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Sample records for cholecystokinin receptor exists

  1. Cannabinoid receptors and cholecystokinin in feeding inhibition.

    Science.gov (United States)

    Alén, Francisco; Ramírez-López, M Teresa; Gómez de Heras, Raquel; Rodríguez de Fonseca, Fernando; Orio, Laura

    2013-01-01

    The endocannabinoid system functions as a potent regulator of feeding behavior and energy balance through complex central and peripheral mechanisms. Recent findings have demonstrated the existence of cooperation between peripheral cannabinoid CB1 receptors and the satiety hormone cholecystokinin (CCK). The two systems have opposing actions in the modulation of feeding: while endocannabinoids such as anandamide promote feeding, CCK controls gastrointestinal motility and appetite suppression. In this review, we examine the individual contribution of endocannabinoids and CCK in the modulation of appetite and explore the interaction between the two systems. We also highlight the potential benefits of simultaneously targeting peripheral CB1 and CCK1 receptors to design new therapies to fight obesity. Copyright © 2013 Elsevier Inc. All rights reserved.

  2. Cholecystokinin and gastrin receptors targeting in gastrointestinal cancer.

    Science.gov (United States)

    Rai, Rajani; Chandra, Vishal; Tewari, Mallika; Kumar, Mohan; Shukla, Hari S

    2012-12-01

    Cholecystokinin and Gastrin are amongst the first gastrointestinal hormone discovered. In addition to classical actions (contraction of gallbladder, growth and secretion in the stomach and pancreas), these also act as growth stimulants for gastrointestinal malignancies and cell lines. Growth of these tumours is inhibited by antagonists of the cholecystokinin and gastrin receptors. These receptors provides most promising approach in clinical oncology and several specific radiolabelled ligands have been synthesized for specific tumour targeting and therapy of tumours overexpressing these receptors. Therefore, definition of the molecular structure of the receptor involved in the autocrine/paracrine loop may contribute to novel therapies for gastrointestinal cancer. Hence, this review tries to focus on the role and distribution of these hormones and their receptors in gastrointestinal cancer with a brief talk about the clinical trial using available agonist and antagonist in gastrointestinal cancers.

  3. Cholecystokinin receptor-1 mediates the inhibitory effects of exogenous cholecystokinin octapeptide on cellular morphine dependence

    Directory of Open Access Journals (Sweden)

    Wen Di

    2012-06-01

    Full Text Available Abstract Background Cholecystokinin octapeptide (CCK-8, the most potent endogenous anti-opioid peptide, has been shown to regulate the processes of morphine dependence. In our previous study, we found that exogenous CCK-8 attenuated naloxone induced withdrawal symptoms. To investigate the precise effect of exogenous CCK-8 and the role of cholecystokinin (CCK 1 and/or 2 receptors in morphine dependence, a SH-SY5Y cell model was employed, in which the μ-opioid receptor, CCK1/2 receptors, and endogenous CCK are co-expressed. Results Forty-eight hours after treating SH-SY5Y cells with morphine (10 μM, naloxone (10 μM induced a cAMP overshoot, indicating that cellular morphine dependence had been induced. The CCK receptor and endogenous CCK were up-regulated after chronic morphine exposure. The CCK2 receptor antagonist (LY-288,513 at 1–10 μM inhibited the naloxone-precipitated cAMP overshoot, but the CCK1 receptor antagonist (L-364,718 did not. Interestingly, CCK-8 (0.1-1 μM, a strong CCK receptor agonist, dose-dependently inhibited the naloxone-precipitated cAMP overshoot in SH-SY5Y cells when co-pretreated with morphine. The L-364,718 significantly blocked the inhibitory effect of exogenous CCK-8 on the cAMP overshoot at 1–10 μM, while the LY-288,513 did not. Therefore, the CCK2 receptor appears to be necessary for low concentrations of endogenous CCK to potentiate morphine dependence in SH-SY5Y cells. An additional inhibitory effect of CCK-8 at higher concentrations appears to involve the CCK1 receptor. Conclusions This study reveals the difference between exogenous CCK-8 and endogenous CCK effects on the development of morphine dependence, and provides the first evidence for the participation of the CCK1 receptor in the inhibitory effects of exogenous CCK-8 on morphine dependence.

  4. A synthetic peptide derivative that is a cholecystokinin receptor antagonist.

    Science.gov (United States)

    Lignon, M F; Galas, M C; Rodriguez, M; Laur, J; Aumelas, A; Martinez, J

    1987-05-25

    So far, there are no known peptidic effective receptor antagonists of both peripheral and central effects of cholecystokinin (CCK). Here, we describe a synthetic peptide derivative of CCK, t-butyloxycarbonyl-Tyr(SO3-)-Met-Gly-D-Trp-Nle-Asp 2-phenylethyl ester 1 (where Nle is norleucine), which is a potent CCK receptor antagonist. In rat and guinea pig dispersed pancreatic acini, this peptide derivative did not alter amylase secretion, but was able to antagonize the stimulation caused by cholecystokinin-related agonists. It caused a parallel rightward shift in the dose-response curve for the stimulation of amylase secretion with half-maximal inhibition of CCK-8-stimulated amylase release at a concentration of about 0.1 microM. Compound 1 was able to inhibit the binding of labeled CCK-9 (the C-terminal nonapeptide of CCK) to rat and guinea pig pancreatic acini (IC50 = 5 X 10(-8) M) as well as to guinea pig cerebral cortical membranes (IC50 = 5 X 10(-7) M). These results indicate that Compound 1 is a potent competitive CCK receptor antagonist.

  5. Control of gallbladder contractions by cholecystokinin through cholecystokinin-A receptors on gallbladder interstitial cells of cajal

    Institute of Scientific and Technical Information of China (English)

    Dan Xu; Bao-Ping Yu; He-Sheng Luo; Ling-Dan Chen

    2008-01-01

    AIM: To identify the cholecystokinin (CCK)-A receptors (CCK-AR) on the guniea pig gallbladder interstitial cells of cajal (ICC) and to study CCK-8 induced gallbladder muscle strip contractions through the CCK-AR.METHODS: The existence of CCK-AR was examined by immunohistofluorescence on sectioned tissue and cultured cells. In vitro contractile response of guinea pig gallbladder muscle strips and the strips with ICC removed were also studied with CCK-8 receptors added.RESULTS: In tissue sections, intensely CCKARimmunoreactive interstitial cells were found mainly in the muscular layers. In cultured cell sections, distinctive double staining of C-kit and CCK-AR ICCs were found.When we removed the ICC of the gallbladder, CCK-8induced muscle strip contraction dose response curve significantly shifted to the right.CONCLUSION: We proved that both the existence of CCK-AR on the guinea pig gallbladder ICC and CCK evoked contraction are mediated through direct action on CCK-AR on the gallbladder ICC.

  6. Gallbladder motor function, plasma cholecystokinin and cholecystokinin receptor of gallbladder in cholesterol stone patients

    Institute of Scientific and Technical Information of China (English)

    Jian Zhu; Tian-Quan Han; Sheng Chen; Yu Jiang; Sheng-Dao Zhang

    2005-01-01

    AIM: To study the interactive relationship of gallbladder motor function, plasma cholecystokinin (CCK) and cholecystokinin A receptor (CCK-R) of gallbladder in patients with cholesterol stone disease.METHODS: Gallbladder motility was studied by ultrasonography in 33 patients with gallbladder stone and 10 health subjects as controls. Plasma CCK concentration was measured by radioimmunoassay in fasting status (CCK-f) and in 30 min after lipid test meal (CCK-30).Radioligand method was employed to analyze the amount and activity of CCK-R from 33 gallstone patients having cholecystectomy and 8 persons without gallstone died of severe trauma as controls.RESULTS: The percentage of cholesterol in the gallstone composition was more than 70%. The cholesterol stone type was indicated for the patients with gallbladder stone in this study. Based on the criterion of gallbladder residual fraction of the control group, 33 gallstone patients were divided into two subgroups, contractor group (14 cases)and non-contractor group (19 cases), The concentration of CCK-30 was significantly higher in non-contractor group than that in both contractor group and control group (55.86±3.86 pmol/l vs 37.85±0.88 pmol/l and 37.95±0.74 pmol/L, P<0.01), but there was no difference between contractor group and control group. Meanwhile no significant difference of the concentration of CCK-f could be observed among three groups. The amount of CCK-R was lower in non-contractor group than those in both control group and contractor group (10.27±0.94 fmol/mg vs24.59±2.39 fmol/mg and 22.66±0.55 fmol/mg, P<0.01).The activity of CCK-R shown as KD in non-contractor group decreased compared to that in control group and contractor group. Only was the activity of CCK-R lower in contractor group than that in control group. The ejection fraction correlated closely with the amount of CCK-R (r = 0.9683,P<0.01), and the concentration of CCK-30 correlated negatively with the amount of CCK-R closely (r = -0

  7. Bovine gallbladder muscularis: Source of a myogenic receptor for cholecystokinin

    Energy Technology Data Exchange (ETDEWEB)

    Schjoldager, B.; Shaw, M.J.; Powers, S.P.; Schmalz, P.E.; Szurszewski, J.; Miller, L.J. (Mayo Clinic and Foundation, Rochester, MN (USA))

    1988-03-01

    Despite being a classic target for the gastrointestinal peptide hormone, cholecystokinin (CCK), the gallbladder CCK receptor is not well characterized. Pharmacological studies of small species suggest that CCK action can be mediated by direct myogenic or by both myogenic and neurogenic receptors. To prepare for the biochemical characterization of a gallbladder CCK receptor and to define the subtype of the receptor being studied. The authors have performed autoradiographic localization and pharmacological characterization of CCK receptors on bovine gallbladder. Autoradiography demonstrated high-affinity specific CCK-binding sites only on the muscularis. CCK-8 stimulated tonic contraction of longitudinal strips of gallbladder muscularis in a concentration-dependent manner. Antagonism at the cholinergic receptor with 1{mu}M atropine or axonal transmission with 1{mu}M tetrodotoxin did not modify CCK-induced contraction, supporting a direct myogenic effect of this hormone. Optimal electrical field stimulation to elicit a neuronal response resulted in muscle strip relaxation, which was abolished with adrenergic blockade. Although acetylcholine administration stimulated contraction, electrical field stimulation did not, even in the presence of phentolamine, propranolol, and/or CCK. Thus, in bovine gallbladder muscularis, there is evidence for a functional CCK receptor only on smooth muscle cells. Demonstration of a single, high-affinity specific CCK-binding site on an enriched plasma membrane preparation of bovine gallbladder muscularis is consistent with this representing a myogenic CCK receptor.

  8. Role of cholecystokinin and central serotonergic receptors in functional dyspepsia

    Institute of Scientific and Technical Information of China (English)

    Andrew Seng Boon Chua; PWN Keeling; TG Dinan

    2006-01-01

    Symptoms of functional dyspepsia are characterized by upper abdominal discomfort or pain, early satiety, postprandial fullness, bloating, nausea and vomiting. It is a chronic disorder, with symptoms more than 3 mo per year, and no evidence of organic diseases. Dysfunctional motility, altered visceral sensation, and psychosocial factors have all been identified as major pathophysiological mechanisms. It is believed that these pathophysiological mechanisms interact to produce the observed symptoms.Dyspepsia has been categorized into three subgroups based on dominant symptoms. Dysmotility-like dyspepsia describes a subgroup of patients whose symptom complex is usually related to a gastric sensorimotor dysfunction. The brain-gut peptide cholecystokinin (CCK)and serotonin (5-HT) share certain physiological effects.Both have been shown to decrease gastric emptying and affect satiety. Furthermore the CCK induced anorexia depended on serotonergic functions probably acting via central pathways. We believe that abnormalities of central serotonergic receptors functioning together with a hyper responsiveness to CCK or their interactions may be responsible for the genesis of symptoms in functional dyspepsia (FD).

  9. The cholecystokinin-B receptor antagonist CI-988 failed to affect CCK-4 induced symptoms in panic disorder patients

    NARCIS (Netherlands)

    vanMegen, HJGM; Westenberg, HGM; denBoer, JA; Slaap, B; vanEsRadhakishun, F; Pande, AC

    1997-01-01

    The effects of the cholecystokinin-B (CCK-B) receptor antagonist CI-988 on symptoms elicited by the cholecystokinin tetrapeptide (CCK4) were studied in DSM-IIIR patients with panic disorder. The study employed a double-blind, two-period incomplete block design. Patients (n = 14) received two differe

  10. Functional synergy between cholecystokinin receptors CCKAR and CCKBR in mammalian brain development.

    Science.gov (United States)

    Nishimura, Sayoko; Bilgüvar, Kaya; Ishigame, Keiko; Sestan, Nenad; Günel, Murat; Louvi, Angeliki

    2015-01-01

    Cholecystokinin (CCK), a peptide hormone and one of the most abundant neuropeptides in vertebrate brain, mediates its actions via two G-protein coupled receptors, CCKAR and CCKBR, respectively active in peripheral organs and the central nervous system. Here, we demonstrate that the CCK receptors have a dynamic and largely reciprocal expression in embryonic and postnatal brain. Using compound homozygous mutant mice lacking the activity of both CCK receptors, we uncover their additive, functionally synergistic effects in brain development and demonstrate that CCK receptor loss leads to abnormalities of cortical development, including defects in the formation of the midline and corpus callosum, and cortical interneuron migration. Using comparative transcriptome analysis of embryonic neocortex, we define the molecular mechanisms underlying these defects. Thus we demonstrate a developmental, hitherto unappreciated, role of the two CCK receptors in mammalian neocortical development.

  11. Effect of ghrelin receptor antagonist on meal patterns in cholecystokinin type 1 receptor null mice.

    Science.gov (United States)

    Lee, Jennifer; Martin, Elizabeth; Paulino, Gabriel; de Lartigue, Guillaume; Raybould, Helen E

    2011-05-03

    Vagal afferent neurons (VAN) express the cholecystokinin (CCK) type 1 receptor (CCK₁R) and, as predicted by the role of CCK in inducing satiation, CCK₁R⁻/⁻ mice ingest larger and longer meals. However, after a short fast, CCK₁R⁻/⁻ mice ingesting high fat (HF) diets initiate feeding earlier than wild-type mice. We hypothesized that the increased drive to eat in CCK₁R⁻/⁻ mice eating HF diet is mediated by ghrelin, a gut peptide that stimulates food intake. The decrease in time to first meal, and the increase in meal size and duration in CCK₁R⁻/⁻ compared to wild-type mice ingesting high fat (HF) diet were reversed by administration of GHSR1a antagonist D-(Lys3)-GHRP-6 (p<0.05). Administration of the GHSR1a antagonist significantly increased expression of the neuropeptide cocaine and amphetamine-regulated transcript (CART) in VAN of HF-fed CCK₁R⁻/⁻ but not wild-type mice. Administration of the GHSR1a antagonist decreased neuronal activity measured by immunoreactivity for fos protein in the nucleus of the solitary tract (NTS) and the arcuate nucleus of both HF-fed wild-type and CCK₁R⁻/⁻ mice. The data show that hyperphagia in CCK₁R⁻/⁻ mice ingesting HF diet is reversed by blockade of the ghrelin receptor, suggesting that in the absence of the CCK₁R, there is an increased ghrelin-dependent drive to feed. The site of action of ghrelin receptors is unclear, but may involve an increase in expression of CART peptide in VAN in HF-fed CCK₁R⁻/⁻ mice.

  12. Effect of lipopolysaccharide on expression and characterization of cholecystokinin receptors in rat pulmonary interstitial macrophages

    Institute of Scientific and Technical Information of China (English)

    Shun-jiang XU; Wei-juan GAO; Bin CONG; Yu-xia YAO; Zhen-yong GU

    2004-01-01

    AIM: To investigate the effect of lipopolysaccharide (LPS) on the expression and the binding characteristics of cholecystokinin receptors (CCK-R) in rat pulmonary interstitial macrophages (PIMs). METHODS: The PIMs isolated from rat lung tissues were purified by the collagenase digestion method combined with alveolar lavage and pulmonary vessel perfusion. The expression of CCK-R mRNA was detected by RT-PCR and Southern blot analysis and the binding experiments were performed by radioligand binding assay (RBA). RESULTS: CCK-A receptor (CCK-AR) and CCK-B receptor (CCK-BR) mRNA were detected in rat PIMs and their RT-PCR amplified products had a size of approximately 1.37 kb and 480 bp, respectively. The relative expression of CCK-BR mRNA was higher than that of CCK-AR mRNA after incubation with LPS for 0.5, 2, and 6 h. The expression of CCK-R mRNA could be upregulated obviously by LPS. Southern blot analysis of RT-PCR amplified CCK-AR and CCK-BR mRNA products using [γ-32p]ATP 5′-end-labelled probe showed specific hybridization bands. The specific binding of [3H] CCK-8S to rat PIM membranes was detected in the rats administered with LPS for 48 h, but not in normal rats.Scatchard analysis of the saturation curves suggested the presence of CCK-R with a high affinity (Kd=0.68+0.28 nmol/L) and a low binding capacity (Bmax=32.5+2.7 fmol.mg-1 protein) in rat PIMs. The specific binding of [3H] CCK-8S to rat PIM membranes was inhibited by unlabelled CCK-8S (ICs0=2.3±0.8 nmol/L), CCK-AR specific antagonist CR1409 (IC50=0.19±0.06 μrmol/L) and CCK-BR specific antagonist CR2945 (IC50=3.2± 1.1 nmol/L).CONCLUSION: Two types of functional CCK-AR and CCK-BR existed in rat PIMs and their expression could be upregulated by LPS.

  13. Fluorescence characteristics of hydrophobic partial agonist probes of the cholecystokinin receptor.

    Science.gov (United States)

    Harikumar, Kaleeckal G; Pinon, Delia I; Miller, Laurence J

    2006-04-01

    Fluorescence spectroscopic studies are powerful tools for the evaluation of receptor structure and the dynamic changes associated with receptor activation. Here, we have developed two chemically distinct fluorescent probes of the cholecystokinin (CCK) receptor by attaching acrylodan or a nitrobenzoxadiazole moiety to the amino terminus of a partial agonist CCK analogue. These two probes were able to bind to the CCK receptor specifically and with high affinity, and were able to elicit only submaximal intracellular calcium responses typical of partial agonists. The fluorescence characteristics of these probes were compared with those previously reported for structurally-related full agonist and antagonist probes. Like the previous probes, the partial agonist probes exhibited longer fluorescence lifetimes and increased anisotropy when bound to the receptor than when free in solution. The receptor-bound probes were not easily quenched by potassium iodide, suggesting that the fluorophores were protected from the extracellular aqueous milieu. The fluorescence characteristics of the partial agonist probes were quite similar to those of the analogous full agonist probes and quite distinct from the analogous antagonist probes. These data suggest that the partially activated conformational state of this receptor is more closely related to its fully active state than to its inactive state.

  14. An intron 1 polymorphism in the cholecystokinin-A receptor gene associated with schizophrenia in males

    DEFF Research Database (Denmark)

    2009-01-01

    OBJECTIVE: To identify whether a genetic variation (rs1800857; IVS1-5T>C) in the neuropeptide cholecystokinin-A receptor (CCKAR) gene is a risk factor in the pathogenesis of schizophrenia. METhod: The variation was analysed in a case-control design comprising 508 patients with schizophrenia...... risk allele was associated with an increased risk of 1.74 (Odds Ratio, OR) and homozygosity (CC) was associated with an OR of 3.19. The variation had no impact on protein synthesis of CCKAR. CONCLUSION: This is the first report associating the CCKAR gene variant with schizophrenia specifically in men...... and 1619 control subjects. A possible functional impact of this variant on CCKAR protein synthesis through alterations in splicing was analysed in an exon-trapping assay. RESULTS: In males only, the risk variant, IVS1-5C, was associated with a significantly increased risk of schizophrenia. Carrying one...

  15. Association analysis of the cholecystokinin type A receptor gene in schizophrenia

    Institute of Scientific and Technical Information of China (English)

    吕文天; 张萱; 张铭; 龚守良; 尉军

    2004-01-01

    @@ Schizophrenia is characterized by clinical heterogeneity and genetic heterogeneity. 1 Because dopamine(DA)overactivity has been thought, over the past 40 years, to play a role in the pathophysiology of schizophrenia, its receptors and metabolic enzymes have been regarded as potentially involved in schizophrenia. 2 However,disease-causing variants among the genes coding for dopamine receptors and the enzymes related to DA have not been found. Cholecystokinin A receptor (CCK-AR)coexists with DA in the same neurons of the midbrain limbic system, as well as the access to the substantia nigra and the corpus striatum, and it acts as a mediator modulating dopaminergic activity. 3 Two CCK receptors,CCK-AR and CCK B receptor (CCK-BR) have been identified. CCK-AR in the medial posterior nucleus accumbens increases DA release, while CCK-BR in the anterior nucleus accumbens decreases DA release. 4 The former has potential effects on human neuropsychiatric diseases linked to DA, such as schizophrenia. Recently,several studies found that the Pst I polymorphic site present in the boundary between intron 1 and exon 2 of the CCK-AR gene is associated with some symptoms of schizophrenia. This finding is particularly important for uncovering the genetic etiology of schizophrenia, although the mechanism linking this polymorphic site to the disease remains unclear. The present work is an attempt to confirm the genetic association between the CCK-AR gene and schizophrenia.

