 150 mA, 4 ms, 4 s, 0.5 – 16 Hz-induced relaxation was measured in tracheal preparations precontracted to 30% with histamine, in the presence of 1 μM atropine and 3 μM indomethacin. The contribution of NO to the EFS-induced relaxation was assessed by the nonselective NOS inhibitor L-NNA (0.1 mM, while the involvement of arginase activity in the regulation of EFS-induced NO production and relaxation was investigated by the effect of the specific arginase inhibitor nor-NOHA (10 μM. Furthermore, the role of substrate availability to nNOS in EFS-induced relaxation was measured in the presence of various concentrations of exogenous L-arginine. Results EFS induced a frequency-dependent relaxation, ranging from 6.6 ± 0.8% at 0.5 Hz to 74.6 ± 1.2% at 16 Hz, which was inhibited with the NOS inhibitor L-NNA by 78.0 ± 10.5% at 0.5 Hz to 26.7 ± 7.7% at 8 Hz (P Conclusion The results indicate that endogenous arginase activity attenuates iNANC nerve-mediated airway relaxation by inhibition of NO generation, presumably by limiting L-arginine availability to nNOS.

  6. Switch from antagonist to agonist after addition of a DOTA chelator to a somatostatin analog

    Energy Technology Data Exchange (ETDEWEB)

    Reubi, Jean Claude; Cescato, Renzo; Waser, Beatrice [University of Berne, Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, PO Box 62, Berne (Switzerland); Erchegyi, Judit; Rivier, Jean E. [The Salk Institute for Biological Studies, The Clayton Foundation Laboratories for Peptide Biology, La Jolla, CA (United States)

    2010-08-15

    Peptide receptor targeting has become an increasingly attractive method to target tumors diagnostically and radiotherapeutically. Peptides linked to a variety of chelators have been developed for this purpose. They have, however, rarely been tested for their agonistic or antagonistic properties. We report here on a somatostatin antagonist that switched to an agonist upon coupling to a DOTA chelator. Two novel somatostatin analogs, 406-040-15 and its DOTA-coupled counterpart 406-051-20, with and without cold Indium labeling, were tested for their somatostatin receptor subtypes 1-5 (sst{sub 1}-sst{sub 5}) binding affinity using receptor autoradiography. Moreover, they were tested functionally for their ability to affect sst{sub 2} and sst{sub 3} internalization in vitro in HEK293 cells stably expressing the human sst{sub 2} or sst{sub 3} receptor, using an immunofluorescence microscopy-based internalization assay. All three compounds were characterized as pan-somatostatin analogs having a high affinity for all five sst. In the sst{sub 2} internalization assay, all three compounds showed an identical behavior, namely, a weak agonistic effect complemented by a weak antagonistic effect, compatible with the behavior of a partial agonist. Conversely, in the sst{sub 3} internalization assay, 406-040-15 was a full antagonist whereas its DOTA-coupled counterpart, 406-051-20, with and without Indium labeling, switched to a full agonist. Adding the DOTA chelator to the somatostatin analog 406-040-15 triggers a switch at sst{sub 3} receptor from an antagonist to an agonist. This indicates that potential radioligands for tumor targeting should always be tested functionally before further development, in particular if a chelator is added. (orig.)

  7. Partial nicotinic acetylcholine (α4β2 agonists as promising new medications for smoking cessation

    Directory of Open Access Journals (Sweden)

    Singh J

    2008-01-01

    Full Text Available Objective: To review the pharmacology, clinical efficacy and safety of partial agonists of a4β 2 nicotinic acetylcholine receptor. Data Sources: Primary literature and review articles were obtained via a PUBMED search (1988-August 2006 using the key terms smoking cessation, partial agonist alpha4beta2 nicotinic acetylcholine receptor, varenicline, cytisine and SSR591813. Additional studies and abstracts were identified from the bibliographies of reviewed literature. Study Selection and Data Extraction: Studies and review articles related to varenicline, cytisine and the partial agonist alpha4beta2 nicotinic acetylcholine receptor were reviewed. Data Synthesis: Smoking is widely recognized as a serious health problem. Smoking cessation has major health benefits. According to the US Public Health Services, all patients attempting to quit smoking should be encouraged to use one or more effective pharmacotherapy. Currently, along with nicotine replacement therapy, bupropion, nortriptyline and clonidine, are the mainstay of pharmacotherapy. More than ¾ of patients receiving treatment for smoking cessation return to smoking within the first year. Nicotine, through stimulating α4β 2 nAChR, releases dopamine in the reward pathway. Partial agonist of α4β 2 nAChR elicits moderate and sustained release of dopamine, which is countered during the cessation attempts; it simultaneously blocks the effects of nicotine by binding with α4β 2 receptors during smoking. Recently, varenicline, a partial agonist at α4β 2 nAChR, has been approved by the FDA (Food and Drug Administration for smoking cessation. Conclusion: Partial agonist α4β 2 nAChR appears to be a promising target in smoking cessation. Varenicline of this group is approved for treatment of smoking cessation by the FDA in May 2006.

  8. Flow-injection chemiluminescence method to detect a β2 adrenergic agonist.

    Science.gov (United States)

    Zhang, Guangbin; Tang, Yuhai; Shang, Jian; Wang, Zhongcheng; Yu, Hua; Du, Wei; Fu, Qiang

    2015-02-01

    A new method for the detection of β2 adrenergic agonists was developed based on the chemiluminescence (CL) reaction of β2 adrenergic agonist with potassium ferricyanide-luminol CL. The effect of β2 adrenergic agonists including isoprenaline hydrochloride, salbutamol sulfate, terbutaline sulfate and ractopamine on the CL intensity of potassium ferricyanide-luminol was discovered. Detection of the β2 adrenergic agonist was carried out in a flow system. Using uniform design experimentation, the influence factors of CL were optimized. The optimal experimental conditions were 1 mmol/L of potassium ferricyanide, 10 µmol/L of luminol, 1.2 mmol/L of sodium hydroxide, a flow speed of 2.6 mL/min and a distance of 1.2 cm from 'Y2 ' to the flow cell. The linear ranges and limit of detection were 10-100 and 5 ng/mL for isoprenaline hydrochloride, 20-100 and 5 ng/mL for salbutamol sulfate, 8-200 and 1 ng/mL for terbutaline sulfate, 20-100 and 4 ng/mL for ractopamine, respectively. The proposed method allowed 200 injections/h with excellent repeatability and precision. It was successfully applied to the determination of three β2 adrenergic agonists in commercial pharmaceutical formulations with recoveries in the range of 96.8-98.5%. The possible CL reaction mechanism of potassium ferricyanide-luminol-β2 adrenergic agonist was discussed from the UV/vis spectra. PMID:24830367

  9. Switch from antagonist to agonist after addition of a DOTA chelator to a somatostatin analog

    International Nuclear Information System (INIS)

    Peptide receptor targeting has become an increasingly attractive method to target tumors diagnostically and radiotherapeutically. Peptides linked to a variety of chelators have been developed for this purpose. They have, however, rarely been tested for their agonistic or antagonistic properties. We report here on a somatostatin antagonist that switched to an agonist upon coupling to a DOTA chelator. Two novel somatostatin analogs, 406-040-15 and its DOTA-coupled counterpart 406-051-20, with and without cold Indium labeling, were tested for their somatostatin receptor subtypes 1-5 (sst1-sst5) binding affinity using receptor autoradiography. Moreover, they were tested functionally for their ability to affect sst2 and sst3 internalization in vitro in HEK293 cells stably expressing the human sst2 or sst3 receptor, using an immunofluorescence microscopy-based internalization assay. All three compounds were characterized as pan-somatostatin analogs having a high affinity for all five sst. In the sst2 internalization assay, all three compounds showed an identical behavior, namely, a weak agonistic effect complemented by a weak antagonistic effect, compatible with the behavior of a partial agonist. Conversely, in the sst3 internalization assay, 406-040-15 was a full antagonist whereas its DOTA-coupled counterpart, 406-051-20, with and without Indium labeling, switched to a full agonist. Adding the DOTA chelator to the somatostatin analog 406-040-15 triggers a switch at sst3 receptor from an antagonist to an agonist. This indicates that potential radioligands for tumor targeting should always be tested functionally before further development, in particular if a chelator is added. (orig.)

  10. Use of alpha-agonists for management of anaphylaxis occurring under anaesthesia: case studies and review.

    Science.gov (United States)

    Heytman, M; Rainbird, A

    2004-12-01

    Anaphylaxis is an uncommon but serious complication of anaesthesia. Most current guidelines for the management of anaphylaxis list only epinephrine as a vasopressor to use in the event of cardiovascular collapse. We present two cases of anaphylaxis under anaesthesia where return of spontaneous circulation was refractory to epinephrine, but occurred following the administration of the alpha-agonist metaraminol. Potential advantages and disadvantages of using epinephrine in this setting, the role of alpha-agonists and some potential mechanisms accounting for their role in successful management are reviewed. PMID:15549981

  11. High specific activity tritium labelling of some sigma-1 receptor agonists

    International Nuclear Information System (INIS)

    The high specific activity tritiation of (+)-SKF-10,047 (1) and N,N-dimethyltryptamine (4) is described. [N-allyl-3H] (+)-SKF-10,047 (3) was prepared by Lindlar catalyst tritiation of (+)-N-propargylnormetazocine (2) and [N-methyl-3H] N,N-dimethyltryptamine (6) was synthesized by the alkylation of N-methyltryptamine (5) with [3H] methyl iodide. Both sigma-1 synthetic agonist 3 and endogenous agonist 6 have been useful in studying this receptor. (author)

  12. The discovery of a selective and potent A2a agonist with extended lung retention

    OpenAIRE

    Åstrand, Annika B. M.; Lamm Bergström, Eva; Hui ZHANG; Börjesson, Lena; Söderdahl, Therese; Wingren, Cecilia; Jansson, Anne-Helene; Smailagic, Amir; Johansson, Camilla; Bladh, Håkan; Shamovsky, Igor; Tunek, Anders; Drmota, Tomas

    2015-01-01

    Although the anti-inflammatory role of the A2a receptor is well established, controversy remains with regard to the therapeutic value for A2a agonists in treatment of inflammatory lung diseases, also as a result of unwanted A2a-mediated cardiovascular effects. In this paper, we describe the discovery and characterization of a new, potent and selective A2a agonist (compound 2) with prolonged lung retention and limited systemic exposure following local administration. To support the lead optimi...

  13. Dopamine agonist increases risk taking but blunts reward-related brain activity.

    Directory of Open Access Journals (Sweden)

    Jordi Riba

    Full Text Available The use of D2/D3 dopaminergic agonists in Parkinson's disease (PD may lead to pathological gambling. In a placebo-controlled double-blind study in healthy volunteers, we observed riskier choices in a lottery task after administration of the D3 receptor-preferring agonist pramipexole thus mimicking risk-taking behavior in PD. Moreover, we demonstrate decreased activation in the rostral basal ganglia and midbrain, key structures of the reward system, following unexpected high gains and therefore propose that pathological gambling in PD results from the need to seek higher rewards to overcome the blunted response in this system.

  14. Dimethyl-diphenyl-propanamide derivatives as nonsteroidal dissociated glucocorticoid receptor agonists.

    Science.gov (United States)

    Yang, Bingwei V; Weinstein, David S; Doweyko, Lidia M; Gong, Hua; Vaccaro, Wayne; Huynh, Tram; Xiao, Hai-Yun; Doweyko, Arthur M; McKay, Lorraine; Holloway, Deborah A; Somerville, John E; Habte, Sium; Cunningham, Mark; McMahon, Michele; Townsend, Robert; Shuster, David; Dodd, John H; Nadler, Steven G; Barrish, Joel C

    2010-12-01

    A series of 2,2-dimethyl-3,3-diphenyl-propanamides as novel glucocorticoid receptor modulators is reported. SAR exploration led to the identification of 4-hydroxyphenyl propanamide derivatives displaying good agonist activity in GR-mediated transrepression assays and reduced agonist activity in GR-mediated transactivation assays. Compounds 17 and 30 showed anti-inflammatory activity comparable to prednisolone in the rat carrageenan-induced paw edema model, with markedly decreased side effects with regard to increases in blood glucose and expression of hepatic tyrosine aminotransferase. A hypothetical binding mode accounting for the induction of the functional activity by a 4-hydroxyl group is proposed. PMID:21073190

  15. Find novel dual-agonist drugs for treating type 2 diabetes by means of cheminformatics

    Directory of Open Access Journals (Sweden)

    Liu L

    2013-04-01

    Full Text Available Lei Liu,1 Ying Ma,2 Run-Ling Wang,2 Wei-Ren Xu,3 Shu-Qing Wang,2,5 Kuo-Chen Chou4,5 1PET/CT Center, General Hospital of Tianjin Medical University, Tianjin, People’s Republic of China; 2Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics, School of Pharmacy, Tianjin Medical University, Tianjin, People’s Republic of China; 3Tianjin Institute of Pharmaceutical Research (TIPR, Tianjin, People’s Republic of China; 4Center of Excellence in Genomic Medicine Research (CEGMR, King Abdulaziz University, Jeddah, Saudi Arabia; 5Gordon Life Science Institute, Belmont, MA, USA Abstract: The high prevalence of type 2 diabetes mellitus in the world as well as the increasing reports about the adverse side effects of the existing diabetes treatment drugs have made developing new and effective drugs against the disease a very high priority. In this study, we report ten novel compounds found by targeting peroxisome proliferator-activated receptors (PPARs using virtual screening and core hopping approaches. PPARs have drawn increasing attention for developing novel drugs to treat diabetes due to their unique functions in regulating glucose, lipid, and cholesterol metabolism. The reported compounds are featured with dual functions, and hence belong to the category of dual agonists. Compared with the single PPAR agonists, the dual PPAR agonists, formed by combining the lipid benefit of PPARα agonists (such as fibrates and the glycemic advantages of the PPARγ agonists (such as thiazolidinediones, are much more powerful in treating diabetes because they can enhance metabolic effects while minimizing the side effects. This was observed in the studies on molecular dynamics simulations, as well as on absorption, distribution, metabolism, and excretion, that these novel dual agonists not only possessed the same function as ragaglitazar (an investigational drug developed by Novo Nordisk for treating type

  16. Positive cooperativity of acetylcholine and other agonists with allosteric ligands on muscarinic acetylcholine receptors.

    Science.gov (United States)

    Jakubík, J; Bacáková, L; El-Fakahany, E E; Tucek, S

    1997-07-01

    It is well known that allosteric modulators of muscarinic acetylcholine receptors can both diminish and increase the affinity of receptors for their antagonists. We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Allosterically induced changes in the affinities for agonists were computed from changes in the ability of a fixed concentration of each agonist to compete with [3H]N-methylscopolamine for the binding to the receptors in the absence and the presence of varying concentrations of allosteric modulators. The effects of allosteric modulators varied greatly depending on the agonists and the subtypes of receptors. The affinity for acetylcholine was augmented by (-)-eburnamonine on the M2 and M4 receptors and by brucine on the M1 and M3 receptors. Brucine also enhanced the affinities for carbachol, bethanechol, furmethide, methylfurmethide, pilocarpine, 3-(3-pentylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1- methylpyridine (pentylthio-TZTP), oxotremorine-M, and McN-A-343 on the M1, M3, and M4 receptors, for pentylthio-TZTP on the M2 receptors, and for arecoline on the M3 receptors. (-)-Eburnamonine enhanced the affinities for carbachol, bethanechol, furmethide, methylfurmethide, pentylthio-TZTP, pilocarpine, oxotremorine and oxotremorine-M on the M2 receptors and for pilocarpine on the M4 receptors. Vincamine, strychnine, and alcuronium displayed fewer positive allosteric interactions with the agonists, but each allosteric modulator displayed positive cooperativity with at least one agonist on at least one muscarinic receptor subtype. The highest degrees of positive cooperativity were observed between (-)-eburnamonine and pilocarpine and (-)-eburnamonine and oxotremorine-M on the M2 receptors (25- and 7-fold increases in

  17. Discovery of biaryls as RORγ inverse agonists by using structure-based design.

    Science.gov (United States)

    Enyedy, Istvan J; Powell, Noel A; Caravella, Justin; van Vloten, Kurt; Chao, Jianhua; Banerjee, Daliya; Marcotte, Douglas; Silvian, Laura; McKenzie, Andres; Hong, Victor Sukbong; Fontenot, Jason D

    2016-05-15

    RORγ plays a critical role in controlling a pro-inflammatory gene expression program in several lymphocyte lineages including T cells, γδ T cells, and innate lymphoid cells. RORγ-mediated inflammation has been linked to susceptibility to Crohn's disease, arthritis, and psoriasis. Thus inverse agonists of RORγ have the potential of modulating inflammation. Our goal was to optimize two RORγ inverse agonists: T0901317 from literature and 1 that we obtained from internal screening. We used information from internal X-ray structures to design two libraries that led to a new biaryl series. PMID:27080181

  18. Angiotensin AT2 receptor agonist prevents salt-sensitive hypertension in obese Zucker rats

    OpenAIRE

    Ali, Quaisar; Patel, Sanket; Hussain, Tahir

    2015-01-01

    High-sodium intake is a risk factor for the pathogenesis of hypertension, especially in obesity. The present study is designed to investigate whether angiotensin type 2 receptor (AT2R) activation with selective agonist C21 prevents high-sodium diet (HSD)-induced hypertension in obese animals. Male obese rats were treated with AT2R agonist C21 (1 mg·kg−1·day−1, oral) while maintained on either normal-sodium diet (NSD; 0.4%) or HSD (4%) for 2 wk. Radiotelemetric recording showed a time-dependen...

  19. Coriolis attenuation in the rare earth region

    International Nuclear Information System (INIS)

    It is shown that the observed rotational band structure in a number of odd-proton and odd-neutron nuclei situated in the rare earth region, can be reproduced in the particle-rotor model without any ad hoc reduction of the Coriolis matrix elements if a value of the pairing gap parameter, which is about 30-40% of that deduced from the corresponding odd-even mass difference, is used. The importance of the proper choice of the pairing gap parameter in the study of the Coriolis attenuation problem is emphasised. (orig.)

  20. Dichotomous roles for externalized cardiolipin in extracellular signaling: Promotion of phagocytosis and attenuation of innate immunity

    Science.gov (United States)

    Balasubramanian, Krishnakumar; Maeda, Akihiro; Lee, Janet S.; Mohammadyani, Dariush; Dar, Haider Hussain; Jiang, Jian Fei; St. Croix, Claudette M.; Watkins, Simon; Tyurin, Vladimir A.; Tyurina, Yulia Y.; Klöditz, Katharina; Polimova, Anastassia; Kapralova, Valentyna I.; Xiong, Zeyu; Ray, Prabir; Klein-Seetharaman, Judith; Mallampalli, Rama K.; Bayir, Hülya; Fadeel, Bengt; Kagan, Valerian E.

    2016-01-01

    Among the distinct molecular signatures present in the mitochondrion is the tetra-acylated anionic phospholipid cardiolipin, a lipid also present in primordial, single-cell bacterial ancestors of mitochondria and multiple bacterial species today. Cardiolipin is normally localized to the inner mitochondrial membrane; however, when cardiolipin becomes externalized to the surface of dysregulated mitochondria, it promotes inflammasome activation and stimulates the elimination of damaged or nonfunctional mitochondria by mitophagy. Given the immunogenicity of mitochondrial and bacterial membranes that are released during sterile and pathogen-induced trauma, we hypothesized that cardiolipins might function as “eat me” signals for professional phagocytes. In experiments with macrophage cell lines and primary macrophages, we found that membranes with mitochondrial or bacterial cardiolipins on their surface were engulfed through phagocytosis, which depended on the scavenger receptor CD36. Distinct from this process, the copresentation of cardiolipin with the Toll-like receptor 4 (TLR4) agonist lipopolysaccharide dampened TLR4-stimulated production of cytokines. These data suggest that externalized, extracellular cardiolipins play a dual role in host-host and host-pathogen interactions by promoting phagocytosis and attenuating inflammatory immune responses. PMID:26396268

  1. Lactodifucotetraose, a human milk oligosaccharide, attenuates platelet function and inflammatory cytokine release.

    Science.gov (United States)

    Newburg, David S; Tanritanir, Ayse C; Chakrabarti, Subrata

    2016-07-01

    Human milk strongly quenches inflammatory processes in vitro, and breastfed infants have lower incidence of inflammatory diseases than those fed artificially. Platelets from neonates, in contrast to those from adults, are less responsive to platelet agonists such as collagen, thrombin, ADP, and epinephrine. Breastfed infants absorb oligosaccharides intact from the human milk in their gut to the circulation. This study was to determine whether these oligosaccharides can attenuate platelet function and platelet secretion of pro-inflammatory proteins, and to identify the active component. The natural mixture of oligosaccharides from human milk and pure individual human milk oligosaccharides were tested for their ability to modulate responses of platelets isolated from human blood following exposure to thrombin, ADP, and collagen. Human milk and the natural mixture of human milk oligosaccharides inhibited platelet release of inflammatory proteins. Of the purified human milk oligosaccharides tested, only lactodifucotetraose (LDFT) significantly inhibited thrombin induced release of the pro-inflammatory proteins RANTES and sCD40L. LDFT also inhibited platelet adhesion to a collagen-coated surface, as well as platelet aggregation induced by ADP or collagen. These data indicate that LDFT may help modulate hemostasis by suppressing platelet-induced inflammatory processes in breastfed infants. This activity suggests further study of LDFT for its potential as a therapeutic agent in infants and adults. PMID:26743063

  2. Pharmacologic attenuation of pelvic pain in a murine model of interstitial cystitis

    Directory of Open Access Journals (Sweden)

    Schaeffer Anthony J

    2009-11-01

    Full Text Available Abstract Background Interstitial cystitis/painful bladder syndrome (IC/PBS is a bladder disease that causes debilitating pelvic pain of unknown origin, and IC/PBS symptoms correlate with elevated bladder lamina propria mast cell counts. Similar to IC/PBS patients, pseudorabies virus (PRV infection in mice induces a neurogenic cystitis associated with bladder lamina propria mast cell accumulation and pelvic pain. We evaluated several drugs to determine the effectiveness of reducing PRV-induced pelvic pain. Methods Neurogenic cystitis was induced by the injection of Bartha's strain of PRV into the abductor caudalis dorsalis tail base muscle of female C57BL/6 mice. Therapeutic modulation of pelvic pain was assessed daily for five days using von Frey filament stimulation to the pelvic region to quantify tactile allodynia. Results Significant reduction of PRV-induced pelvic pain was observed for animals treated with antagonists of neurokinin receptor 1 (NK1R and histamine receptors. In contrast, the H1R antagonist hydroxyzine, proton pump inhibitors, a histamine receptor 3 agonist, and gabapentin had little or no effect on PRV-induced pelvic pain. Conclusion These data demonstrate that bladder-associated pelvic pain is attenuated by antagonists of NK1R and H2R. Therefore, NK1R and H2Rrepresent direct therapeutic targets for pain in IC/PBS and potentially other chronic pain conditions.

  3. Hydroxylase inhibition attenuates colonic epithelial secretory function and ameliorates experimental diarrhea.

    LENUS (Irish Health Repository)

    Ward, Joseph B J

    2012-02-01

    Hydroxylases are oxygen-sensing enzymes that regulate cellular responses to hypoxia. Transepithelial Cl(-) secretion, the driving force for fluid secretion, is dependent on O(2) availability for generation of cellular energy. Here, we investigated the role of hydroxylases in regulating epithelial secretion and the potential for targeting these enzymes in treatment of diarrheal disorders. Ion transport was measured as short-circuit current changes across voltage-clamped monolayers of T(84) cells and mouse colon. The antidiarrheal efficacy of dimethyloxallyl glycine (DMOG) was tested in a mouse model of allergic disease. Hydroxylase inhibition with DMOG attenuated Ca(2+)- and cAMP-dependent secretory responses in voltage-clamped T(84) cells to 20.2 +\\/- 2.6 and 38.8 +\\/- 6.7% (n=16; P<\\/=0.001) of those in control cells, respectively. Antisecretory actions of DMOG were time and concentration dependent, being maximal after 18 h of DMOG (1 mM) treatment. DMOG specifically inhibited Na(+)\\/K(+)-ATPase pump activity without altering its expression or membrane localization. In mice, DMOG inhibited agonist-induced secretory responses ex vivo and prevented allergic diarrhea in vivo. In conclusion, hydroxylases are important regulators of epithelial Cl(-) and fluid secretion and present a promising target for development of new drugs to treat transport disorders.

  4. Hydroxylase inhibition attenuates colonic epithelial secretory function and ameliorates experimental diarrhea.

    LENUS (Irish Health Repository)

    Ward, Joseph B J

    2011-02-01

    Hydroxylases are oxygen-sensing enzymes that regulate cellular responses to hypoxia. Transepithelial Cl(-) secretion, the driving force for fluid secretion, is dependent on O(2) availability for generation of cellular energy. Here, we investigated the role of hydroxylases in regulating epithelial secretion and the potential for targeting these enzymes in treatment of diarrheal disorders. Ion transport was measured as short-circuit current changes across voltage-clamped monolayers of T(84) cells and mouse colon. The antidiarrheal efficacy of dimethyloxallyl glycine (DMOG) was tested in a mouse model of allergic disease. Hydroxylase inhibition with DMOG attenuated Ca(2+)- and cAMP-dependent secretory responses in voltage-clamped T(84) cells to 20.2 ± 2.6 and 38.8 ± 6.7% (n=16; P≤0.001) of those in control cells, respectively. Antisecretory actions of DMOG were time and concentration dependent, being maximal after 18 h of DMOG (1 mM) treatment. DMOG specifically inhibited Na(+)\\/K(+)-ATPase pump activity without altering its expression or membrane localization. In mice, DMOG inhibited agonist-induced secretory responses ex vivo and prevented allergic diarrhea in vivo. In conclusion, hydroxylases are important regulators of epithelial Cl(-) and fluid secretion and present a promising target for development of new drugs to treat transport disorders.

  5. Differential Rho-kinase dependency of full and partial muscarinic receptor agonists in airway smooth muscle contraction

    NARCIS (Netherlands)

    Schaafsma, D; Boterman, M; de Jong, AM; Hovens, Iris; Penninks, JM; Nelemans, SA; Meurs, H; Zaagsma, J

    2006-01-01

    1 In airway smooth muscle (ASM), full and partial muscarinic receptor agonists have been described to have large differences in their ability to induce signal transduction, including Ca2+-mobilization. Despite these differences, partial agonists are capable of inducing a submaximal to maximal ASM co

  6. MUC-1 Tumor Antigen Agonist Epitopes for Enhancing T-cell Responses to Human Tumors | NCI Technology Transfer Center | TTC

    Science.gov (United States)

    Scientists at NIH have identified 7 new agonist epitopes of the MUC-1 tumor associated antigen. Compared to their native epitope counterparts, peptides reflecting these agonist epitopes have been shown to enhance the generation of human tumor cells, which in turn have a greater ability to kill human tumor cells endogenously expressing the native MUC-1 epitope.