  16. Cholecystokinin receptor antagonism by peptidergic and non-peptidergic agents in rat pancreas.

    Science.gov (United States)

    Dembinski, A; Jaworek, J; Konturek, P K; Konturek, S J; Warzecha, Z

    1989-01-01

    1. Graded doses of bombesin infused I.V. into conscious rats with chronic pancreatic fistulae induced a dose-dependent stimulation of protein secretion, similar to that obtained with caerulein. This stimulation does not appear to be mediated by cholecystokinin (CCK) receptors because peptidergic (CR-1409) and non-peptidergic (L-364718) CCK antagonists failed to affect protein secretion at a dose range which caused almost complete suppression of caerulein-induced pancreatic secretion. 2. Studies in vitro on isolated rat pancreatic acini revealed that caerulein, pentagastrin and bombesin all showed the same efficacy in their ability to stimulate amylase release. In contrast, CCK antagonists competitively inhibited amylase release induced by caerulein and pentagastrin but not by bombesin or urecholine, indicating that the latter two agents act directly on acinar cells via receptors which are separate from those involved in stimulation induced by caerulein and pentagastrin. 3. DNA synthesis, measured by the incorporation of [3H]thymidine into DNA, was significantly stimulated by caerulein, soybean trypsin inhibitor (FOY 305), pentagastrin and by bombesin in a dose-dependent manner. CCK receptor antagonists prevented stimulation of DNA synthesis induced by caerulein, FOY 305 and pentagastrin but not by bombesin. 4. This study indicates that bombesin strongly stimulates pancreatic enzyme secretion, with an efficacy similar to that of caerulein, and also exerts a potent growth-promoting action on the pancreas, both effects appearing to be mediated by mechanisms independent of the CCK receptors. PMID:2614728

  17. Exogenous cholecystokinin-8 reduces vagal efferent nerve activity in rats through CCKA receptors

    Science.gov (United States)

    Bucinskaite, Violeta; Kurosawa, Mieko; Lundeberg, Thomas

    2000-01-01

    It has been proposed that the vagus nerve plays a role in mediating cholecystokinin-8 (CCK-8) effect on such gastric functions as motility, emptying and gastric acid secretion. To examine the contribution of the efferent pathways in realizing these effects, efferent mass activity in the ventral gastric vagal nerve in Sprague-Dawley rats was recorded.Intravenous infusion of CCK-8 (0.1–1 nmol) suppressed the efferent activity. The effect of CCK-8 was significantly reduced in animals with total subdiaphragmatic vagotomy in comparison to those with partial vagotomy.Intravenous infusion of CCKA receptor antagonist L-364,718 (1–100×10−6 g) blocked the response of vagal efferent activity to 0.1 nmol CCK-8, but the CCKB receptor antagonist L-365,260 (1–100×10−6 g) did not in the conditions of either partial or total vagotomy.Intracisternal infusion of L-364,718 (1×10−6 g) blocked the response of vagal efferent activity to 0.1 nmol CCK-8 i.v.Infusion of exogenous CCK-8 did not affect the activity of supradiaphragmatic vagal afferents.The results suggest that the effect of systemically administered CCK-8 on vagal efferent activity is mediated by both peripherally (subdiaphragmatically) and centrally localized CCKA receptors. PMID:10780970

  18. Regulation of membrane cholecystokinin-2 receptor by agonists enables classification of partial agonists as biased agonists.

    Science.gov (United States)

    Magnan, Rémi; Masri, Bernard; Escrieut, Chantal; Foucaud, Magali; Cordelier, Pierre; Fourmy, Daniel

    2011-02-25

    Given the importance of G-protein-coupled receptors as pharmacological targets in medicine, efforts directed at understanding the molecular mechanism by which pharmacological compounds regulate their presence at the cell surface is of paramount importance. In this context, using confocal microscopy and bioluminescence resonance energy transfer, we have investigated internalization and intracellular trafficking of the cholecystokinin-2 receptor (CCK2R) in response to both natural and synthetic ligands with different pharmacological features. We found that CCK and gastrin, which are full agonists on CCK2R-induced inositol phosphate production, rapidly and abundantly stimulate internalization. Internalized CCK2R did not rapidly recycle to plasma membrane but instead was directed to late endosomes/lysosomes. CCK2R endocytosis involves clathrin-coated pits and dynamin and high affinity and prolonged binding of β-arrestin1 or -2. Partial agonists and antagonists on CCK2R-induced inositol phosphate formation and ERK1/2 phosphorylation did not stimulate CCK2R internalization or β-arrestin recruitment to the CCK2R but blocked full agonist-induced internalization and β-arrestin recruitment. The extreme C-terminal region of the CCK2R (and more precisely phosphorylatable residues Ser(437)-Xaa(438)-Thr(439)-Thr(440)-Xaa(441)-Ser(442)-Thr(443)) were critical for β-arrestin recruitment. However, this region and β-arrestins were dispensable for CCK2R internalization. In conclusion, this study allowed us to classify the human CCK2R as a member of class B G-protein-coupled receptors with regard to its endocytosis features and identified biased agonists of the CCK2R. These new important insights will allow us to investigate the role of internalized CCK2R·β-arrestin complexes in cancers expressing this receptor and to develop new diagnosis and therapeutic strategies targeting this receptor.

  19. A Cholecystokinin B Receptor-Specific DNA Aptamer for Targeting Pancreatic Ductal Adenocarcinoma

    Science.gov (United States)

    Abraham, Thomas; Pan, Weihua; Tang, Xiaomeng; Linton, Samuel S.; McGovern, Christopher O.; Loc, Welley S.; Smith, Jill P.; Butler, Peter J.; Kester, Mark; Adair, James H.; Matters, Gail L.

    2017-01-01

    Pancreatic ductal adenocarcinomas (PDACs) constitutively express the G-protein-coupled cholecystokinin B receptor (CCKBR). In this study, we identified DNA aptamers (APs) that bind to the CCKBR and describe their characterization and targeting efficacy. Using dual SELEX selection against “exposed” CCKBR peptides and CCKBR-expressing PDAC cells, a pool of DNA APs was identified. Further downselection was based on predicted structures and properties, and we selected eight APs for initial characterizations. The APs bound specifically to the CCKBR, and we showed not only that they did not stimulate proliferation of PDAC cell lines but rather inhibited their proliferation. We chose one AP, termed AP1153, for further binding and localization studies. We found that AP1153 did not activate CCKBR signaling pathways, and three-dimensional Confocal microscopy showed that AP1153 was internalized by PDAC cells in a receptor-mediated manner. AP1153 showed a binding affinity of 15 pM. Bioconjugation of AP1153 to the surface of fluorescent NPs greatly facilitated delivery of NPs to PDAC tumors in vivo. The selectivity of this AP-targeted NP delivery system holds promise for enhanced early detection of PDAC lesions as well as improved chemotherapeutic treatments for PDAC patients. PMID:27754762

  20. Assessment of cholecystokinin 2 receptor (CCK2R) in neoplastic tissue.

    Science.gov (United States)

    Roy, Jyoti; Putt, Karson S; Coppola, Domenico; Leon, Marino E; Khalil, Farah K; Centeno, Barbara A; Clark, Noel; Stark, Valerie E; Morse, David L; Low, Philip S

    2016-03-22

    The expression of cholecystokinin 2 receptor (CCK2R, CCKBR or gastrin receptor) has been reported on a diverse range of cancers such as colorectal, liver, lung, pancreatic, ovarian, stomach, thyroid and numerous neuroendocrine/carcinoid tumors. Some cancers of the colorectum, lung, pancreas and thyroid have been shown to overexpress CCK2R in relation to normal matched tissues of the same organ. This reported overexpression has led to the development of a number of CCK2R-ligand targeted imaging and therapeutic agents. However, no comprehensive study comparing the expression of CCK2R in multiple cancers to multiple normal tissues has been performed. Herein, we report the immunohistochemical analysis of cancer samples from gastrointestinal stromal tumor (GIST), hepatocellular carcinoma (HCC), non-small cell lung cancer (NSCLC), pancreatic adenocarcinoma, and thyroid cancer against multiple normal tissue samples from esophagus, liver, lung, pancreas, stomach, spleen and thyroid. These results show that CCK2R expression is present in nearly all cancer and normal samples tested and that none of the cancer samples had expression that was statistically greater than that of all of the normal samples.

  1. Ligand-induced internalization of the type 1 cholecystokinin receptor independent of recognized signaling activity.

    Science.gov (United States)

    Cawston, Erin E; Harikumar, Kaleeckal G; Miller, Laurence J

    2012-02-01

    Receptor ligands, identified as antagonists, based on the absence of stimulation of signaling, can rarely stimulate receptor internalization. d-Tyr-Gly-[(Nle(28,31),d-Trp(30))CCK-26-32]-2-phenylethyl ester (d-Trp-OPE) is such a ligand that binds to the cholecystokinin (CCK) receptor and stimulates internalization. Here, the molecular basis of this trafficking event is explored, with the assumption that ligand binding initiates conformational change, exposing an epitope to direct endocytosis. Ligand-stimulated internalization was studied morphologically using fluorescent CCK and d-Trp-OPE. d-Trp-OPE occupation of Chinese hamster ovary cell receptors stimulated internalization into the same region as CCK. Arrestin-biased action was ruled out using morphological translocation of fluorescent arrestin 2 and arrestin 3, moving to the membrane in response to CCK, but not d-Trp-OPE. Possible roles of the carboxyl terminus were studied using truncated receptor constructs, eliminating the proline-rich distal tail, the serine/threonine-rich midregion, and the remainder to the vicinal cysteines. None of these constructs disrupted d-Trp-OPE-stimulated internalization. Possible contributions of transmembrane segments were studied using competitive inhibition with peptides that also had no effect. Intracellular regions were studied with a similar strategy using coexpressing cell lines. Peptides corresponding to ends of each loop region were studied, with only the peptide at the carboxyl end of the third loop inhibiting d-Trp-OPE-stimulated internalization but having no effect on CCK-stimulated internalization. The region contributing to this effect was refined to peptide 309-323, located below the recognized G protein-association motif. While a receptor in which this segment was deleted did internalize in response to d-Trp-OPE, it exhibited abnormal ligand binding and did not signal in response to CCK, suggesting an abnormal conformation and possible mechanism of internalization

  2. Expression profile of cholecystokinin type-A receptor in gallbladder cancer and gallstone disease

    Institute of Scientific and Technical Information of China (English)

    Rajani Rai; Mallika Tewari; Mohan Kumar; Tej Bali Singh; Hari S Shukla

    2011-01-01

    BACKGROUND: Regulatorypeptidereceptorshaveattractedthe interest of oncologists as a new promising approach for cancer pathology, imaging and therapy. Although cholecystokinin (CCK) is a potent modulator of gallbladder contractility and plays a potential role in pancreatic carcinogenesis through CCK type-A receptor (CCKAR), its role in gallbladder cancer (GBC) is still unknown and immunohistochemical detection of CCKAR in the gallbladder has not yet been reported. This novel case-control study aimed to investigate the expression profile of CCKAR in GBC and gallstone disease (GSD). METHODS: This study included 162 samples of gallbladder: 94 fromGBCand68fromGSD.ExpressionofCCKARwasanalyzed by immunohistochemistry and immunoblotting. The results were statistically correlated with disease history including age, sex, presenceofgallstone,stageanddifferentiation. RESULTS: CCKAR was positive in 30/68 (44.1%) of GSD and 72/94 (76.6%) of GBC samples. Fifty-one of the 72 (70.8%) CCKAR-positive GBC samples showed over-expression. Interestingly, consistent results also appeared in the immuno-blotting study. CONCLUSIONS: CCKARexpressionwassignificantlyincreased in GBC compared to GSD. Moreover, CCKAR expression was associated with the degree of tumor differentiation, i.e., less expression in poorly-differentiated tumors. Thus, it has future prognostic and therapeutic implications in the management of GBC.

  3. Preclinical evaluation of new radioligand of cholecystokinin/gastrin receptors in endocrine tumors xenograft nude mice

    Energy Technology Data Exchange (ETDEWEB)

    Brillouet, S. [Department of Nuclear Medicine, Institut Claudius Regaud, Toulouse (France) and Inserm U563, Therapeutic Innovation and Molecular Oncologic Department, Institut Claudius Regaud, Toulouse (France)]. E-mail: brillouet.severine@claudiusregaud.fr; Caselles, O. [Department of Nuclear Medicine, Institut Claudius Regaud, Toulouse (France); Dierickx, L.O. [Department of Nuclear Medicine, Institut Claudius Regaud, Toulouse (France); Mestre, B. [CNRS, LSPCMIB-UMR5068, Universite Paul Sabatier, Toulouse (France); Nalis, J. [Department of Nuclear Medicine, Institut Claudius Regaud, Toulouse (France); Picard, C. [CNRS, LSPCMIB-UMR5068, Universite Paul Sabatier, Toulouse (France); Favre, G. [Inserm U563, Therapeutic Innovation and Molecular Oncologic Department, Institut Claudius Regaud, Toulouse (France); Poirot, M. [Inserm U563, Therapeutic Innovation and Molecular Oncologic Department, Institut Claudius Regaud, Toulouse (France); Silvente-Poirot, S. [Inserm U563, Therapeutic Innovation and Molecular Oncologic Department, Institut Claudius Regaud, Toulouse (France); Courbon, F. [Department of Nuclear Medicine, Institut Claudius Regaud, Toulouse (France)

    2007-02-01

    The cholecystokinin(CCK)/gastrin 2 receptors (R-CCK2) are overexpressed in 90% of medullary thyroid cancers (MTC) and in 60% of small cell lung cancers but not or poorly in corresponding healthy tissues. They represent a relevant target for the diagnosis and internal targeted radiotherapy of these tumors. Although previous studies have demonstrated the feasibility of radiolabeled CCK/gastrin to target CCK-2 receptor-expressing tissues in animals and patients, some problems remained unsolved to identify an optimum candidate for in vivo targeting of R-CCK2-expressing tumors. By a rational approach and 'in silico' drug design, we synthesized a new CCK-derivative with high affinity for the R-CCK2. The aim of this study was to achieve the radiolabeling of a new radioligand, to assess its efficacy using a published CCK radioligand ({sup 111}In-DTPA-CCK8) as a control for the R-CCK2 targeting. This new CCK-derivative was radiolabeled with {sup 111}In. Nude mice, bearing the human MTC TT tumors and NIH-3T3 cell line expressing a tumorigenic mutant of the R-CCK2, were injected with this radiolabeled peptide. In vivo planar scintigraphies were acquired. Thereafter, biodistribution studies (%ID/g tissue) were done. The conditions of radiolabelling were optimized to obtain a radiochemical purity >90%. Scintigraphic images of xenograft mice showed significant tumor uptake with a target to nontarget ratio higher than two. These results were confirmed by the biodistribution studies which showed as expected a significant activity in the spleen, the liver and the kidneys. Therefore, this new radiolabeled compound is a promised new candidate for molecular imaging and internal radiotherapy for R-CCK2 tumor targeting.

  4. Expression and Regulation of Cholecystokinin Receptor in the Chicken's Immune Organs and Cells

    Science.gov (United States)

    El-Kassas, Seham; Odemuyiwa, Solomon; Hajishengallis, George; Connell, Terry D; Nashar, Toufic O

    2017-01-01

    Cholecystokinin (CCK) is a neuropeptide that affects growth rate in chickens by regulating appetite. CCK peptides exert their function by binding to two identified receptors, CCKAR and CCKBR in the GI tract and the brain, respectively, as well as in other organs. In mammals, CCK/CCKAR interactions affect a number of immunological parameters, including regulation of lymphocytes and functioning of monocytes. Thus, food intake and growth can potentially be altered by infection and the resulting inflammatory immune response. It is uncertain, however, whether chicken express CCKAR in immune organs and cells, and, if so, whether CCKAR expression is regulated by pathogen derived inflammatory stimuli. Herein, we identify expression of CCKAR protein in chicken peripheral blood mononuclear cells (PBMC) including monocytes, and expression of the CCKAR gene in PBMC, thymus, bursa, and spleen, in selected commercial and pure chicken breeds. Further, stimulation with various types of E. coli heat-labile enterotoxins or lipopolysaccharide significantly regulated expression of CCKAR on monocytes in the different breeds. Ligation of CCKAR with antibodies in PBMC induced mobilization of Ca2+, indicating that CCKAR is signal competent. Injection with polyinosinic: polycytidylic acid (poly I:C), a synthetic analogue of double stranded viral RNA that binds Toll-Like Receptor-3 (TLR3), also regulated gene expressions of CCKAR and proinflammatory cytokines, in the different breeds. Interestingly, variations in the expression levels of proinflammatory cytokines in the different breeds were highly correlated with CCKAR expression levels. Taken together, these findings indicate that the physiological function of CCKAR in the chicken is tightly regulated in immune organs and cells by external inflammatory stimuli, which in turn regulate growth. This is the first report CCKAR expression in immune organs and cells, in any species, and the initial observation that CCKAR is regulated by

  5. Transcriptomic and behavioural characterisation of a mouse model of burn pain identify the cholecystokinin 2 receptor as an analgesic target.

    Science.gov (United States)

    Yin, Kathleen; Deuis, Jennifer R; Lewis, Richard J; Vetter, Irina

    2016-01-01

    Burn injury is a cause of significant mortality and morbidity worldwide and is frequently associated with severe and long-lasting pain that remains difficult to manage throughout recovery. We characterised a mouse model of burn-induced pain using pharmacological and transcriptomic approaches. Mechanical allodynia elicited by burn injury was partially reversed by meloxicam (5 mg/kg), gabapentin (100 mg/kg) and oxycodone (3 and 10 mg/kg), while thermal allodynia and gait abnormalities were only significantly improved by amitriptyline (3 mg/kg) and oxycodone (10 mg/kg). The need for relatively high opioid doses to elicit analgesia suggested a degree of opioid resistance, similar to that shown clinically in burn patients. We thus assessed the gene expression changes in dorsal root ganglion neurons and pathophysiological mechanisms underpinning burn injury-induced pain using a transcriptomic approach. Burn injury was associated with significantly increased expression of genes associated with axon guidance, neuropeptide signalling, behavioural defence response and extracellular signalling, confirming a mixed neuropathic and inflammatory aetiology. Notably, among the pain-related genes that were upregulated post-injury was the cholecystokinin 2 receptor (Cckbr), a G protein-coupled receptor known as a pain target involved in reducing opioid effectiveness. Indeed, the clinically used cholecystokinin receptor antagonist proglumide (30 mg/kg) was effective at reversing mechanical allodynia, with additional analgesia evident in combination with low-dose oxycodone (1 mg/kg), including significant reversal of thermal allodynia. These findings highlight the complex pathophysiological mechanisms underpinning burn injury-induced pain and suggest that cholecystokinin-2 receptor antagonists may be useful clinically as adjuvants to decrease opioid requirements and improve analgesic management.

  6. Characterization of a novel five-transmembrane domain cholecystokinin-2 receptor splice variant identified in human tumors.

    Science.gov (United States)

    Sanchez, Claire; Escrieut, Chantal; Clerc, Pascal; Gigoux, Véronique; Waser, Beatrice; Reubi, Jean Claude; Fourmy, Daniel

    2012-02-26

    The cholecystokinin-2 receptor (CCK2R), is expressed in cancers where it contributes to tumor progression. The CCK2R is over-expressed in a sub-set of tumors, allowing its use in tumor targeting with a radiolabel ligand. Since discrepancies between mRNA levels and CCK2R binding sites were noticed, we searched for abnormally spliced variants in tumors from various origins having been previously reported to frequently express cholecystokinin receptors, such as medullary thyroid carcinomas, gastrointestinal stromal tumors, leiomyomas and leiomyosarcomas, and gastroenteropancreatic tumors. A variant of the CCK2R coding for a putative five-transmembrane domains receptor has been cloned. This variant represented as much as 6% of CCK2R levels. Ectopic expression in COS-7 cells revealed that this variant lacks biological activity due to its sequestration in endoplasmic reticulum. When co-expressed with the CCK2R, this variant diminished membrane density of the CCK2R and CCK2R-mediated activity (phospholipase-C and ERK activation). In conclusion, a novel splice variant acting as a dominant negative on membrane density of the CCK2R may be of importance for the pathophysiology of certain tumors and for their in vivo CCK2R-targeting.

  7. Direct demonstration of unique mode of natural peptide binding to the type 2 cholecystokinin receptor using photoaffinity labeling.

    Science.gov (United States)

    Dong, Maoqing; Miller, Laurence J

    2013-08-01

    Direct analysis of mode of peptide docking using intrinsic photoaffinity labeling has provided detailed insights for the molecular basis of cholecystokinin (CCK) interaction with the type 1 CCK receptor. In the current work, this technique has been applied to the closely related type 2 CCK receptor that also binds the natural full agonist peptide, CCK, with high affinity. A series of photolabile CCK analog probes with sites of covalent attachment extending from position 26 through 32 were characterized, with the highest affinity analogs that possessed full biological activity utilized in photoaffinity labeling. The position 29 probe, incorporating a photolabile benzoyl-phenylalanine in that position, was shown to bind with high affinity and to be a full agonist, with potency not different from that of natural CCK, and to covalently label the type 2 CCK receptor in a saturable, specific and efficient manner. Using proteolytic peptide mapping, mutagenesis, and radiochemical Edman degradation sequencing, this probe was shown to establish a covalent bond with type 2 CCK receptor residue Phe¹²⁰ in the first extracellular loop. This was in contrast to its covalent attachment to Glu³⁴⁵ in the third extracellular loop of the type 1 CCK receptor, directly documenting differences in mode of docking this peptide to these receptors.

  8. Cholecystokinin-2 receptor mediated gene expression in neuronal PC12 cells

    DEFF Research Database (Denmark)

    Hansen, Thomas v O; Borup, Rehannah; Marstrand, Troels;

    2007-01-01

    Cholecystokinin (CCK) is abundantly expressed in the CNS, in which it regulates feeding behavior and long-term memory. Moreover, CCK has been implicated in mental disorders, such as anxiety and schizophrenia. Despite its manifest physiological and pathophysiological role, the molecular targets...... could be identified. Comparison with forskolin- and nerve growth factor (NGF)-treated PC12 cells showed that CCK induced a separate set of target genes. Taken together, we propose that neuronal CCK may have a role in the regulation of the circadian rhythm, the metabolism of cerebral cholesterol...

  9. Presence of CCK-A, B receptors and effect of gastrin and cholecystokinin on growth of pancreatobiliary cancer cell lines

    Institute of Scientific and Technical Information of China (English)

    Jin-Young Jang; Sun-Whe Kim; Ja-Lok Ku; Yong-Hyun Park; Jae-Gahb Park

    2005-01-01

    AIM: To investigate the effects of gastrin and cholecystokinin (CCK) and their specific antagonists on the growth of pancreatic and biliary tract cancer cell lines.METHODS: Five pancreatic and 6 biliary cancer cell lines with 2 conrtol cells were used in this study. Cell proliferation study was done using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) test and direct cell count method. Reverse transcription-polymerase chain reaction (RT-PCR) and slot blot hybridization were performed to examine and quantify the expression of hormonal receptors in these cell lines.RESULTS: SNU-308 showed a growth stimulating effect by gastrin-17, as did SNU-478 by both gastrin-17 and CCK-8. The trophic effect of these two hormones was completely blocked by specific antagonists (L-365, 260for gastrin and L-364, 718 for CCK). Other cell lines did not respond to gastrin or CCK. In RT-PCR, the presence of CCK-A receptor and CCK-B/gastrin receptor mRNA was detected in all biliary and pancreatic cancer cell lines. In slot blot hybridization, compared to the cell lines which did not respond to hormones, those that responded to hormones showed high expression of receptor mRNA.CONCLUSION: Gastrin and CCK exert a trophic action on some of the biliary tract cancers.

  10. Differential body weight and feeding responses to high-fat diets in rats and mice lacking cholecystokinin 1 receptors.

    Science.gov (United States)

    Bi, Sheng; Chen, Jie; Behles, R Ryan; Hyun, Jayson; Kopin, Alan S; Moran, Timothy H

    2007-07-01

    Prior data demonstrated differential roles for cholecystokinin (CCK)1 receptors in maintaining energy balance in rats and mice. CCK1 receptor deficiency results in hyperphagia and obesity of Otsuka Long-Evans Tokushima Fatty (OLETF) rats but not in mice. To ascertain the role of CCK1 receptors in high-fat-diet (HFD)-induced obesity, we compared alterations in food intake, body weight, fat mass, plasma glucose, and leptin levels, and patterns of hypothalamic gene expression in OLETF rats and mice lacking CCK1 receptors in response to a 10-wk exposure to HFD. Compared with Long-Evans Tokushima Otsuka (LETO) control rats, OLETF rats on HFD had sustained overconsumption over the 10-wk period. High fat feeding resulted in greater increases in body weight and plasma leptin levels in OLETF than in LETO rats. In situ hybridization determinations revealed that, while HFD reduced neuropeptide Y (NPY) mRNA expression in both the arcuate nucleus (Arc) and the dorsomedial hypothalamus (DMH) of LETO rats, HFD resulted in decreased NPY expression in the Arc but not in the DMH of OLETF rats. In contrast to these results in OLETF rats, HFD increased food intake and induced obesity to an equal degree in both wild-type and CCK1 receptor(-/-) mice. NPY gene expression was decreased in the Arc in response to HFD, but was not detectable in the DMH in both wild-type and CCK1 receptor(-/-) mice. Together, these data provide further evidence for differential roles of CCK1 receptors in the controls of food intake and body weight in rats and mice.

  11. Coexpression of cholecystokinin-B/gastrin receptor and gastrin gene in human gastric tissues and gastric cancer cell line

    Institute of Scientific and Technical Information of China (English)

    Jian-Jiang Zhou; Man-Ling Chen; Qun-Zhou Zhang; Jian-Kun Hu; Wen-Ling Wang

    2004-01-01

    AIM: To compare the expression patterns of cholecystokininB (CCK-B)/gastrin receptor genes in matched human gastric carcinoma and adjacent non-neoplastic mucosa of patients with gastric cancer, inflammatory gastric mucosa from patients with gastritis, normal stomachs from 2 autopsied patients and a gastric carcinoma cell line (SGC-7901), and to explore their relationship with progression to malignancy of human gastric carcinomas.METHODS: RT-PCR and sequencing were employed to detect the mRNA expression levels of CCK-B receptor and gastrin gene in specimens from 30 patients with gastric carcinoma and healthy bordering non-cancerous mucosa, 10 gastritis patients and normal stomachs from 2 autopsied patients as well as SGC-7901. The results were semi-quantified by normalizing it to the mRNA level of β-actin gene using Lab Image software. The sequences were analyzed by BLAST program. RESULTS: CCK-B receptor transcripts were detected in all of human gastric tissues in this study, including normal, inflammatory and malignant tissues and SGC-7901. However, the expression levels of CCK-B receptor in normal gastric tissues were higher than those in other groups (P<0.05),and its expressions did not correlate with the differentiation and metastasis of gastric cancer (P>0.05). On the other hand, gastrin mRNA was detected in SGC-7901 and in specimens obtained from gastric cancer patients (22/30) but not in other gastric tissues, and its expression was highly correlated with the metastases of gastric cancer (P<0.05). CONCLUSION: Human gastric carcinomas and gastric cancer cell line SGC-7901 cells coexpress CCK-B receptor and gastrin mRNA. Gastrin/CCK-B receptor autocrine or paracrine pathway may possibly play an important role in the progression of gastric cancer.

  12. Synthesis of Z-CCK-27-32-NH2, Z-Tyr(SO-3)-Met-Gly-Trp-Met-Asp-NH2, a cholecystokinin receptor antagonist and an inhibitor of gastrin-induced acid secretion.

    Science.gov (United States)

    Briet, C; Aumelas, A; Martinez, J

    1985-09-01

    The synthesis of the hexapeptide Z-Tyr(SO-3)-Met-Gly-Trp-Met-Asp-NH2, representing the C-terminal sequence of cholecystokinin minus the C-terminal phenylalanyl residue is described. This peptide was shown to be the most potent cholecystokinin receptor antagonist in vitro described to date. It is also able to inhibit gastrin-induced acid secretion in vivo, in the rat and was proved to antagonize the action of the C-terminal octapeptide of cholecystokinin in the central nervous system.

  13. Vagal afferent-dependent cholecystokinin modulation of visceral pain requires central amygdala NMDA-NR2B receptors in rats.

    Science.gov (United States)

    Wang, E M; Li, W T; Yan, X J; Chen, X; Liu, Q; Feng, C C; Cao, Z J; Fang, J Y; Chen, S L

    2015-09-01

    Cholecystokinin (CCK), a gut hormone that is released during feeding, exerts gastrointestinal effects in part through vagal pathway. It is reported to be a potential trigger for increased postprandial visceral sensitivity in healthy subjects and, especially in patients with irritable bowel syndrome. NR2B-containing N-methyl-d-aspartate (NMDA) receptors in the central amygdala (CeA) participate in pain modulation. Systemically administered CCK activates the CeA-innervating neurons. Here, we investigated whether CCK modulation of visceral sensitivity is mediated through CeA NMDA-NR2B receptors and whether this modulation involves vagal pathway. We first examined the visceromotor response (VMR) to colorectal distention (CRD) following i.p. injection of CCK octapeptide (CCK-8) in a rat model. Next, the NR2B antagonist ifenprodil and the NR2A antagonist NVP-AAM077 were microinjected into the CeA before systemic CCK injection. NR2B phosphorylation was detected by Western blot. To down-regulate NR2B gene expression, NR2B-specific small interfering RNA (siRNA) was delivered into CeA neurons by electroporation. In addition, the effects of functional deafferentation by perivagal application of capsaicin and pretreatment with the CCK1 receptor antagonist devazepide were investigated. CCK-8 increased VMR to CRD in a dose-dependent manner. This effect was blunted by intra-CeA administration of ifenprodil (but not NVP-AAM077) and was accompanied by phosphorylation of NR2B subunits in the CeA. CCK failed to increase VMR to CRD in NR2B siRNA-treated rats. Perivagal capsaicin application and pretreatment with devazepide prevented CCK-induced pronociception and CeA NR2B phosphorylation. The pronociception induced by systemic CCK, which is vagal afferent-dependent, requires activation of CeA NMDA-NR2B receptors. © 2015 John Wiley & Sons Ltd.

  14. Synthesis of (R)- and (S)-[C-11]L-365,260 for PET studies of brain cholecystokinin (CCK) receptors

    Energy Technology Data Exchange (ETDEWEB)

    Haradahira, T. [Research Development Corporation of Japan, Tokyo (Japan); Suzuki, K.; Inoue, O. [National Institute of Radiological Sciences, Chiba (Japan)

    1994-05-01

    Cholecystokinin (CCK) is a recognized peptide hormone in the gut and proposed as a neurotransmitter or neuromodulator in the central nervous system. Two distinct CCK receptors termed CCK-A and CCK-B have been characterized. CCK-A receptor is primarily distributed in the peripheral tissues including pancreas and gallbladder and also known to be distributed in a few brain regions. CCK-B receptor is widely distributed in the brain and has been proposed to be involved in anxiety, satiety and nociception. To investigate the functional roles of the CCK receptors in the brain by positron emission tomography, we have synthesized an enantiomeric pair of C-11 labeled non-peptide antagonists against the CCK receptors. L-365,260 [3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N`-(3-methylpheny lurea)] is a potent CCK-B selective non-peptide antagonist (CCK-A/CCK-B ratio of IC50, 140), whereas its (S)-enantiomer is selective toward CCK-A receptor (CCK-A/CCK-B ratio of IC50, 0.02). We have synthesized the (R)- and (S)-enantiomers of [C-11]-365,260 by N-methylation (50{degrees}C for 5 min) of the racemic desmethyl precursor with [C-11]iodomethane using sodium hydride as a base and subsequent optical resolution with HPLC (column: ChiraSpher, 250 x 10 mm, Merck; eluent: n-hexane / 1,4-dioxane / 2-propanol / triethylamine = 70 / 25 / 5 / 0.1). Radiochemical yields (decay corrected) and optical purities were 34%, 99% for R-enantiomer and 36%, 99% for S-enantiomer, respectively. The total synthesis time was 40 min and specific activity was about 37 GBq/{mu}mol. In PET studies on rhesus monkey (R)-enantiomer showed a high uptake of radioactivity in the cerebral cortex, region known to have a high concentration of CCK-B receptor.

  15. Expression and cell-specific localization of cholecystokinin receptors in rat lung

    Institute of Scientific and Technical Information of China (English)

    Bin Cong; Shu-Jin Li; Yi-Ling Ling; Yu-Xia Yao; Zhen-Yong Gu; Jun-xia Wang; Hong-Yu You

    2003-01-01

    AIM: To elucidate whether CCK receptors exist in lung tissues and their precise cellular localization in the lung. METHODS: CCK-AR and CCK-BR mRNA expression andcellular distribution in the rat lung were detected by highly sensitive method of in situ reverse transcription-polymerase chain reaction (RT-PCR) and conventional in situ hybridization. RESULTS: CCK-AR and CCK-BR gene positive signals were observed in bronchial epithelial cells, alveolar epithelial cells,pulmonary macrophages and vascular endothelial cells of the rats' lung byin situ RT-PCR. The hybridization signals of CCK-AR were relatively faint. By in situ hybridization,however, only the signals of CCK-BR but not CCK-AR were detected in the lung, and the positive staining was only found in vascular endothelial cells and macrophages. CONCLUSION: CCK-AR and CCK-BR gene were present in pulmonary vascular endothelial cells, macrophages, bronchial epithelial cells and alveolar epithelial cells, which play an important role in mediating the regulatory actions of CCK-8on these cells.

  16. Localization of the CB1 type cannabinoid receptor in the rat basolateral amygdala: high concentrations in a subpopulation of cholecystokinin-containing interneurons.

    Science.gov (United States)

    McDonald, A J; Mascagni, F

    2001-01-01

    The neuronal localization of the CB1 cannabinoid receptor in the rat basolateral amygdala was studied using peroxidase and fluorescence immunohistochemical techniques. All nuclei of the basolateral amygdala contained a large number of lightly stained pyramidal neurons and a small number of more intensely stained non-pyramidal neurons. Most of the latter cells had medium-sized to large multipolar somata and three to four aspiny dendrites, but some exhibited smaller oval somata. The axon initial segments of some of these non-pyramidal neurons exhibited large swollen varicosities in colchicine-injected animals, suggesting that much of the CB1 receptor protein is transported down the axons of these cells. Double-labeling studies using immunofluorescence histochemistry combined with confocal laser scanning microscopy revealed that the great majority of non-pyramidal neurons with CB1 receptor immunoreactivity belonged to a cholecystokinin-containing subpopulation. Whereas none of the other subpopulations of non-pyramidal neurons (exhibiting immunoreactivity for calretinin, parvalbumin, or somatostatin) expressed high levels of CB1 receptor immunoreactivity, a small percentage of these cells exhibited low levels of immunoreactivity. The results indicate that cannabinoids may modulate the activity of pyramidal projection neurons as well as a subpopulation of cholecystokinin-containing non-pyramidal neurons in the basolateral amygdala. Previous studies indicate that most of the latter are inhibitory interneurons that utilize GABA as a neurotransmitter. The intense staining of the cholecystokinin-containing interneurons and the evidence that large amounts of CB1 receptor protein are transported down the axons of these cells suggests that, as in the hippocampus, cannabinoids may inhibit the release of GABA from the axon terminals of these neurons.

  17. Differential surface density and modulatory effects of presynaptic GABAB receptors in hippocampal cholecystokinin and parvalbumin basket cells.

    Science.gov (United States)

    Booker, Sam A; Althof, Daniel; Degro, Claudius E; Watanabe, Masahiko; Kulik, Ákos; Vida, Imre

    2017-05-02

    The perisomatic domain of cortical neurons is under the control of two major GABAergic inhibitory interneuron types: regular-spiking cholecystokinin (CCK) basket cells (BCs) and fast-spiking parvalbumin (PV) BCs. CCK and PV BCs are different not only in their intrinsic physiological, anatomical and molecular characteristics, but also in their presynaptic modulation of their synaptic output. Most GABAergic terminals are known to contain GABAB receptors (GABABR), but their role in presynaptic inhibition and surface expression have not been comparatively characterized in the two BC types. To address this, we performed whole-cell recordings from CCK and PV BCs and postsynaptic pyramidal cells (PCs), as well as freeze-fracture replica-based quantitative immunogold electron microscopy of their synapses in the rat hippocampal CA1 area. Our results demonstrate that while both CCK and PV BCs contain functional presynaptic GABABRs, their modulatory effects and relative abundance are markedly different at these two synapses: GABA release is dramatically inhibited by the agonist baclofen at CCK BC synapses, whereas a moderate reduction in inhibitory transmission is observed at PV BC synapses. Furthermore, GABABR activation has divergent effects on synaptic dynamics: paired-pulse depression (PPD) is enhanced at CCK BC synapses, but abolished at PV BC synapses. Consistent with the quantitative differences in presynaptic inhibition, virtually all CCK BC terminals were found to contain GABABRs at high densities, but only 40% of PV BC axon terminals contain GABABRs at detectable levels. These findings add to an increasing list of differences between these two interneuron types, with implications for their network functions.

  18. Pituitary tumors containing cholecystokinin

    DEFF Research Database (Denmark)

    Rehfeld, J F; Lindholm, J; Andersen, B N

    1987-01-01

    We found small amounts of cholecystokinin in the normal human adenohypophysis and therefore examined pituitary tumors from 87 patients with acromegaly, Cushing's disease, Nelson's syndrome, prolactinoma, or inactive pituitary adenomas. Five adenomas associated with Nelson's syndrome contained......'s disease and 7 acromegaly with adenomas containing ACTH. The cholecystokinin peptides from the tumors were smaller and less sulfated than cholecystokinin from normal pituitary glands. We conclude that ACTH-producing pituitary cells may also produce an altered form of cholecystokinin....

  19. Progress in developing cholecystokinin (CCK)/gastrin receptor ligands which have therapeutic potential

    Science.gov (United States)

    Berna, Marc J.; Tapia, Jose A.; Sancho, Veronica; Jensen, Robert T.

    2007-01-01

    Summary Gastrin and CCK are two of the oldest hormones and within the last 15 years there has been an exponential increase in knowledge of their pharmacology, cell biology, receptors (CCK1R, CCK2R) and roles in physiology and pathological conditions. Despite these advances there is no approved disease indication for CCK receptor antagonists and only minor use of agonists. In this review the important factors determining this slow therapeutic development are reviewed. To assess this it is necessary to briefly review what is known about the roles of CCK receptors (CCK1R, CCK2R) in normal human physiology, their role in pathologic conditions, the selectivity of available potent CCKR agonists/antagonists as well as review their use in human conditions to date and the results. Despite extensive studies in animals and some in humans, recent studies suggest that monotherapy with CCK1R agonists will not be effective in obesity, nor CCK2R antagonists in panic disorders or CCK2R antagonists to inhibit growth of pancreatic cancer. Areas that require more study include the use of CCK2R agonists for imaging tumors and radiotherapy, CCK2R antagonists in hypergastrinemic states especially with long term PPI use and for potentiation of analgesia as well as use of CCK1R antagonists for a number of gastrointestinal disorders [motility disorders (irritable bowel syndrome, dyspepsia, constipation) and pancreatitis (acute, chronic)]. PMID:17997137

  20. Synthesis of cyclic analogues of cholecystokinin highly selective for central receptors.

    Science.gov (United States)

    Rodriguez, M; Amblard, M; Galas, M C; Lignon, M F; Aumelas, A; Martinez, J

    1990-05-01

    Cyclic CCK analogues in which positions 28 and 31 have been replaced by lysine residues and whose side chains are bridged by a succinic moiety, were synthesized. They were tested for their ability to inhibit the binding of 125I-BH-CCK-8 to isolated rat pancreatic acini and to guinea pig brain membranes. These cyclic CCK-analogues were compared to the potent CCK analogue Boc-[Nle28,31]-CCK-7 and to Boc-Trp-Leu-Asp-Phe-NH2, analogue of CCK-4. These cyclic compounds appeared to be highly selective for central CCK receptors.

  1. Cholecystokinin-8 suppressed /sup 3/H-etorphine binding to rat brain opiate receptors

    Energy Technology Data Exchange (ETDEWEB)

    Wang, X.J.; Fan, S.G.; Ren, M.F.; Han, J.S.

    1989-01-01

    Radioreceptor assay (RRA) was adopted to analyze the influence of CCK-8 on /sup 3/H-etorphine binding to opiate receptors in rat brain synaptosomal membranes (P2). In the competition experiment CCK-8 suppressed the binding of /sup 3/H-etorphine. This effect was completely reversed by proglumide at 1/mu/M. Rosenthal analysis for saturation revealed two populations of /sup 3/H-etorphine binding sites. CCK-8 inhibited /sup 3/H-etorphine binding to the high affinity sites by an increase in Kd and decrease in Bmax without significant changes in the Kd and Bmax of the low affinity sites. This effect of CCK-8 was also completely reversed by proglumide at 1/mu/M. Unsulfated CCK-8 produced only a slight increase in Kd of the high affinity sites without affecting Bmax. The results suggest that CCK-8 might be capable of suppressing the high affinity opioid binding sites via the activation of CCK receptor.

  2. Female mice lacking cholecystokinin 1 receptors have compromised neurogenesis, and fewer dopaminergic cells in the olfactory bulb

    Directory of Open Access Journals (Sweden)

    Yi eSui

    2013-03-01

    Full Text Available Neurogenesis in the adult rodent brain is largely restricted to the subependymal zone (SVZ of the lateral ventricle and subgranular zone (SGZ of the dentate gyrus (DG. We examined whether cholecystokinin (CCK through actions mediated by CCK1 receptors (CCK1R is involved in regulating neurogenesis. Proliferating cells in the SVZ, measured by 5-bromo-2-deoxyuridine (BrdU injected 2 hours prior to death or by immunoreactivity against Ki67, were reduced by 37% and 42%, respectively, in female (but not male mice lacking CCK1Rs (CCK1R-/- compared to wild-type (WT. Generation of neuroblasts in the SVZ and rostral migratory stream was also affected, since the number of doublecortin (DCX-immunoreactive (ir neuroblasts in these regions decreased by 29%. In the SGZ of female CCK1R-/- mice, BrdU-positive (+ and Ki67-ir cells were reduced by 38% and 56%, respectively, while DCX-ir neuroblasts were down 80%. Subsequently, the effect of reduced SVZ/SGZ proliferation on the generation and survival of mature adult-born cells in female CCK1R-/- mice was examined. In the OB granule cell layer (GCL, the number of neuronal nuclei (NeuN-ir and calretinin-ir cells was stable compared to WT, and 42 days after BrdU injections, the number of BrdU+ cells co-expressing GABA- or NeuN-like immunoreactivity (LI was similar. Compared to WT, the granule cell layer of the DG in female CCK1R-/- mice had a similar number of calbindin-ir cells and BrdU+ cells co-expressing calbindin-LI 42 days after BrdU injections. However, the OB glomerular layer (GL of CCK1R-/- female mice had 11% fewer NeuN-ir cells, 23% less TH-ir cells, and a 38% and 29% reduction in BrdU+ cells that co-expressed TH-LI or GABA-LI, respectively. We conclude that CCK, via CCK1Rs, is involved in regulating the generation of proliferating cells and neuroblasts in the adult female mouse brain, and mechanisms are in place to maintain steady neuronal populations in the OB and DG when the rate of proliferation is

  3. Molecular cloning of an unusual bicistronic cholecystokinin receptor mRNA expressed in chicken brain: a structural and functional expression study.

    Science.gov (United States)

    Nilsson, Isabelle B M; Svensson, Samuel P S; Monstein, Hans-Jürg

    2003-06-15

    This report describes the molecular cloning and pharmacological characterization of a transiently expressed chicken brain cholecystokinin receptor (CCK-CHR) in COS-7 cells. A polymerase chain reaction (PCR)-based cloning strategy was applied using: (1) an initial PCR with deoxyinosine-containing primers designed to target conserved regions in CCK receptors, followed by (2) rapid amplification of cDNA ends (RACE), and (3) full-length PCR of the CCK-CHR cDNA. The full-length cloned bicistronic CCK-CHR cDNA contained a short upstream open reading frame (uORF) coding for a putative six-amino-acid-long peptide of unknown function, followed by a long open reading frame (lORF) encoding the 436-amino-acid-long CCK-CHR receptor protein. At the amino acid level, the CCK-CHR shared approximately 50% homology with mammalian and Xenopus laevis CCK receptors. The pharmacological profile of CCK-CHR resembled that of CCK-B receptors using agonists (CCK-8, CCK-4, gastrin-17), whereas CCK-CHR showed higher affinity for the CCK-A receptor antagonist, devazepide, than for the CCK-B receptor antagonist, L-365,260. To the best of our knowledge, this is the first description and functional expression study of a cloned chicken CCK receptor cDNA.