  7. Effect of beta-ADrenergic Agonist on Cyclic AMP Synthesis in Chicken Skeletal Muscle Cells in Culture

    Science.gov (United States)

    Young, R. B.; Bridge, K. Y.; Rose, M. Franklin (Technical Monitor)

    2000-01-01

    Several beta-adrenergic receptor (bAR) agonists are known to cause hypertrophy of skeletal muscle tissue. Because it seems logical that these agonists exert their action on muscle through stimulation of cAMP synthesis, five bAR agonists encompassing a range in activity from strong to weak were evaluated for their ability to stimulate cAMP accumulation in embryonic chicken skeletal muscle cells in culture. Two strong agonists (epinephrine and isoproterenol), one moderate agonist (albuterol), and two weak agonists known to cause hypertrophy in animals (clenbuterol and cimaterol) were studied. Dose response curves were determined over six orders of magnitude in concentration for each agonist, and values were determined for their maximum stimulation of cAMP synthesis rate (Bmax) and the agonist concentration at which 50% stimulation of cAMP synthesis (EC50) occurred. Bmax values decreased in the following order: isoproterenol, epinephrine, albuterol, cimaterol, clenbuterol. Cimaterol and clenbuterol at their Bmax levels were approximately 15-fold weaker than isoproterenol in stimulating the rate of cAMP synthesis. In addition, the EC50 values for isoproterenol, cimaterol, clenbuterol, epinephrine, and albuterol were 360 nM, 630 nM, 900 nM, 2,470 nM, and 3,650 nM, respectively. Finally, dose response curves show that the concentrations of cimaterol and clenbuterol in culture media at concentrations known to cause significant muscle hypertrophy in animals had no detectable effect on stimulation of CAMP accumulation in chicken skeletal muscle cells.

  8. The first X-ray crystal structure of the glucocorticoid receptor bound to a non-steroidal agonist

    Energy Technology Data Exchange (ETDEWEB)

    Madauss, Kevin P.; Bledsoe, Randy K.; Mclay, Iain; Stewart, Eugene L.; Uings, Iain J.; Weingarten, Gordon; Williams, Shawn P. (GSKNC); (GSK)

    2009-07-23

    The amino-pyrazole 2,6-dichloro-N-ethyl benzamide 1 is a selective GR agonist with dexamethasone-like in vitro potency. Its X-ray crystal structure in the GR LBD (Glucocorticoid ligand-binding domain) is described and compared to other reported structures of steroidal GR agonists in the GR LBD (3E7C).

  9. Gamma-lactams--a novel scaffold for highly potent and selective alpha 7 nicotinic acetylcholine receptor agonists.

    Science.gov (United States)

    Enz, Albert; Feuerbach, Dominik; Frederiksen, Mathias U; Gentsch, Conrad; Hurth, Konstanze; Müller, Werner; Nozulak, Joachim; Roy, Bernard L

    2009-03-01

    A novel class of alpha7 nicotinic acetylcholine receptor (nAChR) agonists has been discovered through high-throughput screening. The cis gamma-lactam scaffold has been optimized to reveal highly potent and selective alpha7 nAChR agonists with in vitro activity and selectivity and with good brain penetration in mice. PMID:19208472

  10. A PXR-mediated negative feedback loop attenuates the expression of CYP3A in response to the PXR agonist pregnenalone-16α-carbonitrile.

    OpenAIRE

    Ian Bailey; G Gordon Gibson; Kathryn Plant; Mark Graham; Nick Plant

    2011-01-01

    The nuclear receptor superfamily of ligand-activated transcription factors plays a central role in the regulation of cellular responses to chemical challenge. Nuclear receptors are activated by a wide range of both endogenous and exogenous chemicals, and their target genes include those involved in the metabolism and transport of the activating chemical. Such target gene activation, thus, acts to remove the stimulating xenobiotic or to maintain homeostatic levels of endogenous chemicals. Give...

  11. Attenuation of cocaine-seeking by GABAB receptor agonists baclofen and CGP44532 but not the GABA reuptake inhibitor tiagabine in baboons

    OpenAIRE

    Weerts, Elise M.; Froestl, Wolfgang; Kaminski, Barbara J.; Griffiths, Roland R.

    2007-01-01

    The current study evaluated the effects of drugs that increase GABA levels by activation of GABAB receptors (baclofen and CGP44532) or by inhibition of GABA reuptake (tiagabine) on the reinstatement of extinguished lever responding produced by priming doses of cocaine in baboons (i.e., cocaine-seeking). Cocaine self-injection was established and maintained under a fixed ratio (FR10) schedule of reinforcement during daily 2-h sessions. Lever responding was extinguished by substituting vehicle ...

  12. Vinpocetine attenuates lipid accumulation and atherosclerosis formation

    International Nuclear Information System (INIS)

    Highlights: •Vinpocetine attenuates hyperlipidemia-induced atherosclerosis in a mouse model. •Vinpocetine antagonizes ox-LDL uptake and accumulation in macrophages. •Vinpocetine blocks the induction of ox-LDL receptor LOX-1 in vitro and in vivo. -- Abstract: Atherosclerosis, the major cause of myocardial infarction and stroke, is a chronic arterial disease characterized by lipid deposition and inflammation in the vessel wall. Cholesterol, in low-density lipoprotein (LDL), plays a critical role in the pathogenesis of atherosclerosis. Vinpocetine, a derivative of the alkaloid vincamine, has long been used as a cerebral blood flow enhancer for treating cognitive impairment. Recent study indicated that vinpocetine is a potent anti-inflammatory agent. However, its role in the pathogenesis of atherosclerosis remains unexplored. In the present study, we show that vinpocetine significantly reduced atherosclerotic lesion formation in ApoE knockout mice fed with a high-fat diet. In cultured murine macrophage RAW264.7 cells, vinpocetine markedly attenuated oxidized LDL (ox-LDL) uptake and foam cell formation. Moreover, vinpocetine greatly blocked the induction of ox-LDL receptor 1 (LOX-1) in cultured macrophages as well as in the LOX-1 level in atherosclerotic lesions. Taken together, our data reveal a novel role of vinpocetine in reduction of pathogenesis of atherosclerosis, at least partially through suppressing LOX-1 signaling pathway. Given the excellent safety profile of vinpocetine, this study suggests vinpocetine may be a therapeutic candidate for treating atherosclerosis

  13. Cranking model and attenuation of Coriolis interaction

    International Nuclear Information System (INIS)

    Description of rotational bands of odd deformed nuclei in the self-consistent Cranking model (SCM) is given. Causes of attenuation of the Coriolis interaction in the nuclei investigated are studied, and account of bound of one-particle degrees of freedom with rotation of the Hartree-Fock-Bogolyubov (HFB) self-consistent method is introduced additionally to SCM for qualitative agreement with experimental data. Merits and shortages of SCM in comparison with the quadruparticle-rotor (QR) model are discussed. All know ways for constructing the Hamiltonian QR model (or analog of such Hamiltonian) on the basis of the microscopic theory are shown to include two more approximations besides others: quasi-particle-rotational interaction leading to pair break is taken into account in the second order of the perturbation theory; some exchange diagrams are neglected among diagrams of the second order according to this interaction. If one makes the same approximations in SCM instead of HFB method, then the dependence of level energies on spin obtained in this case is turned out to be close to the results of the QR model. Besides, the problem on renormalization of matrix elements of quasi-rotational interaction occurs in such nonself-consistent approach as in the QR model. In so far as the similar problem does not occur in SCM, one can make the conclusion that the problem of attenuation of Coriolis interaction involves the approximations given above

  14. Exercise Training During Bed Rest Attenuates Deconditioning

    Science.gov (United States)

    Greenleaf, J. E.; Hargens, Alan R. (Technical Monitor)

    1995-01-01

    A 30-day 6 deg. head-down bed rest study was conducted to evaluate high-intensity, short-duration, alternating isotonic cycle ergometer exercise (ITE) training and high-intensity intermittent isokinetic exercise (IKE) training regiments designed to maintain peak VO2 and muscle mass, strength, and endurance at ambulatory control levels throughout prolonged bed rest. Other elements of the deconditioning (acclimation) syndrome, such as proprioception, psychological performance, hypovolemia, water balance, body composition, and orthostatic tolerance, were also measured. Compared with response during bed rest of the no exercise (NOE) control group: the ITE training regimen (a) maintained work capacity (peak VO2), (b) maintained plasma and red cell volume, (c) induced positive body water balance, (d) decreased quality of sleep and mental concentration, and (e) had no effect on the decrease in orthostatic tolerance; the IKE training regimen (a) attenuated the decrease in peak VO2 by 50%, (b) attenuated loss of red cell volume by 40%, but had no effect on loss of plasma volume, (c) induced positive body water balance, (d) had no adverse effect on quality of sleep or concentration, and (e) had no effect on the decrease in orthostatic tolerance. These findings suggest that various elements of the deconditioning syndrome can be manipulated by duration and intensity of ITE or IKE training regiments, and that several different training protocols will be required to maintain or restore physiological and psychological performance of individuals confined to prolonged bed rest.

  15. Vinpocetine attenuates lipid accumulation and atherosclerosis formation

    Energy Technology Data Exchange (ETDEWEB)

    Cai, Yujun [Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester, 601 Elmwood Ave, Rochester, NY 14642 (United States); Li, Jian-Dong [Center for Inflammation, Immunity and Infection, and Department of Biology, Georgia State University, Atlanta, GA 30303 (United States); Yan, Chen, E-mail: Chen_Yan@urmc.rochester.edu [Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester, 601 Elmwood Ave, Rochester, NY 14642 (United States)

    2013-05-10

    Highlights: •Vinpocetine attenuates hyperlipidemia-induced atherosclerosis in a mouse model. •Vinpocetine antagonizes ox-LDL uptake and accumulation in macrophages. •Vinpocetine blocks the induction of ox-LDL receptor LOX-1 in vitro and in vivo. -- Abstract: Atherosclerosis, the major cause of myocardial infarction and stroke, is a chronic arterial disease characterized by lipid deposition and inflammation in the vessel wall. Cholesterol, in low-density lipoprotein (LDL), plays a critical role in the pathogenesis of atherosclerosis. Vinpocetine, a derivative of the alkaloid vincamine, has long been used as a cerebral blood flow enhancer for treating cognitive impairment. Recent study indicated that vinpocetine is a potent anti-inflammatory agent. However, its role in the pathogenesis of atherosclerosis remains unexplored. In the present study, we show that vinpocetine significantly reduced atherosclerotic lesion formation in ApoE knockout mice fed with a high-fat diet. In cultured murine macrophage RAW264.7 cells, vinpocetine markedly attenuated oxidized LDL (ox-LDL) uptake and foam cell formation. Moreover, vinpocetine greatly blocked the induction of ox-LDL receptor 1 (LOX-1) in cultured macrophages as well as in the LOX-1 level in atherosclerotic lesions. Taken together, our data reveal a novel role of vinpocetine in reduction of pathogenesis of atherosclerosis, at least partially through suppressing LOX-1 signaling pathway. Given the excellent safety profile of vinpocetine, this study suggests vinpocetine may be a therapeutic candidate for treating atherosclerosis.

  16. Photon attenuation characteristics of barium enriched cement

    International Nuclear Information System (INIS)

    Nuclear radiations are widely used in several applications of nuclear sciences, medicine and industry. In the design and construction of installations housing high intensity radioactive sources and other radiation generating equipment, a variety of shielding materials are used to minimise the exposure to the individuals. Among the materials used, lead is best known for radiation shielding due to its high density and atomic number. However, in construction of radiation facilities, lead in the form of bricks or slabs cannot be substituted for cement as building material. As an alternative, barium enriched cement, which apart from better compressive strength, smoother surface finish and high abrasive resistance, offers adequate shielding to gamma radiations. In the present work, attenuation properties of commercial as well as barium enriched cements have been studied and compared with that of lead for photons of 662 and 1250 keV emitted from 137Cs and 60Co, respectively. Although photon attenuation data can be obtained by mixture rule theoretically, it is necessary to determine this data experimentally before use

  17. Fuselage panel noise attenuation by piezoelectric switching control

    Science.gov (United States)

    Makihara, Kanjuro; Miyakawa, Takeya; Onoda, Junjiro; Minesugi, Kenji

    2010-08-01

    This paper describes a problem that we encountered in our noise attenuation project and our solution for it. We intend to attenuate low-frequency noise that transmits through aircraft fuselage panels. Our method of noise attenuation is implemented with a piezoelectric semi-active system having a selective switch instead of an active energy-supply system. The semi-active controller is based on the predicted sound pressure distribution obtained from acoustic emission analysis. Experiments and numerical simulations demonstrate that the semi-active method attenuates acoustic levels of not only the simple monochromatic noise but also of broadband noise. We reveal that tuning the electrical parameters in the circuit is the key to effective noise attenuation, to overcome the acoustic excitation problem due to sharp switching actions, as well as to control chattering problems. The results obtained from this investigation provide meaningful insights into designing noise attenuation systems for comfortable aircraft cabin environments.

  18. Applying Echoes Mean Frequency Shift for Attenuation Imaging in Tissue

    Science.gov (United States)

    Litniewski, J.; Klimonda, Z.; Nowicki, A.

    The purpose of this study was to develop the attenuation parametric imaging technique and to apply it for in vivo characterization of tissue. Local attenuation coefficient was determined by evaluating the frequency downshift that encounters the amplitude spectrum of the interrogating ultrasonic pulse during propagation in the absorbing tissue. Operation and accuracy of the processing methods were verified by assessing the size-independent region of interest (ROI) for attenuation determination and calculating the attenuation coefficient distribution for experimentally recorded tissue-phantom scattered waveforms. The Siemens Antares scanner equipped with Ultrasound Research Interface unit allowing for direct radiofrequency (RF) signals recording was used for B-scan imaging of the tissue- mimicking phantom in vitro and liver in vivo. RF data were processed to determine attenuation coefficient along the B-scan lines. Also, the preliminary studies of backscattered signals from skin recorded using a skin scanner were performed to calculate parametric-attenuation images.

  19. Fuselage panel noise attenuation by piezoelectric switching control

    International Nuclear Information System (INIS)

    This paper describes a problem that we encountered in our noise attenuation project and our solution for it. We intend to attenuate low-frequency noise that transmits through aircraft fuselage panels. Our method of noise attenuation is implemented with a piezoelectric semi-active system having a selective switch instead of an active energy-supply system. The semi-active controller is based on the predicted sound pressure distribution obtained from acoustic emission analysis. Experiments and numerical simulations demonstrate that the semi-active method attenuates acoustic levels of not only the simple monochromatic noise but also of broadband noise. We reveal that tuning the electrical parameters in the circuit is the key to effective noise attenuation, to overcome the acoustic excitation problem due to sharp switching actions, as well as to control chattering problems. The results obtained from this investigation provide meaningful insights into designing noise attenuation systems for comfortable aircraft cabin environments

  20. The photon attenuation coefficients of barite, marble and limra

    International Nuclear Information System (INIS)

    The linear attenuation coefficients μ (cm-1) and total mass attenuation coefficients ((μ)/(ρ)) (cm2 g-1) of γ-rays for barite, marble and limra have been calculated using the XCOM program (Version 3.1) at energies from 1 keV to 300 MeV. The calculated results were compared with the estimation coefficients ((μ)/(ρ)) based on the measured total linear attenuation coefficients (μ)

  1. Measurement of crack length by ultrasonic attenuation coefficient

    International Nuclear Information System (INIS)

    In this paper, the ultrasonic attenuation coefficient was measured by variation of crack length for Double-Cantilever Beam(DCB) specimen. The energy release rate, G, was obtained by the experimental measurement of compliance. The experimental results represents that the crack length for the ultrasonic attenuation coefficient and energy release rate is increases proportionally. From the experimental results, we proposed a detecting method of the crack length by the ultrasonic attenuation coefficient and discussed it

  2. Synthesis of carbon-14 labelled indolic 5HT{sub 1} receptor agonists

    Energy Technology Data Exchange (ETDEWEB)

    Waterhouse, Ian; Cable, K.M.; Fellows, Ian; Wipperman, M.D.; Sutherland, D.R. [Glaxo Wellcome Research and Development, Stevenage (United Kingdom). Isotope Chemistry Unit

    1996-11-01

    Syntheses of carbon-14 labelled versions of indolic 5HT{sub 1} agonists sumatriptan (GR43175), GR40370 and naratriptan (GR85548) are described. Introduction of the label via cyanation of ketoformanilides, formed by oxidative cleavage of an indole ring, ensured incorporation of carbon-14 at the metabolically stable C-2 position of the indole. (author).

  3. Therapeutic potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: Recent advances and setbacks.

    Science.gov (United States)

    Wong, Gilbert Y; Gavva, Narender R

    2009-04-01

    The vanilloid receptor TRPV1 is a homotetrameric, non-selective cation channel abundantly expressed in the nociceptors (c-fibers). TRPV1 is considered as a highly validated pain target because, i) its agonists such as capsaicin cause desensitization of TRPV1 channels that relieves pain behaviors in preclinical species, and ii) its antagonists relieve pain behaviors in rodent models of inflammation, osteoarthritis, and cancer. Hence, both agonists and antagonists of TRPV1 are being evaluated as potential analgesics in clinical trials. Clinical trial results of TRPV1 agonists such as resiniferatoxin in interstitial cystitis, NGX 4010 in post-herpetic neuralgia, and 4975 (Adlea) in osteoarthritis, bunionectomy, and Morton's neuroma have been reported. Similarly, clinical trial results of TRPV1 antagonists such as SB-705498 and AMG 517 have also been published recently. Overall, some molecules (e.g., capsaicin) demonstrated potential analgesia in certain conditions (postsurgical pain, postherpetic neuralgia, pain in diabetic neuropathy, osteoarthritis, bunionectomy, and Morton's neuroma), whereas others fell out of the clinic due to on-target liabilities or failed to demonstrate efficacy. This review summarizes recent advances and setbacks of TRPV1 agonists and antagonists in the clinic and predicts future directions. PMID:19150372

  4. Graft versus host disease: New insights into A2A receptor agonist therapy

    Directory of Open Access Journals (Sweden)

    Karlie R. Jones

    2015-01-01

    Full Text Available Allogeneic transplantation can cure many disorders, including sickle cell disease, chronic granulomatous disease (CGD, severe combined immunodeficiency (SCID and many types of cancers. However, there are several associated risks that can result in severe immunological reactions and, in some cases, death. Much of this morbidity is related to graft versus host disease (GVHD [1]. GVHD is an immune mediated reaction in which donor T cells recognize the host as antigenically foreign, causing donor T cells to expand and attack host tissues. The current method of treating recent transplant patients with immunosuppressants to prevent this reaction has met with only partial success, emphasizing a need for new methods of GVHD treatment and prevention. Recently, a novel strategy has emerged targeting adenosine A2A receptors (A2AR through the use of adenosine agonists. These agonists have been shown in vitro to increase the TGFβ-induced generation of FoxP3+ regulatory T cells (Tregs and in vivo to improve weight gain and mortality as well as inhibit the release of pro-inflammatory cytokines in GVHD murine models [2,3]. Positive results involving A2AR agonists in vitro and in vivo are promising, suggesting that A2AR agonists should be a part of the management of clinical GvHD.

  5. Induction of enzyme activities of iodothyronine deiodinases in cultured astroglial cells by purinergic agonists

    International Nuclear Information System (INIS)

    In the present study, the effects of purinergic agonists on iodothyronine 5'-deiodinase (DII ) and 5-deiodinase (DIII) activities, as well as on induction of deiodinase of type I (DI), were examined in cultured astrocytes for the first time. DI, DII, and DIII activities were measured in sonicated of cells (after treatment with agonists) containing 0.4-40 μg of protein in a final volume of 40 μl. During the incubation (30 min at 37 grad C), nonradioactive and 50 000 cpm of the corresponding radioactive iodothyronine substrates were also present together with 10-40 mM dithiothreitol. Aliquots of incubation mixtures were analyzed by TLC using an optimized solvent system. The quantities of separated radiolabelled compounds (rT3, T4, T3, 3,3'-T2, 3'-T1, and I-) were evaluated using the PhosphorImager SF laser scanner. RIA determination of changes in the intracellular concentration of cAMP after short-time (10-30 min) incubation of astrocytes with a series of agonists and antagonists of P2- and P1-purinoceptors, performed in the presence/or absence of IBMX or ADA, enabled us to partially characterize the mechanism of induction of deiodinase activities, caused by the purinergic agonists. (authors)

  6. Optimisation of in silico derived 2-aminobenzimidazole hits as unprecedented selective kappa opioid receptor agonists

    DEFF Research Database (Denmark)

    Sasmal, Pradip K; Krishna, C Vamsee; Sudheerkumar Adabala, S;

    2015-01-01

    and MOR. A short SAR exploration with the objective of identifying more polar and hence less brain penetrant agonists is described herewith. Modeling studies of the recently published structures of KOR, DOR and MOR are used to explain the receptor selectivity. The synthesis, biological evaluation and SAR...

  7. Conformationally constrained farnesoid X receptor (FXR) agonists: Heteroaryl replacements of the naphthalene

    Energy Technology Data Exchange (ETDEWEB)

    Bass, Jonathan Y.; Caravella, Justin A.; Chen, Lihong; Creech, Katrina L.; Deaton, David N.; Madauss, Kevin P.; Marr, Harry B.; McFadyen, Robert B.; Miller, Aaron B.; Mills, Wendy Y.; Navas, III, Frank; Parks, Derek J.; Smalley, Jr., Terrence L.; Spearing, Paul K.; Todd, Dan; Williams, Shawn P.; Wisely, G. Bruce (GSKNC)

    2014-08-13

    To improve on the drug properties of GSK8062 1b, a series of heteroaryl bicyclic naphthalene replacements were prepared. The quinoline 1c was an equipotent FXR agonist with improved drug developability parameters relative to 1b. In addition, analog 1c lowered body weight gain and serum glucose in a DIO mouse model of diabetes.

  8. Development of a radioreceptor assay for {beta}{sub 2} adrenergic agonists

    Energy Technology Data Exchange (ETDEWEB)

    Helbo, V. [Lab. d`analyse des denrees alimentaires d`origine animale, Faculte de Medecine Veterinaire de l`Universite, Liege (Belgium); Vandenbroeck, M. [Lab. d`analyse des denrees alimentaires d`origine animale, Faculte de Medecine Veterinaire de l`Universite, Liege (Belgium); Maghuin-Rogister, G. [Lab. d`analyse des denrees alimentaires d`origine animale, Faculte de Medecine Veterinaire de l`Universite, Liege (Belgium)

    1994-05-01

    Several {beta}{sub 2} adrenergic agonists are illegally used as growth promoters in meat production. We have developed and evaluated a radioreceptor assay for the multianalyte detection of these compounds. The method is based on a competition for binding with receptors (plasma membranes prepared from bovine teat muscles) between a radioactive tracer ({sup 3}H-dihydroalprenolol) and {beta}{sub 2} agonist residues present in the samples. The method has been validated for three {beta}{sub 2} agonists (clenbuterol, mabuterol and cimaterol) in bovine urine samples. The detection limit (mean of ``blank`` values + 3 SEM) in urine was 2.4 ppb clenbuterol. Using this procedure, samples containing at least 5 ppb of clenbuterol, mabuterol or cimaterol could be identified as positive for the presence of {beta}{sub 2} agonists. (orig.) [Deutsch] Mehrere {beta}{sub 2} adrenerge Agonisten werden illegal als Wachstumsfoerderer in der Fleischproduktion eingesetzt. Wir entwickelten und testeten einen RRA (``Radioreceptor Assay``) zur Mehrfachrueckstandsanalyse dieser Zusammensetzungen. Die Methode basiert auf einer Kompetition eines radioaktiven Markers ({sup 3}H-dihydroalpenolol) mit den Rueckstaenden der {beta}{sub 2} Agonisten der Proben um Bindungsstellen der Rezeptoren (Plasmamembranen, welche aus Muskelzellen von Rinderzitzen gewonnen wurden). Die Methode wurde fuer 3 {beta}{sub 2} Agonisten (Clenbuterol, Mabuterol und Cimaterol) in Harnproben anerkannt. Die Nachweisgrenze (Durchschnitt der Leerwerte + 3 Standardabweichungen) bei Harnproben liegt bei 2,4 ppb fuer Clenbuterol. Diese Methode ermoeglicht, Konzentrationen von mindestens 5 ppb an Clenbuterol, Mabuterol und Cimaterol im Probenmaterial nachzuweisen. (orig.)

  9. Transdermal iontophoresis of the dopamine agonist 5-OH-DPAT in human skin in vitro

    NARCIS (Netherlands)

    Nugroho, AK; Li, L; Dijkstra, D; Wikstrom, H; Danhof, M; Bouwstra, JA

    2005-01-01

    The feasibility of transdermal iontophoretic delivery of a potent dopamine agonist 5-OH-DPAT was studied in vitro in side by side diffusion cells across human stratum corneum (HSC) and dermatomed human skin (DHS) according to the following protocol: 6 h of passive diffusion, 9 h of iontophoresis and

  10. Divergent teratogenicity of agonists of retinoid X receptors in embryos of zebrafish (Danio rerio).

    Science.gov (United States)

    Shi, Huahong; Zhu, Pan; Sun, Zhi; Yang, Bo; Zheng, Liang

    2012-07-01

    Zebrafish (Danio rerio) embryos were comparably exposed to seven known agonists of retinoid X receptors (RXRs) including two endogenous compounds (9-cis-retinoic acid and docosahexaenoic acid), four man-made selective ligands (LGD1069, SR11237, fluorobexarotene and CD3254), and a biocide (triphenyltin). The dominant phenotypes of malformation were sharp mouths and small caudal fins in 1 mg/L SR11237-treated group after 5 days exposure. 9-cis-retinoic acid and LGD1069 induced multiple malformations including small eyes, bent notochords, reduced brain, enlarged proctodaems, absence of fins, short tails and edema after 5 days exposure. Fluorobexarotene and CD3254 induced similar phenotypes of malformations after 5 days exposure at low concentration (20 μg/L) to those after the 1st d exposure at high concentrations (50 and 100 μg/L). Triphenlytin induced multiple malformations including deformed eyes, bent notochords, bent tails, and edema in hearts after 5 days exposure at concentrations of 1-10 μg Sn/L. In contrast, no discernible malformations were observed in triphenlytin-treated groups after each separate day exposure. These agonists not only showed different ability of teratogenicity but also induced different phenotypes of malformation in zebrafish embryos. In addition, the sensitive stages of zebrafish embryos were different in response to these agonists. Therefore, our results suggest that the agonists of RXRs had divergent teratogenicity in zebrafish embryos. PMID:22526925

  11. NICOTINE EFFECTS ON THE ACTIVITY OF MICE EXPOSED PRENATALLY TO THE NICOTINIC AGONIST ANATOXIN-A.

    Science.gov (United States)

    Considerable research has shown long-lasting effects of early exposure in experimental animals to nicotine. Anatoxin-a is produced by cyanobacteria and has been shown to be a potent nicotinic agonist. This experiment evaluated the motor activity of adult mice, and their respons...