  4. Role of cholecystokinin in dietary fat-promoted azaserine-induced pancreatic carcinogenesis in rats

    NARCIS (Netherlands)

    Appel, M.J.; Meijers, M.; Garderen-Hoetmer, A. van; Lamers, C.B.H.W.; Rovati, L.C.; Sprij-Mooij, D.; Jansen, J.B.M.J.; Woutersen, R.A.

    1992-01-01

    The role of cholecystokinin in dietary fat-promoted pancreatic carcinogenesis was investigated in azaserine-treated rats, using lorglumide, a highly specific cholecystokinin-receptor antagonist. The animals were killed 8 months after the start of treatment. Cholecystokinin, but not dietary unsaturat

  5. Molecular cloning and tissue distribution of cholecystokinin-1 receptor (CCK-1R) in yellowtail Seriola quinqueradiata and its response to feeding and in vitro CCK treatment.

    Science.gov (United States)

    Furutani, Takahiro; Masumoto, Toshiro; Fukada, Haruhisa

    2013-06-01

    In vertebrates, the peptide cholecystokinin (CCK) is one of the most important neuroregulatory digestive hormones. CCK acts via CCK receptors that are classified into two subtypes, CCK-1 receptor (CCK-1R; formally CCK-A) and CCK-2 receptor (formally CCK-B). In particular, the CCK-1R is involved in digestion and is regulated by CCK. However, very little information is known about CCK-1R in fish. Therefore, we performed molecular cloning of CCK-1R cDNA from the digestive tract of yellowtail Seriola quinqueradiata. Phylogenetic tree analysis showed a high sequence identity between the cloned yellowtail CCK receptor cDNA and CCK-1R, which belongs to the CCK-1R cluster. Furthermore, the expression of yellowtail CCK receptor mRNA was observed in gallbladder, pyloric caeca, and intestines, similarly to CCK-1R mRNA expression in mammals, suggesting that the cloned cDNA is of CCK-1R from yellowtail. In in vivo experiments, the CCK-1R mRNA levels increased in the gallbladder and pyloric caeca after feeding, whereas in vitro, mRNA levels of CCK-1R and digestive enzymes in cultured pyloric caeca increased by the addition of CCK. These results suggest that CCK-1R plays an important role in digestion stimulated by CCK in yellowtail.

  6. Further studies on the role of cholecystokinin-A and B receptors in secretion of anterior pituitary hormones in male rats.

    Science.gov (United States)

    Peuranen, E; Vasar, E; Koks, S; Volke, V; Lang, A; Rauhala, P; Männistö, P T

    1995-01-01

    We compared the effects of unselective cholecystokinin (CCK) agonists (caerulein and CCK-8s) and a CCKB agonist CCK-4 on the secretion of thyrotropin (TSH), growth hormone (GH) and prolactin (PRL) in male rats. The subcutaneous (s.c.) administration of caerulein and CCK-8s suppressed dose-dependently TSH and GH levels. In contrast, when given into the 3rd brain ventricle (i.c.v.) caerulein dose-dependently elevated the GH levels. Next the importance of the afferent vagal nerves was studied in the action of caerulein and CCK-4. Subdiaphragmatic vagotomy itself decreased cold-stimulated TSH levels but abolished the suppressing effect of intraperitoneal (i.p.), and apparently also that of the i.c.v. caerulein. GH and PRL levels were altered neither by vagotomy nor caerulein. CCK-4 did not affect hormone levels. Atropine and butylscopolamine (i.p.) themselves did not alter TSH, PRL or GH secretion in intact rats. Neither did they reverse the effect of caerulein on TSH. In conclusion, CCKA receptors dominate in TSH and CCKB receptors in GH regulation. CCKA receptors in the gastrointestinal tract, related to the nervus vagus are mediating the inhibitory effect of caerulein upon TSH secretion but inhibition of GH secretion does not depend on the nervus vagus. CCKB receptors in the brain stem or near the 3rd brain ventricle are responsible for stimulation of GH secretion.

  7. Natural sweetener agave inhibits gastric emptying in rats by a cholecystokinin-2- and glucagon like peptide-1 receptor-dependent mechanism.

    Science.gov (United States)

    Bihter Gürler, E; Özbeyli, Dilek; Buzcu, Hülya; Bayraktar, Sezin; Carus, İrem; Dağ, Beyza; Geriş, Yasemin; Jeral, Seda; Yeğen, Berrak Ç

    2017-02-22

    Low-calorie sweeteners are considered to be beneficial in calorie control, but the impact of these sweeteners on gastric emptying is not well described. The purpose of this study was to compare the gastric emptying rate of agave nectar with those of glucose and fructose, and to evaluate the interaction of cholecystokinin (CCK)-1, CCK-2 and glucagon-like peptide-1 (GLP-1) receptors in agave-induced alterations in gastric emptying. Female Sprague-Dawley rats were fitted with gastric cannulas. Following the recovery, the gastric emptying rates of glucose, fructose and agave at 12.5%, 15% or 50% concentrations were measured and compared with that of saline. GLP-1 receptor antagonist exendin fragment 9-39 (30 μg kg(-1)), CCK-1 receptor antagonist devazepide (1 mg kg(-1)) or gastrin/CCK-2 receptor antagonist YM022 (1 mg kg(-1)) was injected subcutaneously 1 min before the emptying of glucose, fructose or agave at their 50% concentrations. When compared with saline emptying, gastric emptying of glucose was significantly delayed at its 25% and 50% concentrations, but the emptying of 12.5% glucose was not different from that of saline. Agave emptying, which was delayed with respect to saline emptying, was not altered by CCK-1 receptor blockade; but agave emptied from the stomach as rapidly as saline following the blockade of either CCK-2 or GLP-1 receptors. The findings demonstrate that the inhibitory effect of agave on gastric emptying is mediated by both CCK-2 and GLP-1 receptors, suggesting that natural sweeteners including agave may have satiating effects through the inhibition of gastric motility via enteroendocrine mechanisms.

  8. Molecular and functional characterization of cionin receptors in the ascidian, Ciona intestinalis: the evolutionary origin of the vertebrate cholecystokinin/gastrin family.

    Science.gov (United States)

    Sekiguchi, Toshio; Ogasawara, Michio; Satake, Honoo

    2012-04-01

    Cholecystokinin (CCK) and gastrin are vertebrate brain-gut peptides featured by a sulfated tyrosine residue and a C-terminally amidated tetrapeptide consensus sequence. Cionin, identified in the ascidian, Ciona intestinalis, the closest species to vertebrates, harbors two sulfated tyrosines and the CCK/gastrin consensus tetrapeptide sequence. While a putative cionin receptor, cior, was cloned, the ligand-receptor relationship between cionin and CioR remains unidentified. Here, we identify two cionin receptors, CioR1 and CioR2, which are the aforementioned putative cionin receptor and its novel paralog respectively. Phylogenetic analysis revealed that CioRs are homologous to vertebrate CCK receptors (CCKRs) and diverged from a common ancestor in the Ciona-specific lineage. Cionin activates intracellular calcium mobilization in cultured cells expressing CioR1 or CioR2. Monosulfated and nonsulfated cionin exhibited less potent or no activity, indicating that CioRs possess pharmacological features similar to the vertebrate CCK-specific receptor CCK1R, rather than its subtype CCK2R, given that a sulfated tyrosine in CCK is required for binding to CCK1R, but not to CCK2R. Collectively, the present data reveal that CioRs share a common ancestor with vertebrate CCKRs and indicate that CCK and CCK1R form the ancestral ligand-receptor pair in the vertebrate CCK/gastrin system. Cionin is expressed in the neural complex, digestive organs, oral siphon and atrial siphons, whereas the expression of ciors was detected mainly in these tissues and the ovary. Furthermore, cioninergic neurons innervate both of the siphons. These results suggest that cionin is involved in the regulation of siphonal functions.

  9. Pituitary tumors containing cholecystokinin

    DEFF Research Database (Denmark)

    Rehfeld, J F; Lindholm, J; Andersen, B N

    1987-01-01

    We found small amounts of cholecystokinin in the normal human adenohypophysis and therefore examined pituitary tumors from 87 patients with acromegaly, Cushing's disease, Nelson's syndrome, prolactinoma, or inactive pituitary adenomas. Five adenomas associated with Nelson's syndrome contained...

  10. Disturbance of response to acute thermal pain in naturally occurring cholecystokinin-a receptor gene knockout Otsuka Long-Evans Tokushima Fatty (OLETF) rats.

    Science.gov (United States)

    Miyasaka, Kyoko; Nomoto, Shigeki; Ohta, Minoru; Kanai, Setsuko; Kaneko, Takao; Tahara, Shoichi; Funakoshi, Akihiro

    2006-08-01

    Otsuka Long-Evans Tokushima Fatty (OLETF) rats lack cholecystokinin-A receptor (CCK-AR) because of a genetic abnormality. We observed that body temperature homeostasis in response to changes in ambient temperature was deteriorated in OLETF rats, while the functions of the signal outputs from the hypothalamus to effectors were not impaired. Deteriorated homeostasis was also seen in CCK-AR deficient (-/-) mice. In the present study, we examined whether the sensory pathway involved in transmitting signals about temperature from the skin to the brain was impaired in OLETF rats. To elucidate the involvement of CCK-AR function, we conducted the same experiment in CCK-AR(-/-) mice. Responses to thermal pain were assessed using the Hargreaves' plantar test apparatus. Shortening of withdrawal latency was observed in OLETF rats compared to control rats, indicating thermal hyperalgesia. Behavioral responses following paw withdrawal were disturbed in OLETF rats. The 5-hydroxytryptamine (5-HT) and 5-hydroxyindole acetic acid contents in the hippocampus and frontal cortex of OLETF rats were significantly higher than in those of the controls. CCK-AR(-/-) mice did not show any differences from wild-type mice. In conclusion, OLETF rats showed thermal hyperalgesia and disturbed responses to thermal pain, and an alteration of 5-HT function might have a role in this disturbance.

  11. Chylomicron components activate duodenal vagal afferents via a cholecystokinin A receptor-mediated pathway to inhibit gastric motor function in the rat.

    Science.gov (United States)

    Glatzle, Jörg; Wang, Yuhua; Adelson, David W; Kalogeris, Theodore J; Zittel, Tilman T; Tso, Patrick; Wei, Jen-Yu; Raybould, Helen E

    2003-07-15

    Nutrients in the intestine initiate changes in secretory and motor function of the gastrointestinal (GI) tract. The nature of the 'sensors' in the intestinal wall is not well characterized. Intestinal lipid stimulates the release of cholecystokinin (CCK) from mucosal entero-endocrine cells, and it is proposed that CCK activates CCK A receptors on vagal afferent nerve terminals. There is evidence that chylomicron components are involved in this lipid transduction pathway. The aim of the present study was to determine (1) the pathway mediating reflex inhibition of gastric motility and (2) activation of duodenal vagal afferents in response to chylomicrons. Mesenteric lymph was obtained from awake rats fitted with lymph fistulas during intestinal perfusion of lipid (Intralipid, 170 micromol h(-1), chylous lymph) or a dextrose and/or electrolyte solution (control lymph). Inhibition of gastric motility was measured manometrically in urethane-anaesthetized recipient rats in response to intra-arterial injection of lymph close to the upper GI tract. Chylous lymph was significantly more potent than control lymph in inhibiting gastric motility. Functional vagal deafferentation by perineural capsaicin or CCK A receptor antagonist (devazepide, 1 mg kg(-1), i.v.) significantly reduced chylous lymph-induced inhibition of gastric motility. The discharge of duodenal vagal afferent fibres was recorded from the dorsal abdominal vagus nerve in an in vitro preparation of the duodenum. Duodenal vagal afferent nerve fibre discharge was significantly increased by close-arterial injection of CCK (1-100 pmol) in 43 of 83 units tested. The discharge of 88% of CCK-responsive fibres was increased by close-arterial injection of chylous lymph; devazepide (100 microg, i.a.) abolished the afferent response to chylous lymph in 83% of these units. These data suggest that in the intestinal mucosa, chylomicrons or their products release endogenous CCK which activates CCK A receptors on vagal afferent

  12. Expression of cholecystokinin2-receptor in rat and human L cells and the stimulation of glucagon-like peptide-1 secretion by gastrin treatment.

    Science.gov (United States)

    Cao, Yang; Cao, Xun; Liu, Xiao-Min

    2015-03-01

    Gastrin is a gastrointestinal hormone secreted by G cells. Hypergastrinemia can improve blood glucose and glycosylated hemoglobin levels. These positive effects are primarily due to the trophic effects of gastrin on β-cells. In recent years, many receptors that regulate secretion of glucagon-like peptide 1 (GLP-1) have been identified in enteroendocrine L cell lines. This led us to hypothesize that, in addition to the trophic effects of gastrin on β-cells, L cells also express cholecystokinin2-receptor (CCK2R), which may regulate GLP-1 secretion and have synergistic effects on glucose homeostasis. Our research provides a preliminary analysis of CCK2R expression and the stimulating effect of gastrin treatment on GLP-1 secretion in a human endocrine L cell line, using RT-PCR, Western blot, immunocytochemistry, and ELISA analyses. The expression of proglucagon and prohormone convertase 3, which regulate GLP-1 biosynthesis, were also analyzed by real-time PCR. Double immunofluorescence labeling was utilized to assess the intracellular localization of CCK2R and GLP-1 in L cells harvested from rat colon tissue. Our results showed that CCK2R was expressed in both the human L cell line and the rat L cells. We also showed that treatment with gastrin, a CCK2R agonist, stimulated the secretion of GLP-1, and that this effect was likely due to increased expression of proglucagon and PCSK1 (also known as prohormone convertase 3 (PC3 gene)). These results not only provide a basis for the role gastrin may play in intestinal L cells, and may also provide the basis for the development of a method of gastrin-mediated glycemic regulation.

  13. The extracellular calcium-sensing receptor is required for cholecystokinin secretion in response to L-phenylalanine in acutely isolated intestinal I cells.

    Science.gov (United States)

    Liou, Alice P; Sei, Yoshitatsu; Zhao, Xilin; Feng, Jianying; Lu, Xinping; Thomas, Craig; Pechhold, Susanne; Raybould, Helen E; Wank, Stephen A

    2011-04-01

    The extracellular calcium-sensing receptor (CaSR) has recently been recognized as an L-amino acid sensor and has been implicated in mediating cholecystokinin (CCK) secretion in response to aromatic amino acids. We investigated whether direct detection of L-phenylalanine (L-Phe) by CaSR results in CCK secretion in the native I cell. Fluorescence-activated cell sorting of duodenal I cells from CCK-enhanced green fluorescent protein (eGFP) transgenic mice demonstrated CaSR gene expression. Immunostaining of fixed and fresh duodenal tissue sections confirmed CaSR protein expression. Intracellular calcium fluxes were CaSR dependent, stereoselective for L-Phe over D-Phe, and responsive to type II calcimimetic cinacalcet in CCK-eGFP cells. Additionally, CCK secretion by an isolated I cell population was increased by 30 and 62% in response to L-Phe in the presence of physiological (1.26 mM) and superphysiological (2.5 mM) extracellular calcium concentrations, respectively. While the deletion of CaSR from CCK-eGFP cells did not affect basal CCK secretion, the effect of L-Phe or cinacalcet on intracellular calcium flux was lost. In fact, both secretagogues, as well as superphysiological Ca(2+), evoked an unexpected 20-30% decrease in CCK secretion compared with basal secretion in CaSR(-/-) CCK-eGFP cells. CCK secretion in response to KCl or tryptone was unaffected by the absence of CaSR. The present data suggest that CaSR is required for hormone secretion in the specific response to L-Phe by the native I cell, and that a receptor-mediated mechanism may inhibit hormone secretion in the absence of a fully functional CaSR.

  14. Targeting of a CCK{sub 2} receptor splice variant with {sup 111}In-labelled cholecystokinin-8 (CCK8) and {sup 111}In-labelled minigastrin

    Energy Technology Data Exchange (ETDEWEB)

    Laverman, Peter; Gotthardt, Martin; Oyen, Wim J.G.; Boerman, Otto C. [Radboud University Nijmegen Medical Center, Department of Nuclear Medicine, PO Box 9101, HB Nijmegen (Netherlands); Roosenburg, Susan [Radboud University Nijmegen Medical Center, Department of Nuclear Medicine, PO Box 9101, HB Nijmegen (Netherlands); Radboud University Nijmegen, Institute for Molecules and Materials, Nijmegen (Netherlands); Park, Jeseong; Hellmich, Mark R. [University of Texas Medical Branch, Department of Surgery and the Sealy Center for Cancer Cell Biology, Galveston, TX (United States); Jong, Marion de [Erasmus Medical Center, Department of Nuclear Medicine, Rotterdam (Netherlands); Rutjes, Floris P.J.T.; Delft, Floris L. van [Radboud University Nijmegen, Institute for Molecules and Materials, Nijmegen (Netherlands)

    2008-02-15

    Radiolabelled cholecystokinin (CCK) and gastrin-derived peptides potentially can be used for peptide receptor radionuclide therapy (PRRT). Recently, a splice variant version of the CCK2R has been identified, designated CCK2i4svR. Constitutive expression of this receptor has been demonstrated in human colorectal cancer and in pancreatic cancer, but not in normal tissue. So far, it has never been shown whether radiolabelled peptides can target the CCK2i4svR in vivo. In this paper, we investigated the potential of sulfated {sup 111}In-labelled DOTA-CCK8 (sCCK8), a pan-CCKR-binding peptide, and [{sup 111}In]DOTA-minigastrin (MG0), a CCK2R selective peptide, for the targeting of the CCK2i4svR. The receptor binding affinity of [{sup 111}In]DOTA-sCCK8 and [{sup 111}In]DOTA-MG0 for the CCK2R and CCK2i4svR was determined using stably transfected HEK293 cell lines, expressing either CCK2R or CCK2i4svR. Tumour targeting was studied in HEK293-CCK2i4svR tumour-bearing athymic mice. [{sup 111}In]DOTA-sCCK8 as well as [{sup 111}In]DOTA-MG0 specifically bound both CCK2R and CCK2i4svR with affinities in the low nanomolar range. In vivo experiments revealed that accumulation of both peptides in CCK2i4svR-positive tumours was similar (3.21 {+-} 0.77 and 3.01 {+-} 0.67%ID/g, sCCK8 and MG0, respectively, 24 h p.i.). Kidney retention of [{sup 111}In]DOTA-MG0 (32.4 {+-} 7.5%ID/g, 24 h p.i.) was markedly higher than that of [{sup 111}In]DOTA-sCCK8 (2.75 {+-} 0.31%ID/g, 24 h p.i.). We demonstrated that the CCK2i4svR is a potential target for PRRT using a radiolabelled sulfated CCK8 peptide. As this receptor is expressed on colorectal and pancreatic tumours, but not in normal tissue, these tumours are potentially new targets for PRRT with CCK8 and gastrin analogs. (orig.)

  15. INTRAPANCREATIC CHOLECYSTOKININ MEDIATES VAGALLY STIMULATED EXOCRINE SECRETION FROM THE RAT PANCREAS

    Institute of Scientific and Technical Information of China (English)

    何晓东; MTimothyNelson; HaileTDebas

    1996-01-01

    Although cholecystokinin is localized within neuronal fibres of the pancreas, a physiological role for intrapancreatic cholecystokinin has not been identified. The strategy of this study was to elicit pure vagal stlmulatbx electrically, and to use specific receptor antagonists to idetxtify the mediators of exocrine pancreatic secretion. We conclude that vagal stimulation of the rat pancreas involves ganglionicand neurotransmission and release of acetylcholine and cholecystokinin from intrapanereatic, postganglionic fibres. To our knowledge, this is the first study to demonstrate a physiological role for intrapancreatic cholecystokinin.

  16. Unsulfated cholecystokinin: An overlooked hormone?

    Science.gov (United States)

    Rehfeld, Jens F; Agersnap, Mikkel

    2012-01-10

    Tyrosyl O-sulfation is a common posttranslational derivatization of proteins that may also modify regulatory peptides. Among these are members of the cholecystokinin (CCK)/gastrin family. While sulfation of gastrin peptides is without effect on the bioactivity, O-sulfation is crucial for the cholecystokinetic activity (i.e. gallbladder emptying) of CCK peptides. Accordingly, the purification of CCK as a sulfated peptide was originally monitored by its gallbladder emptying effect. Since then, the dogma has prevailed that CCK peptides are always sulfated. The dogma is correct in a semantic context since the gallbladder expresses only the CCK-A receptor that requires sulfation of the ligand. CCK peptides, however, are also ligands for the CCK-B receptors that do not require ligand sulfation. Consequently, unsulfated CCK peptides may act via CCK-B receptors. Since in vivo occurrence of unsulfated products of proCCK with an intact α-amidated C-terminal tetrapeptide sequence (-Trp-Met-Asp-PheNH(2)) has been reported, it is likely that unsulfated CCK peptides constitute a separate hormone system that acts via CCK-B receptors. This review discusses the occurrence, molecular forms, and possible physiological as well as pathophysiological significance of unsulfated CCK peptides.