  12. The LXR inverse agonist SR9238 suppresses fibrosis in a model of non-alcoholic steatohepatitis

    Directory of Open Access Journals (Sweden)

    Kristine Griffett

    2015-04-01

    Conclusions: Here, we demonstrate that an LXR inverse agonist, SR9238, is effective in reduction of hepatic steatosis, inflammation and fibrosis in an animal model of NASH. These results have important implications for the development of therapeutics for treatment NASH in humans.

  13. GnRH-agonist versus GnRH-antagonist IVF cycles

    DEFF Research Database (Denmark)

    Papanikolaou, E G; Pados, G; Grimbizis, G;

    2012-01-01

    In view of the current debate concerning possible differences in efficacy between the two GnRH analogues used in IVF stimulated cycles, the current study aimed to explore whether progesterone control in the late follicular phase differs when GnRH antagonist is used as compared with GnRH agonist...

  14. Small Molecule Agonists of Cell Adhesion Molecule L1 Mimic L1 Functions In Vivo.

    Science.gov (United States)

    Kataria, Hardeep; Lutz, David; Chaudhary, Harshita; Schachner, Melitta; Loers, Gabriele

    2016-09-01

    Lack of permissive mechanisms and abundance of inhibitory molecules in the lesioned central nervous system of adult mammals contribute to the failure of functional recovery after injury, leading to severe disabilities in motor functions and pain. Peripheral nerve injury impairs motor, sensory, and autonomic functions, particularly in cases where nerve gaps are large and chronic nerve injury ensues. Previous studies have indicated that the neural cell adhesion molecule L1 constitutes a viable target to promote regeneration after acute injury. We screened libraries of known drugs for small molecule agonists of L1 and evaluated the effect of hit compounds in cell-based assays in vitro and in mice after femoral nerve and spinal cord injuries in vivo. We identified eight small molecule L1 agonists and showed in cell-based assays that they stimulate neuronal survival, neuronal migration, and neurite outgrowth and enhance Schwann cell proliferation and migration and myelination of neurons in an L1-dependent manner. In a femoral nerve injury mouse model, enhanced functional regeneration and remyelination after application of the L1 agonists were observed. In a spinal cord injury mouse model, L1 agonists improved recovery of motor functions, being paralleled by enhanced remyelination, neuronal survival, and monoaminergic innervation, reduced astrogliosis, and activation of microglia. Together, these findings suggest that application of small organic compounds that bind to L1 and stimulate the beneficial homophilic L1 functions may prove to be a valuable addition to treatments of nervous system injuries. PMID:26253722

  15. Contradictory effects of GABA-B receptor agonists on cortical epileptic afterdischarges in immature rats

    Czech Academy of Sciences Publication Activity Database

    Mareš, Pavel; Tabashidze, Nana

    2008-01-01

    Roč. 75, č. 1 (2008), s. 173-178. ISSN 0361-9230 R&D Projects: GA ČR(CZ) GA305/05/2581 Institutional research plan: CEZ:AV0Z50110509 Keywords : GABA -B receptor agonists * epileptic afterdischarges * cortex Subject RIV: FH - Neurology Impact factor: 2.281, year: 2008

  16. GnRH agonist for triggering of final oocyte maturation: time for a change of practice?

    DEFF Research Database (Denmark)

    Humaidan, P; Kol, Stefan; Papanikolaou, E G

    2011-01-01

    GnRH agonist (GnRHa) triggering has been shown to significantly reduce the occurrence of ovarian hyperstimulation syndrome (OHSS) compared with hCG triggering; however, initially a poor reproductive outcome was reported after GnRHa triggering, due to an apparently uncorrectable luteal phase...

  17. New Insights into the PPAR γ Agonists for the Treatment of Diabetic Nephropathy.

    Science.gov (United States)

    Jia, Zhanjun; Sun, Ying; Yang, Guangrui; Zhang, Aihua; Huang, Songming; Heiney, Kristina Marie; Zhang, Yue

    2014-01-01

    Diabetic nephropathy (DN) is a severe complication of diabetes and serves as the leading cause of chronic renal failure. In the past decades, angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs) based first-line therapy can slow but cannot stop the progression of DN, which urgently requests the innovation of therapeutic strategies. Thiazolidinediones (TZDs), the synthetic exogenous ligands of nuclear receptor peroxisome proliferator-activated receptor- γ (PPAR γ ), had been thought to be a promising candidate for strengthening the therapy of DN. However, the severe adverse effects including fluid retention, cardiovascular complications, and bone loss greatly limited their use in clinic. Recently, numerous novel PPAR γ agonists involving the endogenous PPAR γ ligands and selective PPAR γ modulators (SPPARMs) are emerging as the promising candidates of the next generation of antidiabetic drugs instead of TZDs. Due to the higher selectivity of these novel PPAR γ agonists on the regulation of the antidiabetes-associated genes than that of the side effect-associated genes, they present fewer adverse effects than TZDs. The present review was undertaken to address the advancements and the therapeutic potential of these newly developed PPAR γ agonists in dealing with diabetic kidney disease. At the same time, the new insights into the therapeutic strategies of DN based on the PPAR γ agonists were fully addressed. PMID:24624137

  18. Quantitative phosphoproteomics dissection of seven-transmembrane receptor signaling using full and biased agonists

    DEFF Research Database (Denmark)

    Christensen, Gitte L; Kelstrup, Christian D; Lyngsø, Christina;

    2010-01-01

    , we performed a global quantitative phosphoproteomics analysis of the AT(1)R signaling network. We analyzed ligand-stimulated SILAC (stable isotope labeling by amino acids in cell culture) cells by high resolution (LTQ-Orbitrap) MS and compared the phosphoproteomes of the AT(1)R agonist angiotensin II...

  19. Effect of GABAB receptor agonist SKF97541 on cortical and hippocampal epileptic afterdischarges

    Czech Academy of Sciences Publication Activity Database

    Fábera, Petr; Mareš, Pavel

    2014-01-01

    Roč. 63, č. 4 (2014), s. 529-534. ISSN 0862-8408 R&D Projects: GA ČR(CZ) GBP304/12/G069; GA ČR(CZ) GAP304/10/1274 Institutional support: RVO:67985823 Keywords : GABAB receptor * agonist * hippocampus * cortex * epileptic afterdischarges * rat Subject RIV: FH - Neurology Impact factor: 1.293, year: 2014

  20. Lixisenatide, a novel GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Christensen, Mikkel; Knop, Filip K; Holst, Jens Juul;

    2009-01-01

    Lixisenatide, under development by sanofi-aventis, is a novel human glucagon-like peptide-1 receptor (GLP-1R) agonist for the treatment of type 2 diabetes mellitus (T2DM; non-insulin dependent diabetes). The structure of lixisenatide, based on exendin-4(1-39) modified C-terminally with six Lys...

  1. Continuous Inhalation of Ipratropium Bromide for Acute Asthma Refractory to β2-agonist Treatment.

    Science.gov (United States)

    Koumbourlis, Anastassios C; Mastropietro, Christopher

    2015-01-01

    To present the case of a patient with persistent bronchospasm, refractory to treatment with β2-agonists, that resolved promptly with continuous inhalation of large dose (1000 mcg/hr) ipratropium bromide, and to discuss the possibility of tolerance to β2-agonists as the cause for his failure to respond to adrenergic medications. The patient had received multiple doses of albuterol, as well as subcutaneous terbutaline (0.3 mg), intravenous magnesium sulfate (1 g) and intravenous dexamethasone (10 mg) prior to his admission to the intensive care unit. He remained symptomatic despite systemic intravenous steroids, continuous intravenous terbutaline (up to 0.6 mcg/kg/min), and continuous nebulized albuterol (up to 20 mg/hr for 57 hr) followed by 49 hours of continuous levalbuterol (7 mg/hr). Due to the lack of response, all β2-agonists were discontinued at 106 hours post-admission, and he was started on large dose ipratropium bromide (1000 mcg/hr) by continuous nebulization. Clinical improvement was evident within 1 hour and complete resolution of his symptoms within 4 hours. Continuous inhalation of large dose ipratropium bromide may be an effective regimen for the treatment of patients hospitalized with acute asthma who are deemed to be nonresponsive and/or tolerant to β2-agonist therapy. PMID:25859173

  2. Tweaking agonist efficacy at N-methyl-D-aspartate receptors by site-directed mutagenesis

    DEFF Research Database (Denmark)

    Hansen, Kasper B; Clausen, Rasmus P; Bjerrum, Esben J; Bechmann, Christian; Greenwood, Jeremy R; Christensen, Caspar; Kristensen, Jesper L; Egebjerg, Jan; Bräuner-Osborne, Hans

    2005-01-01

    . Key residues were selected for mutation based on ligand-protein docking studies using a homology model of NR2B-S1S2 built from the X-ray structure of NR1-S1S2 in complex with glycine. Wild-type and mutant forms of NR2B were coexpressed with NR1 in Xenopus laevis oocytes and characterized by two......The structural basis for partial agonism at N-methyl-D-aspartate (NMDA) receptors is currently unresolved. We have characterized several partial agonists at the NR1/NR2B receptor and investigated the mechanisms underlying their reduced efficacy by introducing mutations in the glutamate binding site...... increased steric clashes between agonists and the residues forming the S1-S2 interface, the agonists clearly show decreased relative efficacy. Furthermore, we demonstrate that the mutation S690A affects both potency and efficacy in an agonist-specific manner. The results indicate that essential residues in...

  3. Melanocortin 1 receptor agonist protects podocytes through catalase and RhoA activation.

    Science.gov (United States)

    Elvin, Johannes; Buvall, Lisa; Lindskog Jonsson, Annika; Granqvist, Anna; Lassén, Emelie; Bergwall, Lovisa; Nyström, Jenny; Haraldsson, Börje

    2016-05-01

    Drugs containing adrenocorticotropic hormone have been used as therapy for patients with nephrotic syndrome. We have previously shown that adrenocorticotropic hormone and a selective agonist for the melanocortin 1 receptor (MC1R) exert beneficial actions in experimental membranous nephropathy with reduced proteinuria, reduced oxidative stress, and improved glomerular morphology and function. Our hypothesis is that MC1R activation in podocytes elicits beneficial effects by promoting stress fibers and maintaining podocyte viability. To test the hypothesis, we cultured podocytes and used highly specific agonists for MC1R. Podocytes were subjected to the nephrotic-inducing agent puromycin aminonucleoside, and downstream effects of MC1R activation on podocyte survival, antioxidant defense, and cytoskeleton dynamics were studied. To increase the response and enhance intracellular signals, podocytes were transduced to overexpress MC1R. We showed that puromycin promotes MC1R expression in podocytes and that activation of MC1R promotes an increase of catalase activity and reduces oxidative stress, which results in the dephosphorylation of p190RhoGAP and formation of stress fibers through RhoA. In addition, MC1R agonists protect against apoptosis. Together, these mechanisms protect the podocyte against puromycin. Our findings strongly support the hypothesis that selective MC1R-activating agonists protect podocytes and may therefore be useful to treat patients with nephrotic syndromes commonly considered as podocytopathies. PMID:26887829

  4. Differential Effects of Cannabinoid Receptor Agonist on Social Discrimination and Contextual Fear in Amygdala and Hippocampus

    Science.gov (United States)

    Segev, Amir; Akirav, Irit

    2011-01-01

    We examined whether the cannabinoid receptor agonist WIN55,212-2 (WIN; 5 [mu]g/side) microinjected into the hippocampus or the amygdala would differentially affect memory processes in a neutral vs. an aversive task. In the aversive contextual fear task, WIN into the basolateral amygdala impaired fear acquisition/consolidation, but not retrieval.…

  5. Identification of higenamine in Radix Aconiti Lateralis Preparata as a beta2-adrenergic receptor agonist

    Institute of Scientific and Technical Information of China (English)

    Gang BAI; Yang YANG; Qian SHI; Ze LIU; Qi ZHANG; Yuan-yuan ZHU

    2008-01-01

    Aim:To screen beta2-adrenergic receptor (β+-AR) agonists from Radix Aconiti Lateralis Preparata (RALP) as potential drug leads for asthma using a sensi-tive cell-based agonist assay.Methods:The β+-AR gene was stably expressed by Chinese hamster ovary (CHO) cells also stably expressing a cyclic adenosine monophosphate (AMP) response element-linked enhanced green fluorescent pro-tein reporter gene.The cells were used to screen agonists from high-performance liquid chromatographic fractions of an extract of RALE The fraction with the highest activity was selected for further compound isolation and the study of the structure-activity relationship.Its active compound was further identified by chromatography and mass spectrometry.Results:Bioactivity-directed fraction-ation of the crude extract of RALP led to the isolation and characterization of the effective compound,namely hignamine.It could dose-dependently relax the iso-lated guinea pig trachea strip precontraction with acetylcholine with EC50 value of (2.60±0.36)x 10-5 mol/L.Further in vivo studies also displayed that higuamine could protect experimental asthma model induced by histamine in guinea pigs to prolong the latent periods of asthma.Conclusion:Hignamine,as a β2-AR ago-nist existing in the extract of RALE is the key compound contributing to the suc-cessful relief of the bronchoconstriction.

  6. Novel non-indolic melatonin receptor agonists differentially entrain endogenous melatonin rhythm and increase its amplitude

    NARCIS (Netherlands)

    Drijfhout, W.J; de Vries, J.B; Homan, E.J; Brons, H.F; Copinga, S; Gruppen, G; Beresford, I.J M; Hagan, R.M; Grol, Cor; Westerink, B.H.C.

    1999-01-01

    In this study we have examined the ability of melatonin and four synthetic melatonin receptor agonists to entrain endogenous melatonin secretion in rats, free running in constant darkness. The circadian melatonin profile was measured by trans-pineal microdialysis, which not only reveals the time of

  7. Small-molecule agonists for the glucagon-like peptide 1 receptor

    DEFF Research Database (Denmark)

    Knudsen, Lotte Bjerre; Kiel, Dan; Teng, Min;

    2007-01-01

    The peptide hormone glucagon-like peptide (GLP)-1 has important actions resulting in glucose lowering along with weight loss in patients with type 2 diabetes. As a peptide hormone, GLP-1 has to be administered by injection. Only a few small-molecule agonists to peptide hormone receptors have been...

  8. Pharmacodynamics of TRPV1 Agonists in a Bioassay Using Human PC-3 Cells

    Directory of Open Access Journals (Sweden)

    Daniel Alvarez-Berdugo

    2014-01-01

    Full Text Available Purpose. TRPV1 is a multimodal channel mainly expressed in sensory neurons. We aimed to explore the pharmacodynamics of the TRPV1 agonists, capsaicin, natural capsaicinoids, and piperine in an in vitro bioassay using human PC-3 cells and to examine desensitization and the effect of the specific antagonist SB366791. Methods. PC-3 cells expressing TRPV1 were incubated with Fluo-4. Fluorescence emission changes following exposition to agonists with and without preincubation with antagonists were assessed and referred to maximal fluorescence following the addition of ionomycin. Concentration-response curves were fitted to the Hill equation. Results. Capsaicin and piperine had similar pharmacodynamics (Emax 204.8 ± 184.3% piperine versus 176.6 ± 35.83% capsaicin, P=0.8814, Hill coefficient 0.70 ± 0.50 piperine versus 1.59 ± 0.86 capsaicin, P=0.3752. In contrast, capsaicinoids had lower Emax (40.99 ± 6.14% capsaicinoids versus 176.6 ± 35.83% capsaicin, P<0.001. All the TRPV1 agonists showed significant desensitization after the second exposition and their effects were strongly inhibited by SB366791. Conclusion. TRPV1 receptor is successfully stimulated by capsaicin, piperine, and natural capsaicinoids. These agonists present desensitization and their effect is significantly reduced by a TRPV1-specific antagonist. In addition, PC-3 cell bioassays proved useful in the study of TRPV1 pharmacodynamics.

  9. Characterisation of beta(2)-adrenoceptors, using the agonist [C-11]formoterol and positron emission tomography

    NARCIS (Netherlands)

    Visser, T.J; van Waarde, Aaren; Doze, P; Elsinga, P.H; van der Mark, Thomas W.; Kraan, Jan; Ensing, Kees; Vaalburg, W.

    1998-01-01

    The agonist radioligand N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-[C-11]-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide ([C-11]formoterol) was synthesised in order to test its ability to visualise pulmonary beta(2)-adrenoceptors in vivo, with positron emission tomography (PET). Formoterol was la

  10. Potential antidepressant-like properties of the TC G-1008, a GPR39 (zinc receptor) agonist.

    Science.gov (United States)

    Młyniec, Katarzyna; Starowicz, Gabriela; Gaweł, Magdalena; Frąckiewicz, Ewelina; Nowak, Gabriel

    2016-09-01

    Some forms of depression appear to be more related to the glutamatergic system. G-coupled protein receptor 39 (GPR39) is the metabotropic zinc receptor, which may be involved in the pathophysiology of depression and in the antidepressant response. Its deficiency abolishes the antidepressant response, which means that GPR39 is required to obtain a therapeutic effect in depression. This raises the possibility that agonists of the zinc receptor may have a role in antidepressant treatment. To explore this possibility we investigated animal behaviour in the forced swim test, the tail suspension test (to assess antidepressant-like properties), the light/dark test and the elevated plus maze test (to assess anxiolytic-like properties), following acute administration of a GPR39 agonist (TC G-1008). We found an antidepressant response (as measured by the forced swim test but not by the tail suspension test) in mice following the GPR39 agonist treatment. Additionally, we observed the opposite results in the light/dark box (decreased overall distance; increased time spent in the lit compartment; decreased time spent in the dark compartment; increased freezing time) and elevated plus maze (no significant changes), which may be a consequence of the sedative effect of TC G-1008. We also found hippocampal GPR39 and brain-derived neurotrophic factor (BDNF) up-regulation following administration of the GPR39 agonist, which may be undiscovered so far as a possible novel agent in the treatment of mood disorders. PMID:27235821

  11. Biostructural and pharmacological studies of bicyclic analogues of the 3-isoxazolol glutamate receptor agonist ibotenic acid

    DEFF Research Database (Denmark)

    Frydenvang, Karla Andrea; Pickering, Darryl S; Greenwood, Jeremy R;

    2010-01-01

    We describe an improved synthesis and detailed pharmacological characterization of the conformationally restricted analogue of the naturally occurring nonselective glutamate receptor agonist ibotenic acid (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-7-carboxylic acid (7-HPCA, 5) at A...

  12. New Insights into the PPARγ Agonists for the Treatment of Diabetic Nephropathy

    Directory of Open Access Journals (Sweden)

    Zhanjun Jia

    2014-01-01

    Full Text Available Diabetic nephropathy (DN is a severe complication of diabetes and serves as the leading cause of chronic renal failure. In the past decades, angiotensin-converting enzyme inhibitors (ACEIs/angiotensin II receptor blockers (ARBs based first-line therapy can slow but cannot stop the progression of DN, which urgently requests the innovation of therapeutic strategies. Thiazolidinediones (TZDs, the synthetic exogenous ligands of nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ, had been thought to be a promising candidate for strengthening the therapy of DN. However, the severe adverse effects including fluid retention, cardiovascular complications, and bone loss greatly limited their use in clinic. Recently, numerous novel PPARγ agonists involving the endogenous PPARγ ligands and selective PPARγ modulators (SPPARMs are emerging as the promising candidates of the next generation of antidiabetic drugs instead of TZDs. Due to the higher selectivity of these novel PPARγ agonists on the regulation of the antidiabetes-associated genes than that of the side effect-associated genes, they present fewer adverse effects than TZDs. The present review was undertaken to address the advancements and the therapeutic potential of these newly developed PPARγ agonists in dealing with diabetic kidney disease. At the same time, the new insights into the therapeutic strategies of DN based on the PPARγ agonists were fully addressed.

  13. Regulation of Glial Cell Functions by PPAR-γ Natural and Synthetic Agonists

    Directory of Open Access Journals (Sweden)

    Luisa Minghetti

    2008-04-01

    Full Text Available In the recent years, the peroxisome proliferator-activated receptor-γ (PPAR-γ, a well known target for type II diabetes treatment, has received an increasing attention for its therapeutic potential in inflammatory and degenerative brain disorders. PPAR-γ agonists, which include naturally occurring compounds (such as long chain fatty acids and the cyclopentenone prostaglandin 15-deoxy Δ12,14 prostaglandin J2, and synthetic agonists (among which the thiazolidinediones and few nonsteroidal anti-inflammatory drugs have shown anti-inflammatory and protective effects in several experimental models of Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, multiple sclerosis and stroke, as well as in few clinical studies. The pleiotropic effects of PPAR-γ agonists are likely to be mediated by several mechanisms involving anti-inflammatory activities on peripheral immune cells (macrophages and lymphocytes, as well as direct effects on neural cells including cerebral vascular endothelial cells, neurons, and glia. In the present article, we will review the recent findings supporting a major role for PPAR-γ agonists in controlling neuroinflammation and neurodegeneration through their activities on glial cells, with a particular emphasis on microglial cells as major macrophage population of the brain parenchyma and main actors in brain inflammation.

  14. Conversion of agonist site to metal-ion chelator site in the beta(2)-adrenergic receptor

    DEFF Research Database (Denmark)

    Elling, C E; Thirstrup, K; Holst, Birgitte;

    1999-01-01

    Previously metal-ion sites have been used as structural and functional probes in seven transmembrane receptors (7TM), but as yet all the engineered sites have been inactivating. Based on presumed agonist interaction points in transmembrane III (TM-III) and -VII of the beta(2)-adrenergic receptor,...

  15. Identification of novel IP receptor agonists using historical ligand biased chemical arrays.

    Science.gov (United States)

    McKeown, Stephen C; Charlton, Steven J; Cox, Brian; Fitch, Helen; Howson, Christopher D; Leblanc, Catherine; Meyer, Arndt; Rosethorne, Elizabeth M; Stanley, Emily

    2014-05-15

    By considering published structural information we have designed high throughput biaryl lipophilic acid arrays leveraging facile chemistry to expedite their synthesis. We rapidly identified multiple hits which were of suitable IP agonist potency. These relatively simple and strategically undecorated molecules present an ideal opportunity for optimization towards our target candidate profile. PMID:24736116

  16. Gonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist assisted reproductive technology cycles

    NARCIS (Netherlands)

    M.A.F.M. Youssef; F. van der Veen; H.G. Al-Inany; G. Griesinger; M.H. Mochtar; M. van Wely

    2010-01-01

    Background Gonadotropin-releasing hormone (GnRH) antagonist protocols for pituitary down regulation in in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) allow the use of GnRH agonists for triggering final oocyte maturation. Currently, human chorionic gonadotropin (HCG) is stil

  17. Bioanalysis and pharmacokinetics of the dopamine D2 agonist N-0923

    NARCIS (Netherlands)

    Swart, Pieter Jacob

    1992-01-01

    This thesis describes the bioanalysis and pharmacokinetics of the S(-) enantiomer (N-0923) of the selective and potent dopamine D2 agonist 2-(N-propyl-N-2-thienylethyl-amino)-5-hydroxytetralin, N-0437 which has possible applications in the treatment of Parkinson’s disease. The R(+) enantiomer (N-092

  18. The Anti-diabetic Effects of GLP-1-gastrin Dual Agonist ZP3022 in ZDF rats

    DEFF Research Database (Denmark)

    Skarbaliene, Jolanta; Secher, Thomas; Jelsing, Jacob;

    2015-01-01

    AIMS/HYPOTHESIS: Combination treatment with exendin-4 and gastrin has proven beneficial in treatment of diabetes and preservation of beta cell mass in diabetic mice. Here, we examined the chronic effects of a GLP-1-gastrin dual agonist ZP3022 on glycemic control and beta cell dysfunction in overtly...

  19. Local immunotherapy based on agonistic CD40 antibodies effectively inhibits experimental bladder cancer

    OpenAIRE

    Sandin, Linda C; Tötterman, Thomas H; Sara M. Mangsbo

    2014-01-01

    Local immunotherapy resurfaces in the field of cancer as a potential way to cure localized and metastatic disease with limited toxic effects. We have recently demonstrated that local administration of agonistic CD40 antibodies can cure localized as well as disseminated bladder neoplasms. This approach reduces the circulating concentrations of antibodies that would result from systemic delivery, hence resulting in limited toxicity.

  20. Intersubunit bridge formation governs agonist efficacy at nicotinic acetylcholine alpha4beta2 receptors

    DEFF Research Database (Denmark)

    Rohde, Line Aagot Hede; Ahring, Philip Kiær; Jensen, Marianne Lerbech; Nielsen, Elsebet Østergaard; Peters, Dan; Helgstrand, Charlotte; Krintel, Christian; Harpsøe, Kasper; Gajhede, Michael; Kastrup, Jette Sandholm; Balle, Thomas

    2012-01-01

    efficacy of a compound appears tightly coupled to its ability to form a strong inter-subunit bridge linking the primary and complementary binding interfaces. For the tested agonists, a specific halogen bond was observed to play a large role in establishing such strong inter-subunit anchoring....

  1. New metabolically stabilized analogues of lysophosphatidic acid: agonists, antagonists and enzyme inhibitors.

    Science.gov (United States)

    Prestwich, G D; Xu, Y; Qian, L; Gajewiak, J; Jiang, G

    2005-12-01

    Lysophosphatidic acid (LPA) is a metabolically labile natural phospholipid with a bewildering array of physiological effects. We describe herein a variety of long-lived receptor-specific agonists and antagonists for LPA receptors. Several LPA and PA (phosphatidic acid) analogues also inhibit LPP (lipid phosphate phosphatase). The sn-1 or sn-2 hydroxy groups have been replaced by fluorine, difluoromethyl, difluoroethyl, O-methyl or O-hydroxyethoxy groups to give non-migrating LPA analogues that resist acyltransferases. Alkyl ether replacement of acyl esters produced lipase and acyltransferase-resistant analogues. Replacement of the bridging oxygen in the monophosphate by an alpha-monofluoromethylene-, alpha-bromomethylene- or alpha,alpha-difluoromethylenephosphonate gave phosphatase-resistant analogues. Phosphorothioate analogues with O-acyl and O-alkyl chains are potent, long-lived agonists for LPA1 and LPA3 receptors. Most recently, we have (i) prepared stabilized O-alkyl analogues of lysobisphosphatidic acid, (ii) explored the structure-activity relationship of stabilized cyclic LPA analogues and (iii) synthesized neutral head group trifluoromethylsulphonamide analogues of LPA. Through collaborative studies, we have collected data for these stabilized analogues as selective LPA receptor (ant)agonists, LPP inhibitors, TREK (transmembrane calcium channel) K+ channel agonists, activators of the nuclear transcription factor PPAR-gamma (peroxisome-proliferator-activated receptor-gamma), promoters of cell motility and survival, and radioprotectants for human B-cells. PMID:16246118

  2. Effectiveness of Low Dose of Gonadotropin Releasing Hormone Agonist on Hormonal Flare-Up

    OpenAIRE

    Bständig, Bettina; Cédrin-Durnerin, Isabelle; Hugues, Jean Noël

    2000-01-01

    Purpose: The hormonal response (flare-up) followingadministration of a standard dose (100 μg) or a low dose(25 μg) of gonadotropin releasing hormone agonist(GnRH-a) (Triptorelin) was compared in patients prior to an in vitrofertilization (IVF) cycle and during the early follicular phaseof a short-term IVF protocol.