  17. The Synergistic Roles of Cholecystokinin B and Dopamine D5 Receptors on the Regulation of Renal Sodium Excretion.

    Directory of Open Access Journals (Sweden)

    Xiaoliang Jiang

    Full Text Available Renal dopamine D1-like receptors (D1R and D5R and the gastrin receptor (CCKBR are involved in the maintenance of sodium homeostasis. The D1R has been found to interact synergistically with CCKBR in renal proximal tubule (RPT cells to promote natriuresis and diuresis. D5R, which has a higher affinity for dopamine than D1R, has some constitutive activity. Hence, we sought to investigate the interaction between D5R and CCKBR in the regulation of renal sodium excretion. In present study, we found D5R and CCKBR increase each other's expression in a concentration- and time-dependent manner in the HK-2 cell, the specificity of which was verified in HEK293 cells heterologously expressing both human D5R and CCKBR and in RPT cells from a male normotensive human. The specificity of D5R in the D5R and CCKBR interaction was verified further using a selective D5R antagonist, LE-PM436. Also, D5R and CCKBR colocalize and co-immunoprecipitate in BALB/c mouse RPTs and human RPT cells. CCKBR protein expression in plasma membrane-enriched fractions of renal cortex (PMFs is greater in D5R-/- mice than D5R+/+ littermates and D5R protein expression in PMFs is also greater in CCKBR-/- mice than CCKBR+/+ littermates. High salt diet, relative to normal salt diet, increased the expression of CCKBR and D5R proteins in PMFs. Disruption of CCKBR in mice caused hypertension and decreased sodium excretion. The natriuresis in salt-loaded BALB/c mice was decreased by YF476, a CCKBR antagonist and Sch23390, a D1R/D5R antagonist. Furthermore, the natriuresis caused by gastrin was blocked by Sch23390 while the natriuresis caused by fenoldopam, a D1R/D5R agonist, was blocked by YF476. Taken together, our findings indicate that CCKBR and D5R synergistically interact in the kidney, which may contribute to the maintenance of normal sodium balance following an increase in sodium intake.

  18. The Synergistic Roles of Cholecystokinin B and Dopamine D5 Receptors on the Regulation of Renal Sodium Excretion.

    Science.gov (United States)

    Jiang, Xiaoliang; Chen, Wei; Liu, Xing; Wang, Zihao; Liu, Yunpeng; Felder, Robin A; Gildea, John J; Jose, Pedro A; Qin, Chuan; Yang, Zhiwei

    2016-01-01

    Renal dopamine D1-like receptors (D1R and D5R) and the gastrin receptor (CCKBR) are involved in the maintenance of sodium homeostasis. The D1R has been found to interact synergistically with CCKBR in renal proximal tubule (RPT) cells to promote natriuresis and diuresis. D5R, which has a higher affinity for dopamine than D1R, has some constitutive activity. Hence, we sought to investigate the interaction between D5R and CCKBR in the regulation of renal sodium excretion. In present study, we found D5R and CCKBR increase each other's expression in a concentration- and time-dependent manner in the HK-2 cell, the specificity of which was verified in HEK293 cells heterologously expressing both human D5R and CCKBR and in RPT cells from a male normotensive human. The specificity of D5R in the D5R and CCKBR interaction was verified further using a selective D5R antagonist, LE-PM436. Also, D5R and CCKBR colocalize and co-immunoprecipitate in BALB/c mouse RPTs and human RPT cells. CCKBR protein expression in plasma membrane-enriched fractions of renal cortex (PMFs) is greater in D5R-/- mice than D5R+/+ littermates and D5R protein expression in PMFs is also greater in CCKBR-/- mice than CCKBR+/+ littermates. High salt diet, relative to normal salt diet, increased the expression of CCKBR and D5R proteins in PMFs. Disruption of CCKBR in mice caused hypertension and decreased sodium excretion. The natriuresis in salt-loaded BALB/c mice was decreased by YF476, a CCKBR antagonist and Sch23390, a D1R/D5R antagonist. Furthermore, the natriuresis caused by gastrin was blocked by Sch23390 while the natriuresis caused by fenoldopam, a D1R/D5R agonist, was blocked by YF476. Taken together, our findings indicate that CCKBR and D5R synergistically interact in the kidney, which may contribute to the maintenance of normal sodium balance following an increase in sodium intake.

  19. Cholecystokinin Elevates Mouse Plasma Lipids

    Science.gov (United States)

    Zhou, Lichun; Yang, Hong; Lin, Xinghua; Okoro, Emmanuel U.; Guo, Zhongmao

    2012-01-01

    Cholecystokinin (CCK) is a peptide hormone that induces bile release into the intestinal lumen which in turn aids in fat digestion and absorption in the intestine. While excretion of bile acids and cholesterol into the feces eliminates cholesterol from the body, this report examined the effect of CCK on increasing plasma cholesterol and triglycerides in mice. Our data demonstrated that intravenous injection of [Thr28, Nle31]-CCK at a dose of 50 ng/kg significantly increased plasma triglyceride and cholesterol levels by 22 and 31%, respectively, in fasting low-density lipoprotein receptor knockout (LDLR−/−) mice. The same dose of [Thr28, Nle31]-CCK induced 6 and 13% increases in plasma triglyceride and cholesterol, respectively, in wild-type mice. However, these particular before and after CCK treatment values did not achieve statistical significance. Oral feeding of olive oil further elevated plasma triglycerides, but did not alter plasma cholesterol levels in CCK-treated mice. The increased plasma cholesterol in CCK-treated mice was distributed in very-low, low and high density lipoproteins (VLDL, LDL and HDL) with less of an increase in HDL. Correspondingly, the plasma apolipoprotein (apo) B48, B100, apoE and apoAI levels were significantly higher in the CCK-treated mice than in untreated control mice. Ligation of the bile duct, blocking CCK receptors with proglumide or inhibition of Niemann-Pick C1 Like 1 transporter with ezetimibe reduced the hypercholesterolemic effect of [Thr28, Nle31]-CCK in LDLR−/− mice. These findings suggest that CCK-increased plasma cholesterol and triglycerides as a result of the reabsorption of biliary lipids from the intestine. PMID:23300532

  20. Cholecystokinin elevates mouse plasma lipids.

    Directory of Open Access Journals (Sweden)

    Lichun Zhou

    Full Text Available Cholecystokinin (CCK is a peptide hormone that induces bile release into the intestinal lumen which in turn aids in fat digestion and absorption in the intestine. While excretion of bile acids and cholesterol into the feces eliminates cholesterol from the body, this report examined the effect of CCK on increasing plasma cholesterol and triglycerides in mice. Our data demonstrated that intravenous injection of [Thr28, Nle31]-CCK at a dose of 50 ng/kg significantly increased plasma triglyceride and cholesterol levels by 22 and 31%, respectively, in fasting low-density lipoprotein receptor knockout (LDLR(-/- mice. The same dose of [Thr28, Nle31]-CCK induced 6 and 13% increases in plasma triglyceride and cholesterol, respectively, in wild-type mice. However, these particular before and after CCK treatment values did not achieve statistical significance. Oral feeding of olive oil further elevated plasma triglycerides, but did not alter plasma cholesterol levels in CCK-treated mice. The increased plasma cholesterol in CCK-treated mice was distributed in very-low, low and high density lipoproteins (VLDL, LDL and HDL with less of an increase in HDL. Correspondingly, the plasma apolipoprotein (apo B48, B100, apoE and apoAI levels were significantly higher in the CCK-treated mice than in untreated control mice. Ligation of the bile duct, blocking CCK receptors with proglumide or inhibition of Niemann-Pick C1 Like 1 transporter with ezetimibe reduced the hypercholesterolemic effect of [Thr28, Nle31]-CCK in LDLR(-/- mice. These findings suggest that CCK-increased plasma cholesterol and triglycerides as a result of the reabsorption of biliary lipids from the intestine.

  1. Lack of Analgesic Synergy of the Cholecystokinin Receptor Antagonist Proglumide and Spinal Cord Stimulation for the Treatment of Neuropathic Pain in Rats.

    Science.gov (United States)

    Inoue, Shinsuke; Johanek, Lisa M; Sluka, Kathleen A

    2017-08-01

    Neuropathic pain is difficult to manage and treat. Spinal cord stimulation (SCS) has become an established procedure for treating chronic neuropathic pain that is refractory to pharmacological therapy. In order to achieve better analgesia, a number of studies have evaluated the effectiveness of combining drug therapy with SCS. Cholecystokinin antagonists, such as proglumide, enhance the analgesic efficacy of endogenous opioids in animal models of pain. We previously reported that both systemic and spinal administration of proglumide enhances analgesia produced by both low- and high-frequency transcutaneous electrical nerve stimulation (TENS). Since SCS produces analgesia through endogenous opioids, we hypothesized that the analgesic effect of SCS would be enhanced through co-administration with proglumide in animals with neuropathic pain. Male Sprague-Dawley rats (n = 40) with spared nerve injury were given proglumide (20 mg/kg, i.p.) or saline prior to treatment with SCS (sham, 4 Hz, and 60 Hz). Mechanical withdrawal thresholds of the paw were measured before and after induction of nerve injury, and after SCS. Physical activity levels were measured after SCS. Both proglumide and SCS when given independently significantly increased withdrawal thresholds two weeks after nerve injury. However, there was no additional effect of combining proglumide and SCS on mechanical withdrawal thresholds or activity levels in animals with nerve injury. Proglumide may be a candidate for achieving analgesia for patients with refractory neuropathic pain conditions, but does not enhance analgesia produced by SCS. © 2017 International Neuromodulation Society.

  2. Species- and dose-specific pancreatic responses and progression in single- and repeat-dose studies with GI181771X: a novel cholecystokinin 1 receptor agonist in mice, rats, and monkeys.

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    Myer, James R; Romach, Elizabeth H; Elangbam, Chandikumar S

    2014-01-01

    Compound-induced pancreatic injury is a serious liability in preclinical toxicity studies. However, its relevance to humans should be cautiously evaluated because of interspecies variations. To highlight such variations, we evaluated the species- and dose-specific pancreatic responses and progression caused by GI181771X, a novel cholecystokinin 1 receptor agonist investigated by GlaxoSmithKline for the treatment of obesity. Acute (up to 2,000 mg/kg GI181771X, as single dose) and repeat-dose studies in mice and/or rats (0.25-250 mg/kg/day for 7 days to 26 weeks) showed wide-ranging morphological changes in the pancreas that were dose and duration dependent, including necrotizing pancreatitis, acinar cell hypertrophy/atrophy, zymogen degranulation, focal acinar cell hyperplasia, and interstitial inflammation. In contrast to rodents, pancreatic changes were not observed in cynomolgus monkeys given GI181771X (1-500 mg/kg/day with higher systemic exposure than rats) for up to 52 weeks. Similarly, no GI181771X treatment-associated abnormalities in pancreatic structure were noted in a 24-week clinical trial with obese patients (body mass index >30 or >27 kg/m(2)) as assessed by abdominal ultrasound or by magnetic resonance imaging. Mechanisms for interspecies variations in the pancreatic response to CCK among rodents, monkeys, and humans and their relevance to human risk are discussed.

  3. Topical cholecystokinin depresses itch-associated scratching behavior in mice.

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    Fukamachi, Shoko; Mori, Tomoko; Sakabe, Jun-Ichi; Shiraishi, Noriko; Kuroda, Etsushi; Kobayashi, Miwa; Bito, Toshinori; Kabashima, Kenji; Nakamura, Motonobu; Tokura, Yoshiki

    2011-04-01

    Cholecystokinin (CCK) serves as a gastrointestinal hormone and also functions as a neuropeptide in the central nervous system (CNS). CCK may be a downregulator in the CNS, as represented by its anti-opioid properties. The existence of CCK in the peripheral nervous system has also been reported. We investigated the suppressive effects of various CCKs on peripheral pruritus in mice. The clipped backs of ICR mice were painted with CCK synthetic peptides and injected intradermally with substance P (SP). The frequency of SP-induced scratching was reduced significantly by topical application of sulfated CCK8 (CCK8S) and CCK7 (CCK7S), but not by nonsulfated CCK8, CCK7, or CCK6. Dermal injection of CCK8S also suppressed the scratching frequency, suggesting that dermal cells as well as epidermal keratinocytes (KCs) are the targets of CCKs. As determined using real-time PCR, mRNA for CCK2R, one of the two types of CCK receptors, was expressed highly in mouse fetal skin-derived mast cells (FSMCs) and moderately in ICR mouse KCs. CCK8S decreased in vitro compound 48/80-promoted degranulation of FSMCs with a transient elevation of the intracellular calcium concentration. These findings suggest that CCK may exert an antipruritic effect via mast cells and that topical CCK may be clinically useful for pruritic skin disorders.

  4. Nonsulfated cholecystokinins in cerebral neurons

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    Agersnap, Mikkel; Zhang, Ming-Dong; Harkany, Tibor

    2016-01-01

    Cholecystokinin (CCK) is a widely expressed neuropeptide system originally discovered in the gut. Both cerebral and peripheral neurons as well as endocrine I-cells in the small intestine process proCCK to tyrosyl-O-sulfated and α-carboxyamidated peptides. Recently, we reported that gut endocrine I...... for nonsulfated CCK-8 with an antibody recognizing both sulfated and nonsulfated CCK. However, nonsulfated CCK immunoreactivity was stronger than that of sulfated CCK in cell bodies and weaker in nerve terminals. We conclude that only a small fraction of neuronal CCK is nonsulfated. The intracellular distribution...... of nonsulfated CCK in neurons suggests that they contribute only modestly to the CCK transmitter activity....

  5. Cholecystokinin hyperresponsiveness in functional dyspepsia

    Institute of Scientific and Technical Information of China (English)

    ASB Chua; PWN Keeling

    2006-01-01

    Functional dyspepsia (FD) is a common disorder of yet uncertain etiology. Dyspeptic symptoms are usually meal related and suggest an association to gastrointestinal (GI) sensorimotor dysfunction. Cholecystokinin (CCK) is an established brain-gut peptide that plays an important regulatory role in gastrointestinal function. It inhibits gastric motility and emptying via a capsaicin sensitive vagal pathway. The effects on emptying are via its action on the proximal stomach and pylorus. CCK is also involved in the regulation of food intake. It is released in the gut in response to a meal and acts via vagal afferents to induce satiety. Furthermore CCK has also been shown to be involved in the pathogenesis of panic disorder, anxiety and pain. Other neurotransmitters such as serotonin and noradrenaline may be implicated with CCK in the coordination of GI activity. In addition,intravenous administration of CCK has been observed to reproduce the symptoms in FD and this effect can be blocked both by atropine and Ioxiglumide (CCK-A antagonist). It is possible that an altered response to CCK may be responsible for the commonly observed gastric sensorimotor dysfunction, which may then be associated with the genesis of dyspeptic symptoms.

  6. Cholecystokinin-8 activates myenteric neurons in 21- and 35-day old but not 4- and 14-day old rats.

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    Washington, Martha C; Murry, Candace R; Raboin, Shannon J; Roberson, Allison E; Mansour, Mahmoud M; Williams, Carol S; Sayegh, Ayman I

    2011-02-01

    Cholecystokinin (CCK) activates the myenteric neurons of adult rats. The goal of this work is to determine the ontogeny of this activation by CCK-8 in the myenteric plexus of the duodenum (2cm immediately following the pyloric sphincter aborally) and compare it with that of the dorsal vagal complex (DVC) - which occurs in 1-day old pups. Despite the existence of both of the CCK receptors, CCK(1) and CCK(2), in 4, 14, 21 and 35 day old rats, CCK-8 (0, 5, 10, 20 and 40μg/kg, i.p.) increased Fos-like immunoreactivity (Fos-LI, a marker for neuronal activation) in the myenteric neurons of 21- and 35-day old rats but in the DVC of all age groups. As such, this belated activation of myenteric neurons by CCK-8 compared to the DVC may reflect a delayed role for these neurons in CCK-related functions.

  7. On the existence and function of galanin receptor heteromers in the Central Nervous System

    Directory of Open Access Journals (Sweden)

    Kjell eFuxe

    2012-10-01

    Full Text Available Galanin receptor (GalR subtypes1-3 linked to central galanin neurons may form heteromers with each other and other types of G protein coupled receptors (GPCRs in the Central Nervous System (CNS. These heteromers may be one molecular mechanism for galanin peptides and their N-terminal fragments (gal 1-15 to modulate the function of different types of glia-neuronal networks in the CNS, especially the emotional and the cardiovascular networks. GalR-5-HT1A heteromers likely exist with antagonistic GalR-5-HT1A receptor-receptor interactions in the ascending midbrain raphe 5-HT neuron systems and their target regions. They represent a novel target for antidepressant drugs. Evidence is given for the existence of GalR1-5-HT1A heteromers in cellular models with transinhibition of the protomer signaling. A GalR1-GalR2 heteromer is proposed to be a galanin N-terminal fragment preferring receptor (1-15 in the CNS. Furthermore, a GalR1-GalR2-5-HT1A heterotrimer is postulated to explain why only galanin (1-15 but not galanin (1-29 can antagonistically modulate the 5-HT1A receptors in the dorsal hippocampus rich in gal fragment binding sites. The results underline a putative role of different types of GalR-5-HT1A heteroreceptor complexes in depression. GalR antagonists may also have therapeutic actions in depression by blocking the antagonistic GalR-NPYY1 receptor interactions in putative GalR-NPYY1 receptor heteromers in the CNS resulting in increases in NPYY1 transmission and antidepressant effects. In contrast the galanin fragment receptor (a postulated GalR1-GalR2 heteromer appears to be linked to the NPYY2 receptor enhancing the affinity of the NPYY2 binding sites in a putative GalR1-GalR2-NPYY2 heterotrimer. Finally, putative GalR-α2-adrenoreceptor heteromers with antagonistic receptor-receptor interactions may be a widespread mechanism in the CNS for integration of galanin and noradrenaline signals also of likely relevance for depression.

  8. Cholecystokinin and pancreatic cancer: the chicken or the egg?

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    Smith, Jill P; Solomon, Travis E

    2014-01-01

    The gastrointestinal peptide cholecystokinin (CCK) causes the release of pancreatic digestive enzymes and growth of the normal pancreas. Exogenous CCK administration has been used in animal models to study pancreatitis and also as a promoter of carcinogen-induced or Kras-driven pancreatic cancer. Defining CCK receptors in normal human pancreas has been problematic because of its retroperitoneal location, high concentrations of pancreatic proteases, and endogenous RNase. Most studies indicate that the predominant receptor in human pancreas is the CCK-B type, and CCK-A is the predominant form in rodent pancreas. In pancreatic cancer cells and tumors, the role of CCK is better established because receptors are often overexpressed by these cancer cells and stimulation of such receptors promotes growth. Furthermore, in established cancer, endogenous production of CCK and/or gastrin occurs and their actions stimulate the synthesis of more receptors plus growth by an autocrine mechanism. Initially it was thought that the mechanism by which CCK served to potentiate carcinogenesis was by interplay with inflammation in the pancreatic microenvironment. But with the recent findings of CCK receptors on early PanIN (pancreatic intraepithelial neoplasia) lesions and on stellate cells, the question has been raised that perhaps CCK actions are not the result of cancer but an early driving promoter of cancer. This review will summarize what is known regarding CCK, its receptors, and pancreatic cancer, and also what is unknown and requires further investigation to determine which comes first, the chicken or the egg, "CCK or the cancer."

  9. STUDIES ON THE HDL RECEPTORS I:EVIDENCE FOR THE EXISTENCE OF HDL RECEPTORS IN BEIJING DUCK LIVER

    Institute of Scientific and Technical Information of China (English)

    武须军; 王克勤

    1994-01-01

    It hab been found that Beijing ducks (BD)have a high level of HDL(70%),high LCAT but very low CETP activity and will not develop atheroscletosis on an atherogenic diet,suggesting that cholesterol ester is mainly carried by HDL and metabolized through an HDL receptor pathway in the liver.However,evidence of this recep-tor′s existence in the liver is not yet complete.In this paper,the HDL receptor in BD liver has been studied.Our experiments showed:1)ApoE-free 125I-HDL could bind specifically to duck hepatic cell membrane with high affinity (Kd=9.6 μg/ml)and was saturable(Bmax=8.9μg/mg cell membrane protein)at room temperature.2)Competitive inhibition studies with unlabelled duck,human,rat and chick HDL and duck apo AI and its lipo-somes formed with PC or DMPC could inhibit the binding of 125I-HDL to duck hepatic cell membranes,but LDL,apo Eand their liposomes with PC or DMPC could not with the exception of duck LDL.3)The receptor could rec-ognize apo AI but not apo B or E.4)Both phosphorase A2 and pronase could inhibit the binding activity.The above results give strong evidence for the existence of a specific HLD receptor pathway in the duck liver,support-ing our hypothesis that CE in Beijing ducks is metabolized directly through the hepatic HDL receptor instead of be-ing transfered back to VLDL and LDL,then through the LDL receptor pathway.This unique way of metabolizing CE may be behind the Beijing duck′s antiatherogenicity.

  10. The brain decade in debate: VIII. Peptide hormones and behavior: cholecystokinin and prolactin

    Directory of Open Access Journals (Sweden)

    M.C. Beinfeld

    2001-11-01

    Full Text Available This article is a transcription of an electronic symposium held on November 28, 2000 in which active researchers were invited by the Brazilian Society of Neuroscience and Behavior (SBNeC to discuss the advances of the last decade in the peptide field with particular focus on central actions of prolactin and cholecystokinin. The comments in this symposium reflect the diversity of prolactin and cholecystokinin research and demonstrate how the field has matured. Since both peptides play a role in reproductive behaviors, particularly mother-infant interactions, this was the starting point of the discussion. Recent findings on the role of the receptor subtypes as well as interaction with other peptides in this context were also discussed. Another issue discussed was the possible role of these peptides in dopamine-mediated rewarding systems. Both prolactin and cholecystokinin are involved in mechanisms controlling food intake and somatic pain thresholds. The role of peripheral inputs through vagal afferents modulating behavior was stressed. The advent of knockout animals as potential generators of new knowledge in this field was also addressed. Finally, interactions with other neuropeptides and investigation of the role of these peptides in other fields such as immunology were mentioned. Knowledge about the central functions of prolactin and cholecystokinin has shown important advances. The role of these peptides in neurological and psychiatric syndromes such as anorexia, drug abuse and physiological disturbances that lead to a compromised maternal behavior seems relevant.