  3. Comparison of dexmedetomidine and lignocaine on attenuation of airway and pressor responses during tracheal extubation

    Directory of Open Access Journals (Sweden)

    Vivek Bharti Sharma

    2014-01-01

    Full Text Available Background: Haemodynamic stability and rapid emergence after general anaesthesia used in spinal surgery is a common practice, the goal of which is to permit early neurological motor and sensory examination. Extubation is almost always associated with hypertension, increased airway response and arrhythmias. We have compared the effects of the α-2 agonist Dexmedetomidine and Lignocaine given at the end of the procedure on attenuation of airway and pressor responses following tracheal extubation. This study is a randomised, placebo-controlled, double-blinded study. Materials and Methods: Sixty ASA I-III patients, aged 18-70 years, scheduled to undergo spinal surgery at the level of thoracic, lumbar or sacral region were randomly divided into three groups. Balanced general anaesthesia comprising standard procedures and drugs were used for monitoring, induction and maintenance. At the last skin suture, inhalation anaesthetic was discontinued. After turning the patient supine and return of spontaneous efforts, in Group D Dexmedetomidine 0.5 μg/kg, in Group L Lignocaine 1.5 mg/kg and in Group P normal saline (10 ml were administered as bolus intravenously over 60 seconds. Systolic, diastolic and mean arterial pressures and heart rate were recorded before intravenous administration and also every minute for 3 minutes, at 5, 10 and 15 minutes post-extubation. Duration of emergence and extubation were noted and attenuation of airway response and quality of extubation was evaluated on cough grading. Results: Mean arterial pressures and heart rate were higher in Group L and Group P than in Group D but not statistically significant. The duration of emergence, extubation and recovery were comparable in all the groups (P > 0.05. Extubation Quality Scores was 1 in 80%, 2 in 20% in Group D; in Group L, the quality scores were 1 for 55%, 2 for 45% and I Group P 1 for 35%, 2 for 45% and 3 for 20% of the patients. The requirement of rescue analgesia was also less

  4. Modulation of TLR3/TLR4 inflammatory signaling by the GABAB receptor agonist baclofen in glia and immune cells: relevance to therapeutic effects in multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Tadhg eCrowley

    2015-07-01

    Full Text Available The GABAB receptor agonist, baclofen, is used to treat muscle tightness and cramping caused by spasticity in a number of disorders including Multiple Sclerosis (MS, but its precise mechanism of action is unknown. Neuroinflammation drives the central pathology in MS and is mediated by both immunoreactive glial cells and invading lymphocytes. Furthermore, a body of data indicates that the Toll-like receptor (TLR family of innate immune receptors is implicated in MS progression. In the present study we investigated whether modulation of GABAB receptors using baclofen can exert anti-inflammatory effects by targeting TLR3 and(or TLR4-induced inflammatory signaling in murine glial cells and human peripheral blood mononuclear cells (PBMCs isolated from healthy control individuals and patients with the relapse-remitting (RR form of MS. TLR3 and TLR4 stimulation promoted the nuclear sequestration of NF-κB and pro-inflammatory cytokine expression in murine glia, while TLR4, but not TLR3, promoted pro-inflammatory cytokine expression in PBMCs isolated from both healthy donors and RR-MS patients. Importantly, this effect was exacerbated in RR-MS patient immune cells. We present further evidence that baclofen dose-dependently attenuated TLR3- and TLR4-induced inflammatory signaling in primary glial cells. Pre-exposure of PBMCs isolated from healthy donors to baclofen attenuated TLR4-induced TNF-α expression, but did not affect TLR4-induced TNF-α expression in RR-MS patient PBMCs. Interestingly, mRNA expression of the GABAB receptor was reduced in PBMCs from RR-MS donors when compared to healthy controls, an effect that might contribute to the differential sensitivity to baclofen seen in healthy and RR-MS patient cells. Overall these findings indicate that baclofen differentially regulates TLR3 and TLR4 signaling in glia and immune cells, and offers insight on the role of baclofen in the treatment of neuroinflammatory disease states including MS.

  5. Differential effects of LY235959, a competitive antagonist of the NMDA receptor on kappa-opioid receptor agonist induced responses in mice and rats.

    Science.gov (United States)

    Bhargava, H N; Thorat, S N

    1997-02-01

    The effects of the competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, LY235959, were determined on the analgesic and hypothermic effects as well as on the development of tolerance to these effects of U-50,488H, a kappa-opioid receptor agonist in mice and rats. In the mouse, a single injection of LY235959 given 10 min prior to U-50,488H did not modify the analgesic action of the latter. Similarly, chronic administration of LY235959 twice a day for 4 days did not modify U-50,488H-induced analgesia in mice. Repeated pretreatment of mice with LY235959 dose-dependently attenuated the development of tolerance to the analgesic actions of U-50,488H. In the rat, LY235959 by itself produced a significant analgesia and prior treatment of rats with LY235959 enhanced the analgesic action of U-50,488H. Similar effects were seen with the hypothermic action. Pretreatment of rats with LY235959 attenuated the development of tolerance to the analgesic but not to the hypothermic action of U-50,488H. These results provide evidence that LY235959 produces differential actions on nociception and thermic responses by itself and when given acutely with U-50,488H in mice and rats. However, when the animals are pretreated with LY235959, similar inhibitory effects are observed on the development of tolerance to the analgesic action of U-50,488H in both the species. These studies demonstrate an involvement of the NMDA receptor in the development of kappa-opioid tolerance and suggest that the biochemical consequences of an opioid's interaction with the opioid receptor are not the only factors that contribute to the acute and chronic actions of opioid analgesic drugs. PMID:9045999

  6. Functional potencies of dopamine agonists and antagonists at human dopamine D₂ and D₃ receptors.

    Science.gov (United States)

    Tadori, Yoshihiro; Forbes, Robert A; McQuade, Robert D; Kikuchi, Tetsuro

    2011-09-01

    We measured the functional agonist potencies of dopamine agonists including antiparkinson drugs, and functional antagonist potencies of antipsychotics at human dopamine D(2) and D(3) receptors. In vitro pharmacological assessment included inhibition of forskolin-stimulated cAMP accumulation and the reversal of dopamine-induced inhibition in clonal Chinese hamster ovary cells expressing low and high densities of human dopamine D(2L) and D(2S) receptors (hD(2L)-Low, hD(2L)-High, hD(2S)-Low and hD(2S)-High, respectively) and human dopamine D(3) Ser-9 and D(3) Gly-9 receptors (hD(3)-Ser-9 and hD(3)-Gly-9, respectively). Cabergoline, bromocriptine, pergolide, (±)-7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), talipexole, pramipexole, R-(+)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-olhydrochloride (PD128907) and ropinirole behaved as dopamine D(2) and D(3) receptor full agonists and showed higher potencies in hD(2L)-High and hD(2S)-High compared to hD(2L)-Low and hD(2S)-Low. In hD(3)-Ser-9 and hD(3)-Gly-9 compared to hD(2L)-Low and hD(2S)-Low, dopamine, ropinirole, PD128907, and pramipexole potencies were clearly higher; talipexole and 7-OH-DPAT showed slightly higher potencies; pergolide showed slightly lower potency; and, cabergoline and bromocriptine potencies were lower. Aripiprazole acted as an antagonist in hD(2L)-Low; a low intrinsic activity partial agonist in hD(2S)-Low; a moderate partial agonist in hD(3)-Ser-9 and hD(3)-Gly-9; a robust partial agonist in hD(2L)-High; and a full agonist in hD(2S)-High. Amisulpride, sulpiride and perphenazine behaved as preferential antagonists; and chlorpromazine and asenapine behaved as modest preferential antagonists; whereas fluphenazine, haloperidol, and blonanserin behaved as non-preferential antagonists in hD(2S)-Low and hD(2S)-High compared to hD(3)-Ser-9 and hD(3)-Gly-9. These findings may help to elucidate the basis of therapeutic benefit observed with these drugs, with

  7. Importance of Attenuation Correction (AC for Small Animal PET Imaging

    Directory of Open Access Journals (Sweden)

    Henrik H. El Ali

    2012-10-01

    Full Text Available The purpose of this study was to investigate whether a correction for annihilation photon attenuation in small objects such as mice is necessary. The attenuation recovery for specific organs and subcutaneous tumors was investigated. A comparison between different attenuation correction methods was performed. Methods: Ten NMRI nude mice with subcutaneous implantation of human breast cancer cells (MCF-7 were scanned consecutively in small animal PET and CT scanners (MicroPETTM Focus 120 and ImTek’s MicroCATTM II. CT-based AC, PET-based AC and uniform AC methods were compared. Results: The activity concentration in the same organ with and without AC revealed an overall attenuation recovery of 9–21% for MAP reconstructed images, i.e., SUV without AC could underestimate the true activity at this level. For subcutaneous tumors, the attenuation was 13 ± 4% (9–17%, for kidneys 20 ± 1% (19–21%, and for bladder 18 ± 3% (15–21%. The FBP reconstructed images showed almost the same attenuation levels as the MAP reconstructed images for all organs. Conclusions: The annihilation photons are suffering attenuation even in small subjects. Both PET-based and CT-based are adequate as AC methods. The amplitude of the AC recovery could be overestimated using the uniform map. Therefore, application of a global attenuation factor on PET data might not be accurate for attenuation correction.

  8. Attenuation characteristics of ultrasonic pulse in carbon/phenolic composite

    International Nuclear Information System (INIS)

    The presence of porosity in a fiber-reinforced composite may have a critical effect on the composite's mechanical properties and service performance. Detection and characterization of porosity by nondestructive, especially ultrasonic, testing have received considerable attention in recent years. In this paper, the velocity and attenuation of longitudinal and shear ultrasonic pulse in carbon/phenolic composite were measured using through-transmission technique. And the attenuation characteristics were determined and analyzed as a function of frequency. These results show that the main mechanism of attenuation is Rayleigh scattering from porosity and the change of the volume fraction of porosity is associated with that of attenuation slope.

  9. Rain Attenuation Analysis using Synthetic Storm Technique in Malaysia

    Science.gov (United States)

    Lwas, A. K.; Islam, Md R.; Chebil, J.; Habaebi, M. H.; Ismail, A. F.; Zyoud, A.; Dao, H.

    2013-12-01

    Generated rain attenuation time series plays an important role for investigating the rain fade characteristics in the lack of real fade measurements. A suitable conversion technique can be applied to measured rain rate time series to produce rain attenuation data and be utilized to understand the rain fade characteristics. This paper focuses on applicability of synthetic storm technique (SST) to convert measured rain rate data to rain attenuation time series. Its performance is assessed for time series generation over a tropical location Kuala Lumpur, in Malaysia. From preliminary analysis, it is found that SST gives satisfactory results to estimate the rain attenuation time series from the rain rate measurements over this region.

  10. Damping factor estimation using spin wave attenuation in permalloy film

    International Nuclear Information System (INIS)

    Damping factor of a Permalloy (Py) thin film is estimated by using the magnetostatic spin wave propagation. The attenuation lengths are obtained by the dependence of the transmission intensity on the antenna distance, and decrease with increasing magnetic fields. The relationship between the attenuation length, damping factor, and external magnetic field is derived theoretically, and the damping factor was determined to be 0.0063 by fitting the magnetic field dependence of the attenuation length, using the derived equation. The obtained value is in good agreement with the general value of Py. Thus, this estimation method of the damping factor using spin waves attenuation can be useful tool for ferromagnetic thin films

  11. Systemic administration of the neurotensin NTS1 receptor agonist PD149163 improves performance on a memory task in naturally deficient male Brown Norway rats

    OpenAIRE

    Keiser, Ashley A.; Matazel, Katelin S.; Esser, Melissa K.; Feifel, David; Prus, Adam J.

    2014-01-01

    Agonists for neurotensin NTS1 receptor consistently exhibit antipsychotic effects in animal models without producing catalepsy, suggesting that NTS1 receptor agonists may be a novel class of drugs to treat schizophrenia. Moreover, studies utilizing NTS1 agonists have reported improvements in some aspects of cognitive functioning, including prepulse inhibition and learning procedures, that suggest an ability of NTS1 receptor agonists to diminish neurocognitive deficits. The present study sough...

  12. Antineoplastic Effects of PPARγ Agonists, with a Special Focus on Thyroid Cancer.

    Science.gov (United States)

    Ferrari, Silvia Martina; Materazzi, Gabriele; Baldini, Enke; Ulisse, Salvatore; Miccoli, Paolo; Antonelli, Alessandro; Fallahi, Poupak

    2016-01-01

    Peroxisome Proliferator-Activated Receptor-γ (PPARγ) is a ligand-activated nuclear hormone receptor that functions as transcription factor and plays an important role in lipid metabolism and insulin sensitization. Recent studies have shown that PPARγ is overexpressed in many tumor types, including cancers of breast, lung, pancreas, colon, glioblastoma, prostate and thyroid differentiated/anaplastic cancers. These data suggest a role of PPARγ in tumor development and/or progression. PPARγ is emerging as a growth-limiting and differentiation-promoting factor, and it exerts a tumor suppressor role. Moreover, naturally-occurring and synthetic PPARγ agonists promote growth inhibition and apoptosis. Thiazolidinediones (TZDs) are synthetic agonists of PPARγ that were developed to treat type II diabetes. These compounds also display anticancer effects which appear mainly to be independent of their PPARγ agonist activity. Various preclinical and clinical studies strongly suggest a role for TZDs both alone and in combination with existing chemotherapeutic agents, for the treatment of cancer. Differentiation therapy involves the use of agents with the ability to induce differentiation in cells that have lost this ability, i.e. cancer cells, targeting pathways capable of re-activating blocked terminal differentiation programs. PPARγ agonists have been shown to induce differentiation in solid tumors such as thyroid differentiated/ anaplastic cancers and sarcomas. However, emerging data suggest that chronic use of TZDs is associated with increased risk of adverse cardiovascular events. The exploration of newer PPARγ agonists can help in unveiling the underlying mechanisms of these drugs, providing new molecules that are able to treat cancer, without increasing the cardiovascular risk of neoplastic patients. PMID:26844838

  13. Evaluation of tocolytic efficacy of selective beta2 adrenoceptor agonists on buffalo uterus.

    Science.gov (United States)

    Garg, Satish K; Garg, K M; Sabir, M

    2004-09-01

    Present study was conducted on prostaglandin F2alpha (PGF2alpha), oxytocin, (OT), potassium chloride (KCI) and barium chloride (BaCl2) pre-contracted perimetrial uterine strips of dioestrus and pregnant buffaloes to evaluate the tocolytic efficacy of selective beta2 adrenoceptor agonists-albuterol (salbutamol) and terbutaline. Cumulative concentration-response curves of both the beta2 adrenoceptor agonists were constructed and the mean effective concentration (EC50) values determined and compared statistically. Based on the comparative EC50 values in relaxing the pre-contracted uterine strips with different spasmogens, the rank order potency of albuterol was found to be--PGF2alpha > BaCl2 > OT > KCl on uterine strips from dioestrus animals, while OT> BaCl2> PGF2alpha >KCl on the uterine strips of pregnant buffaloes. The rank order potency of terbutaline on uterine strips from dioestrus stage animals was- BaCl2 > OT > KCl > PGF2alpha, while BaCl2 > PGF2alpha > KCl > OT on uterine tissues of pregnant animals. Thus, irrespective of the state of uterus, whether gravid or non-gravid, KCl-depolarized uterine tissues required comparatively higher concentrations of albuterol or terbutaline to produce tocolytic effect. High concentrations of K+ in biophase may have interfered with the beta2 adrenoceptor agonists-induced outward K+ current and hyperpolarization. From the results of present study, it was evident that selective beta2 adrenergic agonists had good tocolytic efficacy on the uterus of buffaloes. Further, indirectly the possibility of existence and activation of K(Ca) channels by selective beta2 adrenoceptor agonists in mediating tocolysis of buffalo myometrium can not be ruled out, however, detailed studies using specific K(Ca) channel blockers are required for characterizing the nature of such channels in buffalo uterus. PMID:15462186

  14. Estrogen Receptor β Agonists Differentially Affect the Growth of Human Melanoma Cell Lines.

    Directory of Open Access Journals (Sweden)

    Monica Marzagalli

    Full Text Available Cutaneous melanoma is an aggressive malignancy; its incidence is increasing worldwide and its prognosis remains poor. Clinical observations indicate that estrogen receptor β (ERβ is expressed in melanoma tissues and its expression decreases with tumor progression, suggesting its tumor suppressive function. These experiments were performed to investigate the effects of ERβ activation on melanoma cell growth.Protein expression was analyzed by Western blot and immunofluorescence assays. Cell proliferation was assessed by counting the cells by hemocytometer. ERβ transcriptional activity was evaluated by gene reporter assay. Global DNA methylation was analyzed by restriction enzyme assay and ERβ isoforms were identified by qRT-PCR. We demonstrated that ERβ is expressed in a panel of human melanoma cell lines (BLM, WM115, A375, WM1552. In BLM (NRAS-mutant cells, ERβ agonists significantly and specifically inhibited cell proliferation. ERβ activation triggered its cytoplasmic-to-nuclear translocation and transcriptional activity. Moreover, the antiproliferative activity of ERβ agonists was associated with an altered expression of G1-S transition-related proteins. In these cells, global DNA was found to be hypomethylated when compared to normal melanocytes; this DNA hypomethylation status was reverted by ERβ activation. ERβ agonists also decreased the proliferation of WM115 (BRAF V600D-mutant cells, while they failed to reduce the growth of A375 and WM1552 (BRAF V600E-mutant cells. Finally, we could observe that ERβ isoforms are expressed at different levels in the various cell lines. Specific oncogenic mutations or differential expression of receptor isoforms might be responsible for the different responses of cell lines to ERβ agonists.Our results demonstrate that ERβ is expressed in melanoma cell lines and that ERβ agonists differentially regulate the proliferation of these cells. These data confirm the notion that melanoma is a

  15. Transient occult cardiotoxicity in children receiving continuous beta-agonist therapy

    Institute of Scientific and Technical Information of China (English)

    Christopher L Carroll; Melinda Coro; Allison Cowl; Kathleen A Sala; Craig M Schramm

    2014-01-01

    Background: Continuous beta-agonist therapy, typically in the form of inhaled albuterol, is the first line therapy for the treatment of acute and severe bronchospasm in children. Although this treatment is commonly used, concerns about cardiotoxicity have been raised. We aimed to investigate the cardiotoxic effects of continuous beta-agonist therapy in children. Methods: We conducted a retrospective review of children admitted to the intensive care unit (ICU) between May 2008 and April 2009, who were treated with continuous beta-agonist therapy (intravenous and nebulized). Results: Twenty of the 36 children treated with continuous albuterol had repeated serum troponin-T and lactate levels measured. Eleven patients (55%) were also treated with continuous intravenous terbutaline. Elevated levels of troponin-T levels were found in 25% of children, and elevated lactate levels were found in 60%. However, all returned to normal levels within 48 hours of ICU admission, despite continued beta-agonist therapy. No children experienced arrhythmias during therapy. There was no association between intravenous terbutaline use and elevated troponin-T [odds ratio (OR), 1.3; 95% CI, 0.2-10.3] or with elevated serum lactate (OR, 0.6; 95% CI, 0.1-3.7). There was also no association between elevated troponin-T or lactate and ICU or hospital length of stay. Conclusions: In this small study, a significant proportion of children had elevated serum troponin-T and lactate levels while receiving inhaled continuous beta-agonist therapy, irrespective of intravenous therapy. However, these abnormal values all returned to normal within 48 hours of ICU admission and were not associated with increased duration of hospitalization.

  16. Time and space profiling of NMDA receptor co-agonist functions.

    Science.gov (United States)

    Mothet, Jean-Pierre; Le Bail, Matildé; Billard, Jean-Marie

    2015-10-01

    The N-Methyl D-Aspartic acid (NMDA) receptors (NMDAR) are key tetrameric ionotropic glutamate receptors that transduce glutamatergic signals throughout the central nervous system (CNS) and spinal cord. Although NMDARs are diverse in their subunit composition, subcellular localization, and biophysical and pharmacological properties, their activation always requires the binding of a co-agonist that has long been thought to be glycine. However, intense research over the last decade has challenged this classical model by showing that another amino acid, d-serine, is the preferential co-agonist for a subset of synaptic NMDARs in many areas of the adult brain. Nowadays, a totally new picture of glutamatergic synapses at work is emerging where both glycine and d-serine are involved in a complex interplay to regulate NMDAR functions in the CNS following time and space constraints. The purpose of this review was to highlight the particular role of each co-agonist in modulating NMDAR-dependent activities in healthy and diseased brains. We have herein integrated our most advanced knowledge of how glycine and d-serine may orchestrate synapse dynamics and drive neuronal network activity in a time- and synapse-specific manner and how changes in synaptic availability of these amino acids may contribute to cognitive impairments such as those associated with healthy aging, epilepsy, and schizophrenia. The N-Methyl D-Aspartic acid (NMDA) subtype of glutamate receptors are central to many physiological functions and are linked to brain disorders. Their functions require glutamate and a co-agonist d-serine or glycine. After years of intense research and controversy on the identity of the amino acid that serves as the right co-agonist, we are just entering a new era of consensus where glycine and d-serine are teaming up to regulate the function of different subsets of NMDA receptors and at different synapses during different time windows of brain development. PMID:26088787

  17. Heterologous Expression in Remodeled C. elegans: A Platform for Monoaminergic Agonist Identification and Anthelmintic Screening.

    Directory of Open Access Journals (Sweden)

    Wenjing Law

    2015-04-01

    Full Text Available Monoamines, such as 5-HT and tyramine (TA, paralyze both free-living and parasitic nematodes when applied exogenously and serotonergic agonists have been used to clear Haemonchus contortus infections in vivo. Since nematode cell lines are not available and animal screening options are limited, we have developed a screening platform to identify monoamine receptor agonists. Key receptors were expressed heterologously in chimeric, genetically-engineered Caenorhabditis elegans, at sites likely to yield robust phenotypes upon agonist stimulation. This approach potentially preserves the unique pharmacologies of the receptors, while including nematode-specific accessory proteins and the nematode cuticle. Importantly, the sensitivity of monoamine-dependent paralysis could be increased dramatically by hypotonic incubation or the use of bus mutants with increased cuticular permeabilities. We have demonstrated that the monoamine-dependent inhibition of key interneurons, cholinergic motor neurons or body wall muscle inhibited locomotion and caused paralysis. Specifically, 5-HT paralyzed C. elegans 5-HT receptor null animals expressing either nematode, insect or human orthologues of a key Gαo-coupled 5-HT1-like receptor in the cholinergic motor neurons. Importantly, 8-OH-DPAT and PAPP, 5-HT receptor agonists, differentially paralyzed the transgenic animals, with 8-OH-DPAT paralyzing mutant animals expressing the human receptor at concentrations well below those affecting its C. elegans or insect orthologues. Similarly, 5-HT and TA paralyzed C. elegans 5-HT or TA receptor null animals, respectively, expressing either C. elegans or H. contortus 5-HT or TA-gated Cl- channels in either C. elegans cholinergic motor neurons or body wall muscles. Together, these data suggest that this heterologous, ectopic expression screening approach will be useful for the identification of agonists for key monoamine receptors from parasites and could have broad application for

  18. Enhanced Attenuation Technologies: Passive Soil Vapor Extraction

    Energy Technology Data Exchange (ETDEWEB)

    Vangelas, K.; Looney, B.; Kamath, R.; Adamson, D.; Newell, C.

    2010-03-15

    Passive soil vapor extraction (PSVE) is an enhanced attenuation (EA) approach that removes volatile contaminants from soil. The extraction is driven by natural pressure gradients between the subsurface and atmosphere (Barometric Pumping), or by renewable sources of energy such as wind or solar power (Assisted PSVE). The technology is applicable for remediating sites with low levels of contamination and for transitioning sites from active source technologies such as active soil vapor extraction (ASVE) to natural attenuation. PSVE systems are simple to design and operate and are more cost effective than active systems in many scenarios. Thus, PSVE is often appropriate as an interim-remedial or polishing strategy. Over the past decade, PSVE has been demonstrated in the U.S. and in Europe. These demonstrations provide practical information to assist in selecting, designing and implementing the technology. These demonstrations indicate that the technology can be effective in achieving remedial objectives in a timely fashion. The keys to success include: (1) Application at sites where the residual source quantities, and associated fluxes to groundwater, are relatively low; (2) Selection of the appropriate passive energy source - barometric pumping in cases with a deep vadose zone and barrier (e.g., clay) layers that separate the subsurface from the atmosphere and renewable energy assisted PSVE in other settings and where higher flow rates are required. (3) Provision of sufficient access to the contaminated vadose zones through the spacing and number of extraction wells. This PSVE technology report provides a summary of the relevant technical background, real-world case study performance, key design and cost considerations, and a scenario-based cost evaluation. The key design and cost considerations are organized into a flowchart that dovetails with the Enhanced Attenuation: Chlorinated Organics Guidance of the Interstate Technology and Regulatory Council (ITRC). The PSVE

  19. Definition of Genetically Distinct Attenuation Mechanisms in Naturally Virulence-Attenuated Listeria monocytogenes by Comparative Cell Culture and Molecular Characterization

    OpenAIRE

    Roberts, Angela; Chan, Yvonne; Wiedmann, Martin

    2005-01-01

    Listeria monocytogenes is a foodborne pathogen able to cause serious disease in humans and animals. Not all isolates are equally pathogenic, however, and several isolates have been characterized as naturally virulence attenuated. We sought to identify the genetic basis of natural virulence attenuation using cell culture assays and molecular techniques. By comparing the phenotypes of naturally virulence-attenuated isolates to those of defined virulence gene mutants in plaque, cytotoxicity, and...

  20. Core disgust is attenuated by ingroup relations.

    Science.gov (United States)

    Reicher, Stephen D; Templeton, Anne; Neville, Fergus; Ferrari, Lucienne; Drury, John

    2016-03-01

    We present the first experimental evidence to our knowledge that ingroup relations attenuate core disgust and that this helps explain the ability of groups to coact. In study 1, 45 student participants smelled a sweaty t-shirt bearing the logo of another university, with either their student identity (ingroup condition), their specific university identity (outgroup condition), or their personal identity (interpersonal condition) made salient. Self-reported disgust was lower in the ingroup condition than in the other conditions, and disgust mediated the relationship between condition and willingness to interact with target. In study 2, 90 student participants smelled a sweaty target t-shirt bearing either the logo of their own university, another university, or no logo, with either their student identity or their specific university identity made salient. Walking time to wash hands and pumps of soap indicated that disgust was lower where the relationship between participant and target was ingroup rather than outgroup or ambivalent (no logo). PMID:26903640