  11. Cholecystokinin exerts an effect via the endocannabinoid system to inhibit GABAergic transmission in midbrain periaqueductal gray.

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    Mitchell, Vanessa A; Jeong, Hyo-Jin; Drew, Geoffrey M; Vaughan, Christopher W

    2011-08-01

    Cholecystokinin modulates pain and anxiety via its functions within brain regions such as the midbrain periaqueductal gray (PAG). The aim of this study was to examine the cellular actions of cholecystokinin on PAG neurons. Whole-cell patch clamp recordings were made from rat midbrain PAG slices in vitro to examine the postsynaptic effects of cholecystokinin and its effects on synaptic transmission. Sulfated cholecystokinin-(26-33) (CCK-S, 100-300 nM), but not non-sulfated cholecystokinin-(26-33) (CCK-NS, 100-300 nM) produced an inward current in a sub-population of opioid sensitive and insensitive PAG neurons, which did not reverse over a range of membrane potentials. The CCK-S-induced current was abolished by the CCK1 selective antagonist devazepide (100 nM), but not by the CCK2 selective antagonists CI988 (100 nM, 1 μM) and LY225910 (1 μM). CCK-S, but not CCK-NS produced a reduction in the amplitude of evoked GABA(A)-mediated inhibitory postsynaptic currents (IPSCs) and an increase in the evoked IPSC paired-pulse ratio. By contrast, CCK-S had little effect on the rate and amplitude of TTX-resistant miniature IPSCs under basal conditions and when external K(+) was elevated. The CCK-S-induced inhibition of evoked IPSCs was abolished by the cannabinoid CB1 receptor antagonist AM251 (3 μM), the mGluR5 antagonist MPEP (10 μM) and the 1, 2-diacylglycerol lipase (DAGLα) inhibitor tetrahydrolipstatin (10 μM). In addition, CCK-S produced an increase in the rate of spontaneous non-NMDA-mediated, TTX-dependent excitatory postsynaptic currents (EPSCs). These results suggest that cholecystokinin produces direct neuronal depolarisation via CCK1 receptors and inhibits GABAergic synaptic transmission via action potential-dependent release of glutamate and mGluR5-induced endocannabinoid signaling. Thus, cholecystokinin has cellular actions within the PAG that can both oppose and reinforce opioid and cannabinoid modulation of pain and anxiety within this

  12. Receptor Signaling Directs Global Recruitment of Pre-existing Transcription Factors to Inducible Elements

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    Cockerill, Peter N.

    2016-01-01

    Gene expression programs are largely regulated by the tissue-specific expression of lineage-defining transcription factors or by the inducible expression of transcription factors in response to specific stimuli. Here I will review our own work over the last 20 years to show how specific activation signals also lead to the wide-spread re-distribution of pre-existing constitutive transcription factors to sites undergoing chromatin reorganization. I will summarize studies showing that activation of kinase signaling pathways creates open chromatin regions that recruit pre-existing factors which were previously unable to bind to closed chromatin. As models I will draw upon genes activated or primed by receptor signaling in memory T cells, and genes activated by cytokine receptor mutations in acute myeloid leukemia. I also summarize a hit-and-run model of stable epigenetic reprograming in memory T cells, mediated by transient Activator Protein 1 (AP-1) binding, which enables the accelerated activation of inducible enhancers. PMID:28018147

  13. The slope parameter of concentration-response curves used as a touchstone for the existence of spare receptors.

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    Agneter, E; Singer, E A; Sauermann, W; Feuerstein, T J

    1997-09-01

    The present work was stimulated by findings of a large reserve of presynaptic alpha2-autoreceptors in rat neocortex by different investigators and our own group, using classical models of receptor agonism. The mathematical background of these classical models seems erroneous since the asymmetry that spare receptors introduce into concentration-response curves is not considered appropriately. This asymmetry leads to a steepening of curve fits based on the logistic function. Therefore, the slope parameter c of a logistically fitted concentration-response curve can be used as a touchstone for the existence of spare receptors. Spare receptors induce a c > 1. Concentration-response data of the alpha2-autoreceptor-mediated inhibition of evoked [3H]-noradrenaline release in rat neocortex slices were re-analysed. The estimates of the slope parameter c of logistically fitted concentration-response curves obtained after treatment of rats with either vehicle or N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) to achieve an irreversible inactivation of alpha2-autoreceptors, were not compatible with the existence of a large receptor reserve. A model for nonlinear regression analysis developed under the a priori assumption of spare receptors confirmed the absence of spare receptors. Evaluation methods which neglect the alteration of the geometrical form of concentration-response curves due to non-proportionality between receptor occupation and relative response do not seem appropriate to quantify spare receptors. These methods may detect spare receptors where they do not exist.

  14. Roles of interleukin-9 in the growth and cholecystokinin-induced intracellular calcium signaling of cultured interstitial cells of Cajal.

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    Yaoyao Gong

    Full Text Available Interstitial cells of Cajal (ICC are pacemaker cells in the gastrointestinal (GI tract and loss of ICC is associated with many GI motility disorders. Previous studies have shown that ICC have the capacity to regenerate or restore, and several growth factors are critical to their growth, maintenance or regeneration. The present study aimed to investigate the roles of interleukin-9 (IL-9 in the growth, maintenance and pacemaker functions of cultured ICC. Here, we report that IL-9 promotes proliferation of ICC, and culturing ICC with IL-9 enhances cholecystokinin-8-induced Ca²⁺ transients, which is probably caused by facilitating maintenance of ICC functions under culture condition. We also show co-localizations of cholecystokinin-1 receptor and IL-9 receptor with c-kit by double-immunohistochemical labeling. In conclusion, IL-9 can promote ICC growth and help maintain ICC functions; IL-9 probably performs its functions via IL-9 receptors on ICC.

  15. Roles of interleukin-9 in the growth and cholecystokinin-induced intracellular calcium signaling of cultured interstitial cells of Cajal.

    Science.gov (United States)

    Gong, Yaoyao; Huang, Lei; Cheng, Wenfang; Li, Xueliang; Lu, Jia; Lin, Lin; Si, Xinmin

    2014-01-01

    Interstitial cells of Cajal (ICC) are pacemaker cells in the gastrointestinal (GI) tract and loss of ICC is associated with many GI motility disorders. Previous studies have shown that ICC have the capacity to regenerate or restore, and several growth factors are critical to their growth, maintenance or regeneration. The present study aimed to investigate the roles of interleukin-9 (IL-9) in the growth, maintenance and pacemaker functions of cultured ICC. Here, we report that IL-9 promotes proliferation of ICC, and culturing ICC with IL-9 enhances cholecystokinin-8-induced Ca²⁺ transients, which is probably caused by facilitating maintenance of ICC functions under culture condition. We also show co-localizations of cholecystokinin-1 receptor and IL-9 receptor with c-kit by double-immunohistochemical labeling. In conclusion, IL-9 can promote ICC growth and help maintain ICC functions; IL-9 probably performs its functions via IL-9 receptors on ICC.

  16. Lipid transport in cholecystokinin knockout mice.

    Science.gov (United States)

    King, Alexandra; Yang, Qing; Huesman, Sarah; Rider, Therese; Lo, Chunmin C

    2015-11-01

    Cholecystokinin (CCK) is released in response to lipid feeding and regulates pancreatic digestive enzymes vital to the absorption of nutrients. Our previous reports demonstrated that cholecystokinin knockout (CCK-KO) mice fed for 10 weeks of HFD had reduced body fat mass, but comparable glucose uptake by white adipose tissues and skeletal muscles. We hypothesized that CCK is involved in energy homeostasis and lipid transport from the small intestine to tissues in response to acute treatment with dietary lipids. CCK-KO mice with comparable fat absorption had increased energy expenditure and were resistant to HFD-induced obesity. Using intraduodenal infusion of butter fat and intravenous infusion using Liposyn III, we determined the mechanism of lipid transport from the small intestine to deposition in lymph and adipocytes in CCK-KO mice. CCK-KO mice had delayed secretion of Apo B48-chylomicrons, lipid transport to the lymphatic system, and triglyceride (TG)-derived fatty acid uptake by epididymal fat in response to acute treatment of intraduodenal lipids. In contrast, CCK-KO mice had comparable TG clearance and lipid uptake by white adipocytes in response to TGs in chylomicron-like emulsion. Thus, we concluded that CCK is important for lipid transport and energy expenditure to control body weight in response to dietary lipid feeding.

  17. Progesterone receptor (PR) variants exist in breast cancer cells characterised as PR negative.

    Science.gov (United States)

    Cork, David M W; Lennard, Thomas W J; Tyson-Capper, Alison J

    2012-12-01

    Progesterone receptor (PR) expression is measured in breast cancer by immunohistochemistry using N-terminally targeted antibodies and serves as a biomarker for endocrine therapeutic decisions. Extensive PR alternative splicing has been reported which may generate truncated PR variant proteins which are not detected by current breast cancer screening or may alter the function of proteins detected in screening. However, the existence of such truncated PR variants remains controversial. We have characterised PR protein expression in breast cancer cell lines using commercial PR antibodies targeting different epitopes. Truncated PR proteins are detected in reportedly PR negative MDA-MB-231 cells using a C-terminally targeted antibody. Antibody specificity was confirmed by immunoblotting following siRNA knockdown of PR expression. We have further demonstrated that alternatively spliced PR mRNA is present in MDA-MB-231 cells and in reportedly PR-negative breast tumour tissue which could encode the truncated PR proteins detected by the C-terminal antibody. The potential function of PR variant proteins present in MDA-MB-231 cells was also assessed, indicating the ability of these PR variants to bind progesterone, interact with a nuclear PR co-factor and bind DNA. These findings suggest that alternative splicing may generate functional truncated PR variant proteins which are not detected by breast cancer screening using N-terminally targeted antibodies leading to misclassification as PR negative.

  18. Cholecystokinin plays a novel protective role in diabetic kidney through anti-inflammatory actions on macrophage: anti-inflammatory effect of cholecystokinin.

    Science.gov (United States)

    Miyamoto, Satoshi; Shikata, Kenichi; Miyasaka, Kyoko; Okada, Shinichi; Sasaki, Motofumi; Kodera, Ryo; Hirota, Daisho; Kajitani, Nobuo; Takatsuka, Tetsuharu; Kataoka, Hitomi Usui; Nishishita, Shingo; Sato, Chikage; Funakoshi, Akihiro; Nishimori, Hisakazu; Uchida, Haruhito Adam; Ogawa, Daisuke; Makino, Hirofumi

    2012-04-01

    Inflammatory process is involved in the pathogenesis of diabetic nephropathy. In this article, we show that cholecystokinin (CCK) is expressed in the kidney and exerts renoprotective effects through its anti-inflammatory actions. DNA microarray showed that CCK was upregulated in the kidney of diabetic wild-type (WT) mice but not in diabetic intracellular adhesion molecule-1 knockout mice. We induced diabetes in CCK-1 receptor (CCK-1R) and CCK-2R double-knockout (CCK-1R(-/-),-2R(-/-)) mice, and furthermore, we performed a bone marrow transplantation study using CCK-1R(-/-) mice to determine the role of CCK-1R on macrophages in the diabetic kidney. Diabetic CCK-1R(-/-),-2R(-/-) mice revealed enhanced albuminuria and inflammation in the kidney compared with diabetic WT mice. In addition, diabetic WT mice with CCK-1R(-/-) bone marrow-derived cells developed more albuminuria than diabetic CCK-1R(-/-) mice with WT bone marrow-derived cells. Administration of sulfated cholecystokinin octapeptide (CCK-8S) ameliorated albuminuria, podocyte loss, expression of proinflammatory genes, and infiltration of macrophages in the kidneys of diabetic rats. Furthermore, CCK-8S inhibited both expression of tumor necrosis factor-α and chemotaxis in cultured THP-1 cells. These results suggest that CCK suppresses the activation of macrophage and expression of proinflammatory genes in diabetic kidney. Our findings may provide a novel strategy of therapy for the early stage of diabetic nephropathy.

  19. Loss of cholecystokinin-containing terminals in temporal lobe epilepsy.

    Science.gov (United States)

    Sun, Chengsan; Sun, Jianli; Erisir, Alev; Kapur, Jaideep

    2014-02-01

    Altered GABA-mediated inhibition is proposed to play a role in the pathogenesis of epilepsy. Previous studies have demonstrated a loss of somatostatin-containing GABAergic interneurons innervating granule cells in epileptic animals. However, the reorganization of synapses between interneurons and granule cells has not been investigated. We studied synapse organization in an animal model of temporal lobe epilepsy (TLE) using continuous hippocampal stimulation. The distribution of axon terminals and inhibitory synapses on granule cell dendrites was studied using a combination of immunohistochemistry and pre-embedding electron microscopy techniques. A whole-cell patch-clamp technique was applied to study the functional changes in GABAergic input from different interneurons. In epileptic animals, the density of cholecystokinin (CCK)-immunoreactive (IR) fibers and α2 subunit containing GABAA receptors in the inner molecular layer of the dentate gyrus was reduced. Quantitative immuno-electron microscopy study revealed that the ratio of CCK-containing symmetric synapses to the total symmetric synapses was reduced. The frequency of GABAergic synaptic currents (sIPSC) was decreased and their amplitude was increased. The inhibitory effect of the activation of cannabinoid 1 (CB1) receptors was also reduced in epileptic animals. Isolation of CCK- and parvalbumin (PV)-containing GABAergic inputs by N- and P/Q-type calcium channel blockers respectively suggested that GABA release from CCK-containing interneurons was selectively reduced in epileptic rats. This study found that there was a loss of CCK-containing GABAergic synapses to granule cells both morphologically and functionally. These studies add to our understanding of the mechanisms that contribute to altering GABAergic inhibition of granule cells in TLE.

  20. The predominant cholecystokinin in human plasma and intestine is cholecystokinin-33

    DEFF Research Database (Denmark)

    Rehfeld, J F; Sun, G; Christensen, T;

    2001-01-01

    Cholecystokinin (CCK) occurs in multiple molecular forms; the major ones are CCK-58, -33, -22, and -8. Their relative abundance in human plasma and intestine, however, is debated. To settle the issue, extracts of intestinal biopsies and plasma from 10 human subjects have been examined...... is the second most abundant ( approximately 34% and 30%, respectively). In contrast, CCK-58 is less abundant in human intestines ( approximately 18%) and plasma ( approximately 11%). Its predominance in feline intestines, however, was confirmed. Hence, the results show a significant species variation...

  1. Postsynaptic Depolarization Enhances GABA Drive to Dorsomedial Hypothalamic Neurons through Somatodendritic Cholecystokinin Release.

    Science.gov (United States)

    Crosby, Karen M; Baimoukhametova, Dinara V; Bains, Jaideep S; Pittman, Quentin J

    2015-09-23

    Somatodendritically released peptides alter synaptic function through a variety of mechanisms, including autocrine actions that liberate retrograde transmitters. Cholecystokinin (CCK) is a neuropeptide expressed in neurons in the dorsomedial hypothalamic nucleus (DMH), a region implicated in satiety and stress. There are clear demonstrations that exogenous CCK modulates food intake and neuropeptide expression in the DMH, but there is no information on how endogenous CCK alters synaptic properties. Here, we provide the first report of somatodendritic release of CCK in the brain in male Sprague Dawley rats. CCK is released from DMH neurons in response to repeated postsynaptic depolarizations, and acts in an autocrine fashion on CCK2 receptors to enhance postsynaptic NMDA receptor function and liberate the retrograde transmitter, nitric oxide (NO). NO subsequently acts presynaptically to enhance GABA release through a soluble guanylate cyclase-mediated pathway. These data provide the first demonstration of synaptic actions of somatodendritically released CCK in the hypothalamus and reveal a new form of retrograde plasticity, depolarization-induced potentiation of inhibition. Significance statement: Somatodendritic signaling using endocannabinoids or nitric oxide to alter the efficacy of afferent transmission is well established. Despite early convincing evidence for somatodendritic release of neurohypophysial peptides in the hypothalamus, there is only limited evidence for this mode of release for other peptides. Here, we provide the first evidence for somatodendritic release of the satiety peptide cholecystokinin (CCK) in the brain. We also reveal a new form of synaptic plasticity in which postsynaptic depolarization results in enhancement of inhibition through the somatodendritic release of CCK.

  2. Cardiovascular and inflammatory response to cholecystokinin during endotoxemic shock.

    Science.gov (United States)

    Saia, Rafael Simone; Bertozi, Giuliana; Mestriner, Fabíola Leslie; Antunes-Rodrigues, José; Queiróz Cunha, Fernando; Cárnio, Evelin Capellari

    2013-01-01

    Cholecystokinin (CCK) was first described as a gastrointestinal hormone, but its receptors have been located in cardiac and vascular tissues, as well as in immune cells. Our aims were to investigate the role of CCK on lipopolysaccharide (LPS)-induced hypotension and its ability to modulate previously reported inflammatory mediators, therefore affecting cardiovascular function. To conduct these experiments, rats had their jugular vein cannulated for drug administration, and also, the femoral artery cannulated for mean arterial pressure (MAP) and heart rate records. Endotoxemia induced by LPS from Escherichia coli (1.5 mg/kg; i.v.) stimulated the release of CCK, a progressive drop in MAP, and increase in heart rate. Plasma tumor necrosis factor α (TNF-α), interleukin 10 (IL-10), nitrate, vasopressin, and lactate levels were elevated in the endotoxemic rats. The pretreatment with proglumide (nonselective CCK antagonist; 30 mg/kg; i.p.) aggravated the hypotension and also increased plasma TNF-α and lactate levels. On the other hand, CCK (0.4 μg/kg; i.v.) administered before LPS significantly restored MAP, reduced aortic and hepatic inducible nitric oxide synthase (iNOS) production, and elevated plasma vasopressin and IL-10 concentrations; it did not affect TNF-α. Physiological CCK concentration reduced nitrite and iNOS synthesis by peritoneal macrophages, possibly through a self-regulatory IL-10-dependent mechanism. Together, these data suggest a new role for the peptide CCK in modulating MAP, possibly controlling the inflammatory response, stimulating the anti-inflammatory cytokine, IL-10, and reducing vascular and macrophage iNOS-derived nitric oxide production. Based on these findings, CCK could be used as an adjuvant therapeutic agent to improve cardiovascular function.

  3. The subfornical organ: a novel site of action of cholecystokinin.

    Science.gov (United States)

    Ahmed, Al-Shaimaa F; Dai, Li; Ho, Winnie; Ferguson, Alastair V; Sharkey, Keith A

    2014-03-01

    The subfornical organ (SFO) is an important sensory circumventricular organ implicated in the regulation of fluid homeostasis and energy balance. We investigated whether the SFO is activated by the hormone cholecystokinin (CCK). CCK₁ and CCK₂ receptors were identified in the SFO by RT-PCR. Dissociated SFO neurons that responded to CCK (40/77), were mostly depolarized (9.2 ± 0.9 mV, 30/77), but some were hyperpolarized (-7.3 ± 1.1 mV, 10/77). We next examined the responses of SFO neurons in vivo to CCK (16 μg/kg ip), in the presence and absence of CCK₁ or CCK₂ receptor antagonists (devazepide; 600 μg/kg and L-365,260; 100 μg/kg, respectively), using the functional activation markers c-Fos and phosphorylated extracellular signal-related kinase (p-ERK). The nucleus of the solitary tract (NTS) served as a control for CCK-induced activity. There was a significant increase in c-Fos expression in the NTS (259.2 ± 20.8 neurons) compared with vehicle (47.5 ± 2.5). Similarly, in the SFO, c-Fos was expressed in 40.5 ± 10.6 neurons in CCK-treated compared with 6.6 ± 2.7 in vehicle-treated rats (P < 0.01). Devazepide significantly reduced the effects of CCK in the NTS but not in SFO. L-365,260 blocked the effects of CCK in both brain regions. CCK increased the number of p-ERK neurons in NTS (27.0 ± 4.0) as well as SFO (18.0 ± 4.0), compared with vehicle (8.0 ± 2.6 and 4.3 ± 0.6, respectively; P < 0.05). Both devazepide and L-365,260 reduced CCK-induced p-ERK in NTS, but only L-365,260 reduced it in the SFO. In conclusion, the SFO represents a novel brain region at which circulating CCK may act via CCK₂ receptors to influence central autonomic control.

  4. Effect of cholecystokinin on experimental neuronal aging

    Institute of Scientific and Technical Information of China (English)

    Xiao-Jiang Sun; Qin-Chi Lu; Yan Cai

    2005-01-01

    AIM: To observe the effect of cholecystokinin (CCK) on lipofusin value, neuronal dendrite and spine ultrastructure, and total cellular protein during the process of experimental neuronal aging.METHODS: Experimental neuronal aging study model was established by NBA2cellular serum-free culture method. By using single irtracellular lipofusin value from microspectrophotometry,morphology of neuronal dendrites and spines from the scanner electron microscopy, and total cellular protein as the indexes of experimental neuronal aging, we observed the effect of CCK8 on the process of experimental neuronal aging.RESULTS: Under the condition of serum-free culture,intracellular fluorescence value (%) increased with the extension of culture time (1 d 8.51±3.43; 5 d 10.12±3.03;10 d 20.54±10.3; 15 d 36.88±10.49; bP<0.01). When CCK was added to serum-free culture medium, intracellular lipofusin value (%) decreased remarkably after consecutive CCK reaction for 10 and 15 d (control 36.88±10.49; 5 d 32.03±10.01; 10 d 14.37±5.55; 15 d 17.31±4.80; bP<0.01).As the time of serum-free culturing was prolonged, the number of neuronal dendrite and spine cells decreased.The later increased in number when CCK8 was added. CCK8 could improve the total cellular protein in the process of experimental neuronal aging.CONCLUSION: CCK8 may prolong the process of experimental neuronal aging by maintaining the structure and the number of neuronal dendrite and spine cells and changing the total cellular protein.

  5. Comprehensive gene expression analysis of rice aleurone cells: probing the existence of an alternative gibberellin receptor.

    Science.gov (United States)

    Yano, Kenji; Aya, Koichiro; Hirano, Ko; Ordonio, Reynante Lacsamana; Ueguchi-Tanaka, Miyako; Matsuoka, Makoto

    2015-02-01

    Current gibberellin (GA) research indicates that GA must be perceived in plant nuclei by its cognate receptor, GIBBERELLIN INSENSITIVE DWARF1 (GID1). Recognition of GA by GID1 relieves the repression mediated by the DELLA protein, a model known as the GID1-DELLA GA perception system. There have been reports of potential GA-binding proteins in the plasma membrane that perceive GA and induce α-amylase expression in cereal aleurone cells, which is mechanistically different from the GID1-DELLA system. Therefore, we examined the expression of the rice (Oryza sativa) α-amylase genes in rice mutants impaired in the GA receptor (gid1) and the DELLA repressor (slender rice1; slr1) and confirmed their lack of response to GA in gid1 mutants and constitutive expression in slr1 mutants. We also examined the expression of GA-regulated genes by genome-wide microarray and quantitative reverse transcription-polymerase chain reaction analyses and confirmed that all GA-regulated genes are modulated by the GID1-DELLA system. Furthermore, we studied the regulatory network involved in GA signaling by using a set of mutants defective in genes involved in GA perception and gene expression, namely gid1, slr1, gid2 (a GA-related F-box protein mutant), and gamyb (a GA-related trans-acting factor mutant). Almost all GA up-regulated genes were regulated by the four named GA-signaling components. On the other hand, GA down-regulated genes showed different expression patterns with respect to GID2 and GAMYB (e.g. a considerable number of genes are not controlled by GAMYB or GID2 and GAMYB). Based on these observations, we present a comprehensive discussion of the intricate network of GA-regulated genes in rice aleurone cells.

  6. Expression of receptors for gut peptides in pancreata of BOP-treated and control hamsters

    NARCIS (Netherlands)

    Tang, C.; Biemond, I.; Appel, M.J.; Visser, C.J.T.; Woutersen, R.A.; Lamers, C.B.H.W.

    1996-01-01

    The growth of pancreatic cancers may be influenced by certain gut peptides. However, the alteration of gut peptide receptors in the progress of pancreatic carcinogenesis is largely unknown. With storage phosphor autoradiography, this study visualized and characterized receptors for cholecystokinin (

  7. An electrophysiological investigation of the effects of cholecystokinin entric neurons.

    NARCIS (Netherlands)

    Schutte, I.W.M.

    1998-01-01

    Cholecystokinin (CCK) is a peptide, which is present in the gastrointestinat tract in endocrine cells and in the enteric nervous system (ENS). A possible function in the control of motility of the small intestine has been attributed to neuronal CCK. The aim of this thesis was  to obtain a fundamenta

  8. Synthesis and biological activities of some cholecystokinin analogues substituted in position 29 by a beta-alanine.

    Science.gov (United States)

    Rodriguez, M; Rolland, M; Lignon, M F; Galas, M C; Laur, J; Aumelas, A; Martinez, J

    1989-11-01

    Syntheses of analogues of the C-terminal heptapeptide of cholecystokinin are described. These analogues were obtained by replacing glycine 29 by a beta-alanine. The C-terminal phenylalanine amide was in some cases substituted by 2-phenylethyl alcohol and/or residues of the C-terminal tetrapeptide by their D-enantiomers. These compounds were tested for their action on stimulation of amylase release from rat pancreatic acini and for their ability to inhibit binding of labeled CCK to rat pancreatic acini and guinea pig brain membranes. Some of these derivatives behaved as CCK receptor antagonists.

  9. Adipocytes promote prostate cancer stem cell self-renewal through amplification of the cholecystokinin autocrine loop.

    Science.gov (United States)

    Tang, Kai-Dun; Liu, Ji; Jovanovic, Lidija; An, Jiyuan; Hill, Michelle M; Vela, Ian; Lee, Terence Kin-Wah; Ma, Stephanie; Nelson, Colleen; Russell, Pamela J; Clements, Judith A; Ling, Ming-Tat

    2016-01-26

    Obesity has long been linked with prostate cancer progression, although the underlying mechanism is still largely unknown. Here, we report that adipocytes promote the enrichment of prostate cancer stem cells (CSCs) through a vicious cycle of autocrine amplification. In the presence of adipocytes, prostate cancer cells actively secrete the peptide hormone cholecystokinin (CCK), which not only stimulates prostate CSC self-renewal, but also induces cathepsin B (CTSB) production of the adipocytes. In return, CTSB facilitates further CCK secretion by the cancer cells. More importantly, inactivation of CCK receptor not only suppresses CTSB secretion by the adipocytes, but also synergizes the inhibitory effect of CTSB inhibitor on adipocyte-promoted prostate CSC self-renewal. In summary, we have uncovered a novel mechanism underlying the mutual interplay between adipocytes and prostate CSCs, which may help explaining the role of adipocytes in prostate cancer progression and provide opportunities for effective intervention.

  10. Effects of growth hormone deficiency and recombinant growth hormone therapy on postprandial gallbladder motility and cholecystokinin release.

    NARCIS (Netherlands)

    Moschetta, A.; Twickler, M.; Rehfeld, J.F.; Ooteghem, N.A. van; Castro Cabezas, M.; Portincasa, P.; Berge-Henegouwen, G.P. van; Erpecum, K.J. van

    2004-01-01

    In addition to cholecystokinin, other hormones have been suggested to be involved in regulation of postprandial gallbladder contraction. We aimed to evaluate effects of growth hormone (GH) on gallbladder contractility and cholecystokinin release. Gallbladder and gastric emptying (by ultrasound) and

  11. A conserved dopamine-cholecystokinin signaling pathway shapes context-dependent Caenorhabditis elegans behavior.

    Science.gov (United States)

    Bhattacharya, Raja; Touroutine, Denis; Barbagallo, Belinda; Climer, Jason; Lambert, Christopher M; Clark, Christopher M; Alkema, Mark J; Francis, Michael M

    2014-08-01

    An organism's ability to thrive in changing environmental conditions requires the capacity for making flexible behavioral responses. Here we show that, in the nematode Caenorhabditis elegans, foraging responses to changes in food availability require nlp-12, a homolog of the mammalian neuropeptide cholecystokinin (CCK). nlp-12 expression is limited to a single interneuron (DVA) that is postsynaptic to dopaminergic neurons involved in food-sensing, and presynaptic to locomotory control neurons. NLP-12 release from DVA is regulated through the D1-like dopamine receptor DOP-1, and both nlp-12 and dop-1 are required for normal local food searching responses. nlp-12/CCK overexpression recapitulates characteristics of local food searching, and DVA ablation or mutations disrupting muscle acetylcholine receptor function attenuate these effects. Conversely, nlp-12 deletion reverses behavioral and functional changes associated with genetically enhanced muscle acetylcholine receptor activity. Thus, our data suggest that dopamine-mediated sensory information about food availability shapes foraging in a context-dependent manner through peptide modulation of locomotory output.

  12. Cholecystokinin facilitates neuronal excitability in the entorhinal cortex via activation of TRPC-like channels.

    Science.gov (United States)

    Wang, Shouping; Zhang, An-Ping; Kurada, Lalitha; Matsui, Toshimitsu; Lei, Saobo

    2011-09-01

    Cholecystokinin (CCK) is one of the most abundant neuropeptides in the brain, where it interacts with two G protein-coupled receptors (CCK-1 and CCK-2). Activation of both CCK receptors increases the activity of PLC, resulting in increases in intracellular calcium ion (Ca(2+)) release and activation of PKC. Whereas high density of CCK receptors has been detected in the superficial layers of the entorhinal cortex (EC), the functions of CCK in this brain region have not been determined. Here, we studied the effects of CCK on neuronal excitability of layer III pyramidal neurons in the EC. Our results showed that CCK remarkably increased the firing frequency of action potentials (APs). The effects of CCK on neuronal excitability were mediated via activation of CCK-2 receptors and required the functions of G proteins and PLC. However, CCK-mediated facilitation of neuronal excitability was independent of inositol trisphosphate receptors and PKC. CCK facilitated neuronal excitability by activating a cationic channel to generate membrane depolarization. The effects of CCK were suppressed by the generic, nonselective cationic channel blockers, 2-aminoethyldiphenyl borate and flufenamic acid, but potentiated by gadolinium ion and lanthanum ion at 100 μM. Depletion of extracellular Ca(2+) also counteracted CCK-induced increases in AC firing frequency. Moreover, CCK-induced enhancement of neuronal excitability was inhibited significantly by intracellular application of the antibody to transient receptor potential channel 5 (TRPC5), suggesting the involvement of TRPC5 channels. Our results provide a cellular and molecular mechanism to help explain the functions of CCK in vivo.

  13. Serotonin and cholecystokinin mediate nutrient-induced segmentation in guinea pig small intestine.

    Science.gov (United States)

    Ellis, Melina; Chambers, Jordan D; Gwynne, Rachel M; Bornstein, Joel C

    2013-04-15

    Segmentation is an important process in nutrient mixing and absorption; however, the mechanisms underlying this motility pattern are poorly understood. Segmentation can be induced by luminal perfusion of fatty acid in guinea pig small intestine in vitro and mimicked by the serotonin (5-HT) reuptake inhibitor fluoxetine (300 nM) and by cholecystokinin (CCK). Serotonergic and CCK-related mechanisms underlying nutrient-induced segmentation were investigated using selective 5-HT and CCK receptor antagonists on isolated segments of small intestine luminally perfused with 1 mM decanoic acid. Motility patterns were analyzed using video imaging and spatiotemporal maps. Segmenting activity mediated by decanoic acid was depressed following luminal application of the 5-HT receptor antagonists granisetron (5-HT(3), 1 μM) and SB-207266 (5-HT(4), 10 nM) and the CCK receptor antagonists devazepide (CCK-1, 300 nM) and L-365260 (CCK-2, 300 nM), but these antagonists did not further depress segmentation when combined. The P2 receptor antagonist pyridoxal phosphate-6-azophenyl-2',4'-disulfonate (10 μM) had no effect on activity. Serosal application of 5-HT antagonists had little effect on segmentation in the duodenum but reduced activity in the jejunum when granisetron and SB-207266 were applied together. These results reveal that 5-HT(3) and 5-HT(4) receptors, as well as CCK-1 and CCK-2 receptors, are critical in regulating decanoic acid-induced segmentation. Computational simulation indicated that these data are consistent with decanoic acid activating two pathways in the mucosa that converge within the enteric neural circuitry, while contraction-induced release of 5-HT from the mucosa provides feedback into the neural circuit to set the time course of the overall contractile activity.

  14. Duodenal myotomy blocks reduction of meal size and prolongation of intermeal interval by cholecystokinin.

    Science.gov (United States)

    Lateef, Dalya M; Washington, Martha C; Raboin, Shannon J; Roberson, Allison E; Mansour, Mahmoud M; Williams, Carol S; Sayegh, Ayman I

    2012-02-01

    We have shown that vagotomy (VGX) attenuates the reduction of meal size (MS) produced by cholecystokinin (CCK) -8 and -33 and that celiaco-mesenteric ganglionectomy (CMGX) attenuates the prolongation of the intermeal interval (IMI) produced by CCK-33. Here, we report the following novel data. First, by determining the distribution of CCK(1) receptor messenger RNA, which mediates reduction of MS and prolongation of IMI by CCK, in seven regions of the gastrointestinal tract in the adult rat we found that the duodenum contains the highest concentration of this receptor in the gut. Second, based on the previous finding we performed a unique surgical technique known as duodenal myotomy (MYO), which severs all the nerves of the gut wall in the duodenum including vagus, splanchnic and enteric nerves. Third, we determined MS and IMI in duodenal MYO rats in responses to endogenous CCK-58 released by the non-nutrient, trypsin inhibitor, camostat and CCK-8 to test the possibility that the duodenum is the site of action for reduction of MS and prolongation of IMI. We found that, similar to the previous work reported by using CCK-8 and MS, duodenal MYO also blocked reduction of MS by camostat. Forth, duodenal MYO blocked prolongation of IMI by camostat. As such, our current results suggest that the duodenum is the gut site that communicates both feeding signals of endogenous CCK, MS and IMI, with the brain through vagal and splanchnic afferents.

  15. Systemic cholecystokinin amplifies vago-vagal reflex responses recorded in vagal motor neurones.

    Science.gov (United States)

    Viard, Edouard; Rogers, Richard C; Hermann, Gerlinda E

    2012-02-01

    Cholecystokinin (CCK) is a potent regulator of visceral functions as a consequence of its actions on vago-vagal reflex circuit elements. This paper addresses three current controversies regarding the role of CCK to control gastric function via vago-vagal reflexes. Specifically: (a) whether CNS vs. peripheral (vagal afferent) receptors are dominant, (b) whether the long (58) vs. short (8) isoform is more potent and (c) whether nutritional status impacts the gain or even the direction of vago-vagal reflexes. Our in vivo recordings of physiologically identified gastric vagal motor neurones (gastric-DMN) involved in the gastric accommodation reflex (GAR) show unequivocally that: (a) receptors in the coeliac-portal circulation are more sensitive in amplifying gastric vagal reflexes; (b) in the periphery, CCK8 is more potent than CCK58; and (c) the nutritional status has a marginal effect on gastric reflex control. While the GAR reflex is more sensitive in the fasted rat, CCK amplifies this sensitivity. Thus, our results are in stark contrast to recent reports which have suggested that vago-vagal reflexes are inverted by the metabolic status of the animal and that this inversion could be mediated by CCK within the CNS.

  16. Characterization and ligand identification of a membrane progesterone receptor in fungi: existence of a novel PAQR in Sporothrix schenckii

    Directory of Open Access Journals (Sweden)

    Gonzalez-Velazquez Waleska

    2012-09-01

    Full Text Available Abstract Background Adaptive responses in fungi result from the interaction of membrane receptors and extracellular ligands. Many different classes of receptors have been described in eukaryotic cells. Recently a new family of receptors classified as belonging to the progesterone-adiponectin receptor (PAQR family has been identified. These receptors have the seven transmembrane domains characteristic of G-protein coupled receptors, but their activity has not been associated directly to G proteins. They share sequence similarity to the eubacterial hemolysin III proteins. Results A new receptor, SsPAQR1 (Sporothrixschenckiiprogesterone-adiponectinQ receptor1, was identified as interacting with Sporothrix schenckii G protein alpha subunit SSG-2 in a yeast two-hybrid assay. The receptor was identified as a member of the PAQR family. The cDNA sequence revealed a predicted ORF of 1542 bp encoding a 514 amino acids protein with a calculated molecular weight of 57.8 kDa. Protein domain analysis of SsPAQR1 showed the 7 transmembrane domains (TM characteristic of G protein coupled receptors and the presence of the distinctive motifs that characterize PAQRs. A yeast-based assay specific for PAQRs identified progesterone as the agonist. S. schenckii yeast cells exposed to progesterone (0.50 mM showed an increase in intracellular levels of 3′, 5′ cyclic adenosine monophosphate (cAMP within the first min of incubation with the hormone. Different progesterone concentrations were tested for their effect on the growth of the fungus. Cultures incubated at 35°C did not grow at concentrations of progesterone of 0.05 mM or higher. Cultures incubated at 25°C grew at all concentrations tested (0.01 mM-0.50 mM with growth decreasing gradually with the increase in progesterone concentration. Conclusion This work describes a receptor associated with a G protein alpha subunit in S. schenckii belonging to the PAQR family. Progesterone was identified as the ligand

  17. C-terminal truncated cannabinoid receptor 1 coexpressed with G protein trimer in Sf9 cells exists in a precoupled state and shows constitutive activity.

    Science.gov (United States)

    Chillakuri, Chandramouli Reddy; Reinhart, Christoph; Michel, Hartmut

    2007-12-01

    We have investigated the existence of a precoupled form of the distal C-terminal truncated cannabinoid receptor 1 (CB1-417) and heterotrimeric G proteins in a heterologous insect cell expression system. CB1-417 showed higher production levels than the full-length receptor. The production levels obtained in our expression system were double the values reported in the literature. We also observed that at least the distal C-terminus of the receptor was not involved in receptor dimerization, as was predicted in the literature. Using fluorescence resonance energy transfer, we found that CB1-417 and Galpha(i1)beta(1)gamma(2) proteins were colocalized in the cells. GTPgammaS binding assays with the Sf9 cell membranes containing CB1-417 and the G protein trimer showed that the receptor could constitutively activate the Galpha(i1) protein in the absence of agonists. A CB1-specific antagonist (SR 141716A) inhibited this constitutive activity of the truncated receptor. We found that the CB1-417/Galpha(i1)beta(1)gamma(2) complex could be solubilized from Sf9 cell membranes and coimmunoprecipitated. In this study, we have proven that the receptor and G proteins can be coexpressed in higher yields using Sf9 cells, and that the protein complex is stable in detergent solution. Thus, our system can be used to produce sufficient quantities of the protein complex to start structural studies.

  18. Leptin resistance in vagal afferent neurons inhibits cholecystokinin signaling and satiation in diet induced obese rats.

    Directory of Open Access Journals (Sweden)

    Guillaume de Lartigue

    Full Text Available BACKGROUND AND AIMS: The gastrointestinal hormone cholecystokinin (CCK plays an important role in regulating meal size and duration by activating CCK1 receptors on vagal afferent neurons (VAN. Leptin enhances CCK signaling in VAN via an early growth response 1 (EGR1 dependent pathway thereby increasing their sensitivity to CCK. In response to a chronic ingestion of a high fat diet, VAN develop leptin resistance and the satiating effects of CCK are reduced. We tested the hypothesis that leptin resistance in VAN is responsible for reducing CCK signaling and satiation. RESULTS: Lean Zucker rats sensitive to leptin signaling, significantly reduced their food intake following administration of CCK8S (0.22 nmol/kg, i.p., while obese Zucker rats, insensitive to leptin, did not. CCK signaling in VAN of obese Zucker rats was reduced, preventing CCK-induced up-regulation of Y2 receptor and down-regulation of melanin concentrating hormone 1 receptor (MCH1R and cannabinoid receptor (CB1. In VAN from diet-induced obese (DIO Sprague Dawley rats, previously shown to become leptin resistant, we demonstrated that the reduction in EGR1 expression resulted in decreased sensitivity of VAN to CCK and reduced CCK-induced inhibition of food intake. The lowered sensitivity of VAN to CCK in DIO rats resulted in a decrease in Y2 expression and increased CB1 and MCH1R expression. These effects coincided with the onset of hyperphagia in DIO rats. CONCLUSIONS: Leptin signaling in VAN is required for appropriate CCK signaling and satiation. In response to high fat feeding, the onset of leptin resistance reduces the sensitivity of VAN to CCK thus reducing the satiating effects of CCK.

  19. Phospholipase C not protein kinase C is required for the activation of TRPC5 channels by cholecystokinin.

    Science.gov (United States)

    Grisanti, Laurel A; Kurada, Lalitha; Cilz, Nicholas I; Porter, James E; Lei, Saobo

    2012-08-15

    Cholecystokinin (CCK) is one of the most abundant neuropeptides in the brain where it interacts with two G protein-coupled receptors (CCK1 and CCK2). Both types of CCK receptors are coupled to G(q/11) proteins resulting in increased function of phospholipase C (PLC) pathway. Whereas CCK has been suggested to increase neuronal excitability in the brain via activation of cationic channels, the types of cationic channels have not yet been identified. Here, we co-expressed CCK2 receptors and TRPC5 channels in human embryonic kidney (HEK) 293 cells and studied the effects of CCK on TRPC5 channels using patch-clamp techniques. Our results demonstrate that activation of CCK2 receptors robustly potentiates the function of TRPC5 channels. CCK-induced activation of TRPC5 channels requires the functions of G-proteins and PLC and depends on extracellular Ca(2+). The activation of TRPC5 channels mediated by CCK2 receptors is independent of IP(3) receptors and protein kinase C. CCK-induced opening of TRPC5 channels is not store-operated because application of thapsigargin to deplete intracellular Ca(2+) stores failed to alter CCK-induced TRPC5 channel currents significantly. Bath application of CCK also significantly increased the open probability of TRPC5 single channel currents in cell-attached patches. Because CCK exerts extensive effects in the brain, our results may provide a novel mechanism to explain its roles in modulating neuronal excitability.

  20. Synthesis of analogues of the Des-Phe-NH2 C-terminal hexapeptide of cholecystokinin showing gastrin antagonist activity.

    Science.gov (United States)

    Laur, J; Rodriguez, M; Aumelas, A; Bali, J P; Martinez, J

    1986-04-01

    Four analogues of Z-CCK-27-32-NH2, Z-Tyr(SO3-)-Met-Gly-Trp-Met-Asp-NH2, a cholecystokinin receptor antagonist have been synthesized by solution methodology. In these analogues, Z-Tyr(SO3-)-Nle-Gly-Trp-Met-Asp-NH2 16, Z-Tyr(SO3-)-Nle-Gly-Trp-Nle-Asp-NH2 17, BOC-Tyr(SO3-)-Met-Gly-Trp-Met-Asp-NH2 24 and Boc-Tyr(SO3-)-Met-Gly-Trp-Nle-Asp-NH2 25 methionyl residues were replaced by norleucyl residues. Preliminary biological activity on gastrin-induced acid secretion, in rat, are reported. These derivatives proved to antagonize the action of gastrin, with ED 50 of between 0.5 and 3 mg/kg.

  1. [Protein malnutrition and response of pancreatic acinar cells to stimulation by cholecystokinin].

    Science.gov (United States)

    Prost, J; Belleville, J

    1988-01-01

    Pancreatic lobules were isolated from 2 groups of male Wistar rats after 23 days of diet. A control group (C) fed on a 20% protein diet (16% gluten + 4% casein) and an experimental group (E) on a 5% protein diet (4% gluten + 1% casein). After isolation, lobules were preincubated 10 min with 10 muCi [3H]-leucine, washed, then incubate within Krebs Ringer bicarbonate Hepes. Basal secretion, then stimulated secretion (50 pM of cholecystokinin (CCK] of radioactive and non-radioactive protein and amylase outputs were measured. During basal secretion, in (E) group, lobules secreted more proteins than (C) one, the same outputs of amylase and radioactive protein were observed in both groups. The stimulated secretion by CCK increased the outputs of non-radioactive protein and amylase of lobules (T) (2-3 fold), but was without effect on lobule (E) outputs. Therefore, a low-protein diet involved a decrease of CCK sensibility on acinar cells, this fact might be mediated by a decreasing number and/or affinity of their CCK receptors.

  2. Plasminogen activator inhibitor (PAI)-1 suppresses inhibition of gastric emptying by cholecystokinin (CCK) in mice.

    Science.gov (United States)

    Gamble, Joanne; Kenny, Susan; Dockray, Graham J

    2013-08-10

    The intestinal hormone cholecystokinin (CCK) delays gastric emptying and inhibits food intake by actions on vagal afferent neurons. Recent studies suggest plasminogen activator inhibitor (PAI)-1 suppresses the effect of CCK on food intake. In this study we asked whether PAI-1 also modulated CCK effects on gastric emptying. Five minute gastric emptying of liquid test meals was studied in conscious wild type mice (C57BL/6) and in transgenic mice over-expressing PAI-1 in gastric parietal cells (PAI-1H/Kβ mice), or null for PAI-1. The effects of exogenous PAI-1 and CCK8s on gastric emptying were studied after ip administration. Intragastric peptone delayed gastric emptying in C57BL/6 mice by a mechanism sensitive to the CCK-1 receptor antagonist lorglumide. Peptone did not delay gastric emptying in PAI-1-H/Kβ mice. Exogenous CCK delayed gastric emptying of a control test meal in C57BL/6 mice and this was attenuated by administration of PAI-1; exogenous CCK had no effect on emptying in PAI-1-H/Kβ mice. Prior administration of gastrin to increase gastric PAI-1 inhibited CCK-dependent effects on gastric emptying in C57BL/6 mice but not in PAI-1 null mice. Thus, both endogenous and exogenous PAI-1 inhibit the effects of CCK (whether exogenous or endogenous) on gastric emptying. The data are compatible with emerging evidence that gastric PAI-1 modulates vagal effects of CCK.

  3. Gastrointestinal Hormone Cholecystokinin Increases P-Glycoprotein Membrane Localization and Transport Activity in Caco-2 Cells.

    Science.gov (United States)

    Yano, Kentaro; Shimizu, Saori; Tomono, Takumi; Ogihara, Takuo

    2017-09-01

    It was reported that stimulation of taste receptor type 2 member 38 by a bitter substance, phenylthiocarbamide (PTC), increased P-glycoprotein (P-gp) mRNA level and transport activity via release of the gastrointestinal hormone cholecystokinin-8 (CCK-8) at 9 h. Therefore, we hypothesized that CCK-8 and PTC might also regulate P-gp activity more rapidly via a different mechanism. As a result, we found that the pretreatment of human colon adenocarcinoma (Caco-2) cells with 10-mM PTC significantly decreased the intracellular accumulation of P-gp substrate rhodamine 123 (Rho123) compared with the control after 90-min incubation. Moreover, CCK-8 treatments significantly reduced the accumulation of Rho123 within 30 min, compared with the control. On the other hand, when Caco-2 cells were pretreated with PTC, the efflux ratio of Rho123 was significantly increased compared with control. The efflux ratio of Rho123 in CCK-8 treatment cells was also significantly increased compared with control. Furthermore, CCK-8 increased the phosphorylation of the scaffold proteins ezrin, radixin, and moesin, which regulate translocation of P-gp to the plasma membrane. Therefore, our results indicate that PTC induced release of CCK-8, which in turn induced the phosphorylation of ezrin, radixin, and moesin proteins, leading to upregulation of P-gp transport activity via increased membrane localization of P-gp. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  4. Ileal interposition attenuates the satiety responses evoked by cholecystokinin-8 and -33.

    Science.gov (United States)

    Metcalf, Shannon A; Washington, Martha C; Brown, Thelma A L; Williams, Carol S; Strader, April D; Sayegh, Ayman I

    2011-06-01

    One of the possible mechanisms by which the weight-reducing surgical procedure ileal interposition (II) works is by increasing circulating levels of lower gut peptides that reduce food intake, such as glucagon like peptide-1 and peptide YY. However, since this surgery involves both lower and upper gut segments, we tested the hypothesis that II alters the satiety responses evoked by the classic upper gut peptide cholecystokinin (CCK). To test this hypothesis, we determined meal size (MS), intermeal interval (IMI) and satiety ratio (SR) evoked by CCK-8 and -33 (0, 1, 3, 5nmol/kg, i.p.) in two groups of rats, II and sham-operated. CCK-8 and -33 reduced MS more in the sham group than in the II group; CCK-33 prolonged IMI in the sham group and increased SR in both groups. Reduction of cumulative food intake by CCK-8 in II rats was blocked by devazepide, a CCK(1) receptor antagonist. In addition, as previously reported, we found that II resulted in a slight reduction in body weight compared to sham-operated rats. Based on these observations, we conclude that ileal interposition attenuates the satiety responses of CCK. Therefore, it is unlikely that this peptide plays a significant role in reduction of body weight by this surgery.

  5. The feeding responses evoked by endogenous cholecystokinin are regulated by different gastrointestinal sites.

    Science.gov (United States)

    Washington, Martha C; Williams, Kasey; Sayegh, Ayman I

    2016-02-01

    The current study tested the hypothesis that cholecystokinin (CCK) A receptor (CCKAR) in areas supplied by the celiac artery (CA), stomach and upper duodenum, and the cranial mesenteric artery (CMA), small and parts of the large intestine, is necessary for reduction of meal size, prolongation of the intermeal interval (time between first and second meal) and increased satiety ratio (intermeal interval/meal size or amount of food consumed during any given unit of time) by the non-nutrient stimulator of endogenous CCK release camostat. Consistent with our previous findings camostat reduced meal size, prolonged the intermeal interval and increased the satiety ratio. Here, we report that blocking CCKAR in the area supplied by the celiac artery attenuated reduction of meal size by camostat more so than the cranial mesenteric artery route. Blocking CCKAR in the area supplied by the cranial mesenteric artery attenuated prolongation of the intermeal interval length and increased satiety ratio by camostat more so than the celiac artery route. Blocking CCKAR in the areas supplied by the femoral artery (control) failed to alter the feeding responses evoked by camostat. These results support the hypothesis that CCKAR in the area supplied by the CA is necessary for reduction of meal size by camostat whereas CCKAR in the area supplied by the CMA is necessary for prolongation of the intermeal interval and increased satiety ratio by this substance. Our results demonstrate that meal size and intermeal interval length by camostat are regulated through different gastrointestinal sites.

  6. Appetite controlled by a cholecystokinin nucleus of the solitary tract to hypothalamus neurocircuit.

    Science.gov (United States)

    D'Agostino, Giuseppe; Lyons, David J; Cristiano, Claudia; Burke, Luke K; Madara, Joseph C; Campbell, John N; Garcia, Ana Paula; Land, Benjamin B; Lowell, Bradford B; Dileone, Ralph J; Heisler, Lora K

    2016-03-14

    The nucleus of the solitary tract (NTS) is a key gateway for meal-related signals entering the brain from the periphery. However, the chemical mediators crucial to this process have not been fully elucidated. We reveal that a subset of NTS neurons containing cholecystokinin (CCK(NTS)) is responsive to nutritional state and that their activation reduces appetite and body weight in mice. Cell-specific anterograde tracing revealed that CCK(NTS) neurons provide a distinctive innervation of the paraventricular nucleus of the hypothalamus (PVH), with fibers and varicosities in close apposition to a subset of melanocortin-4 receptor (MC4R(PVH)) cells, which are also responsive to CCK. Optogenetic activation of CCK(NTS) axon terminals within the PVH reveal the satiating function of CCK(NTS) neurons to be mediated by a CCK(NTS)→PVH pathway that also encodes positive valence. These data identify the functional significance of CCK(NTS) neurons and reveal a sufficient and discrete NTS to hypothalamus circuit controlling appetite.

  7. Cholecystokinin in plasma predicts cardiovascular mortality in elderly females

    DEFF Research Database (Denmark)

    Gøtze, Jens P.; Rehfeld, Jens F; Alehagen, Urban

    2016-01-01

    observed a marked difference between the genders, where CCK concentrations in the 4th quartile were associated with a higher 5-year cardiovascular mortality in female patients (HR 8.99, 95% C.I.: 3.49-102.82, p=0.0007) compared to men (1.47, 95% C.I.: 0.7-3.3, p=0.35). In contrast, no significant...... information was obtained from 4th quartile gastrin concentrations on 5-year cardiovascular mortality risk. CONCLUSIONS: CCK in plasma is an independent marker of cardiovascular mortality in elderly female patients. The study thus introduces measurement of plasma CCK in gender-specific cardiovascular risk......BACKGROUND: Cholecystokinin (CCK) and gastrin are related gastrointestinal hormones with documented cardiovascular effects of exogenous administration. It is unknown whether measurement of endogenous CCK or gastrin in plasma contains information regarding cardiovascular mortality. METHODS...

  8. Cholecystokinin expression in tumors: biogenetic and diagnostic implications.

    Science.gov (United States)

    Rehfeld, Jens F

    2016-09-01

    Cholecystokinin (CCK) is a classic gut hormone. CCK is also a complex system of peptides expressed in several molecular forms in enteroendocrine I cells, in cerebral and peripheral neurons, in cardiac myocytes and spermatozoa. CCK gene expression has now been found at protein or peptide level in different neuroendocrine tumors; cerebral gliomas and astrocytomas and specific pediatric tumors. Tumor hypersecretion of CCK was recently reported in a patient with a metastatic islet cell tumor and hypercholecystokininemia resulting in a novel tumor syndrome, the cholecystokininoma syndrome. This review presents an overview of the cell-specific biogenesis of CCK peptides, and a description of the CCK expression in tumors and of the cholecystokininoma syndrome. Finally, assays for the diagnosis of CCK-producing tumors are reviewed.

  9. Cholecystokinin-octapeptide restored morphine-induced hippocampal long-term potentiation impairment in rats.

    Science.gov (United States)

    Wen, Di; Zang, Guoqing; Sun, DongLei; Yu, Feng; Mei, Dong; Ma, Chunling; Cong, Bin

    2014-01-24

    Cholecystokinin-octapeptide (CCK-8), which is a typical brain-gut peptide, exerts a wide range of biological activities on the central nervous system. We have previously reported that CCK-8 significantly alleviated morphine-induced amnesia and reversed spine density decreases in the CA1 region of the hippocampus in morphine-treated animals. Here, we investigated the effects of CCK-8 on long-term potentiation (LTP) in the lateral perforant path (LPP)-granule cell synapse of rat dentate gyrus (DG) in acute saline or morphine-treated rats. Population spikes (PS), which were evoked by stimulation of the LPP, were recorded in the DG region. Acute morphine (30mg/kg, s.c.) treatment significantly attenuated hippocampal LTP and CCK-8 (1μg, i.c.v.) restored the amplitude of PS that was attenuated by morphine injection. Furthermore, microinjection of CCK-8 (0.1 and 1μg, i.c.v.) also significantly augmented hippocampal LTP in saline-treated (1ml/kg, s.c.) rats. Pre-treatment of the CCK2 receptor antagonist L-365,260 (10μg, i.c.v) reversed the effects of CCK-8, but the CCK1 receptor antagonist L-364,718 (10μg, i.c.v) did not. The present results demonstrate that CCK-8 attenuates the effect of morphine on hippocampal LTP through CCK2 receptors and suggest an ameliorative function of CCK-8 on morphine-induced memory impairment.

  10. 吗啡对原代培养大鼠海马神经元CCK受体mRNA表达的影响%Effect of expression of cholecystokinin receptor mRNA in primary culturing hippocampus neurons of newborn rat induced by morphine

    Institute of Scientific and Technical Information of China (English)

    赵丽; 丛斌; 吴嫒嫒; 李淑瑾; 闫玉仙; 姚玉霞; 倪志宇

    2006-01-01

    目的探讨原代培养大鼠海马神经元上胆囊收缩素(cholecystokinin,CCK)受体CCK-AR及CCK-BR mRNA表达及吗啡对其表达的影响.方法采用新生大鼠海马神经元无血清原代培养技术,用吗啡(100 μmol·L-1培养基)孵育3,6,12,18,24,36,48,72 h,以及采用不同浓度吗啡(10,100,150 μmol·L-1)孵育6、30 h后,RT-PCR及测序方法观察CCK-AR及CCK-BR mRNA表达及吗啡对其表达的影响.结果 RT-PCR结果显示,CCK-AR和CCK-BR mRNA在原代大鼠海马神经元上均有表达;CCK-AR mRNA RT-PCR扩增产物为218 bp, CCK-BR mRNA RT-PCR扩增产物为444 bp,经测序证实结果的可靠性;CCK-BR mRNA的表达量明显高于CCK-AR.吗啡作用后可使2种CCK受体mRNA表达上调.吗啡浓度及作用时间的不同对CCK-AR和CCK-BR mRNA表达的影响不同.结论原代大鼠海马神经元上有CCK-AR和CCK-BR,以CCK-BR为主;吗啡可使2种CCK受体mRNA表达上调.

  11. Interaction between the cholecystokinin and endogenous cannabinoid systems in cued fear expression and extinction retention.

    Science.gov (United States)

    Bowers, Mallory E; Ressler, Kerry J

    2015-02-01

    Post-traumatic stress disorder (PTSD) is thought to develop, in part, from improper inhibition of fear. Accordingly, one of the most effective treatment strategies for PTSD is exposure-based psychotherapy. Ideally, neuroscience would inform adjunct therapies that target the neurotransmitter systems involved in extinction processes. Separate studies have implicated the cholecystokinin (CCK) and endocannabinoid systems in fear; however, there is a high degree of anatomical colocalization between the cannabinoid 1 receptor (Cnr1) and CCK in the basolateral amygdala (BLA), a brain region critical for emotion regulation. Although most research has focused on GABA and GABAergic plasticity as the mechanism by which Cnr1 mediates fear inhibition, we hypothesize that a functional interaction between Cnr1 and CCKB receptor (CCKBR) is critical for fear extinction processes. In this study, systemic pharmacological manipulation of the cannabinoid system modulated cued fear expression in C57BL/6J mice after consolidation of auditory fear conditioning. Knockout of the CCKBR, however, had no effect on fear- or anxiety-like behaviors. Nonetheless, administration of a Cnr1 antagonist increased freezing behavior during a cued fear expression test in wild-type subjects, but had no effect on freezing behavior in CCKBR knockout littermates. In addition, we found that Cnr1-positive fibers form perisomatic clusters around CCKBR-positive cell bodies in the BLA. These CCKBR-positive cells comprise a molecularly heterogenous population of excitatory and inhibitory neurons. These findings provide novel evidence that Cnr1 contributes to cued fear expression via an interaction with the CCK system. Dysfunctional Cnr1-CCKBR interactions might contribute to the etiology of, or result from, fear-related psychiatric disease.

  12. Neuronal network of panic disorder: the role of the neuropeptide cholecystokinin.

    Science.gov (United States)

    Zwanzger, P; Domschke, K; Bradwejn, J

    2012-09-01

    Panic disorder (PD) is characterized by panic attacks, anticipatory anxiety and avoidance behavior. Its pathogenesis is complex and includes both neurobiological and psychological factors. With regard to neurobiological underpinnings, anxiety in humans seems to be mediated through a neuronal network, which involves several distinct brain regions, neuronal circuits and projections as well as neurotransmitters. A large body of evidence suggests that the neuropeptide cholecystokinin (CCK) might be an important modulator of this neuronal network. Key regions of the fear network, such as amygdala, hypothalamus, peraqueductal grey, or cortical regions seem to be connected by CCKergic pathways. CCK interacts with several anxiety-relevant neurotransmitters such as the serotonergic, GABA-ergic and noradrenergic system as well as with endocannabinoids, NPY and NPS. In humans, administration of CCK-4 reliably provokes panic attacks, which can be blocked by antipanic medication. Also, there is some support for a role of the CCK system in the genetic pathomechanism of PD with particularly strong evidence for the CCK gene itself and the CCK-2R (CCKBR) gene. Thus, it is hypothesized that genetic variants in the CCK system might contribute to the biological basis for the postulated CCK dysfunction in the fear network underlying PD. Taken together, a large body of evidence suggests a possible role for the neuropeptide CCK in PD with regard to neuroanatomical circuits, neurotransmitters and genetic factors. This review article proposes an extended hypothetical model for human PD, which integrates preclinical and clinical findings on CCK in addition to existing theories of the pathogenesis of PD.

  13. Presynaptically mediated effects of cholecystokinin-8 on the excitability of area postrema neurons in rat brain slices.

    Science.gov (United States)

    Sugeta, Shingo; Hirai, Yoshiyuki; Maezawa, Hitoshi; Inoue, Nobuo; Yamazaki, Yutaka; Funahashi, Makoto

    2015-08-27

    Cholecystokinin (CCK) is a well-known gut hormone that shows anorexigenic effects via action at peripheral and central receptors. CCK is also widely distributed throughout the mammalian brain and appears to function as a neurotransmitter and neuromodulator. The area postrema is one of the circumventricular organs, located on the dorsal surface of the medulla oblongata at the caudal end of the fourth ventricle. Blood vessels in the area postrema lack a blood brain barrier, offering specific central neural elements unique access to circulating substances. Immunohistochemical studies show CCK-A receptors in the area postrema, and we reported CCK-sensitive area postrema neurons. However, the receptive mechanism of CCK in area postrema neurons still remains unexplained. We investigated the responses of area postrema neurons to agonists and antagonists of CCK receptors using whole cell and perforated patch-clamp recordings in rat brain slices. The application of CCK-8 elicited excitatory responses, such as increases in the frequency of mEPSCs (miniature excitatory postsynaptic currents), a shift toward larger amplitude mEPSCs, and increases in the frequency of action potentials. These changes were found mostly in cells not displaying the hyperpolarization-activated cation current (Ih), except for small excitatory changes in a minority of Ih-positive neurons. Tonic inward currents or an inhibitory response to CCK-8 were never seen. Analysis of the amplitude of mEPSCs before and after the administration of CCK-8 indicated the responses mediated via the presynaptic receptors. The effect of CCK-8 was abolished in the presence of CNQX (AMPA type glutamate receptor antagonist). In the presence of lorglumide (a selective CCK-A receptor antagonist), CCK-8-induced excitatory responses were inhibited. No cells responded to the administration of non-sulfated CCK-8 (CCK-8NS, a selective CCK-B receptor agonist). We conclude that CCK-8 exerts its action via presynaptic CCK-A receptors

  14. Fiber mediated receptor masking in non-infected bystander cells restricts adenovirus cell killing effect but promotes adenovirus host co-existence.

    Directory of Open Access Journals (Sweden)

    Johan Rebetz

    Full Text Available The basic concept of conditionally replicating adenoviruses (CRAD as oncolytic agents is that progenies generated from each round of infection will disperse, infect and kill new cancer cells. However, CRAD has only inhibited, but not eradicated tumor growth in xenograft tumor therapy, and CRAD therapy has had only marginal clinical benefit to cancer patients. Here, we found that CRAD propagation and cancer cell survival co-existed for long periods of time when infection was initiated at low multiplicity of infection (MOI, and cancer cell killing was inefficient and slow compared to the assumed cell killing effect upon infection at high MOI. Excessive production of fiber molecules from initial CRAD infection of only 1 to 2% cancer cells and their release prior to the viral particle itself caused a tropism-specific receptor masking in both infected and non-infected bystander cells. Consequently, the non-infected bystander cells were inefficiently bound and infected by CRAD progenies. Further, fiber overproduction with concomitant restriction of adenovirus spread was observed in xenograft cancer therapy models. Besides the CAR-binding Ad4, Ad5, and Ad37, infection with CD46-binding Ad35 and Ad11 also caused receptor masking. Fiber overproduction and its resulting receptor masking thus play a key role in limiting CRAD functionality, but potentially promote adenovirus and host cell co-existence. These findings also give important clues for understanding mechanisms underlying the natural infection course of various adenoviruses.

  15. No relationship exists between itai-itai disease and TA repeat polymorphisms of the estrogen receptor alpha gene.

    Science.gov (United States)

    Sadewa, Hamim Ahmad; Miyabe, Yuri; Nishio, Hisahide; Hayashi, Chiyo; Sutomo, Retno; Lee, Myeong Jin; Ayaki, Hitoshi; Koizumi, Naoko; Sumino, Kimiaki

    2002-08-01

    Itai-itai (ouch-ouch) disease is a syndrome accompanied by bone mineral disorders that may be related to oral cadmium exposure. Itai-itai predominantly affects postmenopausal women with a history of multiple childbirth. In a previous study we have examined the genotype distributions of PvuII and XbaI restriction fragment length polymorphisms of the estrogen receptor alpha (ER alpha) gene in patients with itai-itai disease and compared them with those of controls. However, no significant differences were shown between the genotype distributions of the patients and controls. In the present study, we determined the TA repeat polymorphisms of the patients and controls. The distributions of the patients were: HH 25.0%, HL 50.0%, and LL 25.0%; where HH includes two alleles with a high number of TA repeats (TA> or =16), HL includes one high number allele and one low number allele (TAitai-itai disease.

  16. The role of cholecystokinin in the induction of aggressive behavior: a focus on the available experimental data (review).

    Science.gov (United States)

    Katsouni, E; Zarros, A; Skandali, N; Tsakiris, Stylianos; Lappas, D

    2013-12-01

    Cholecystokinin (CCK) is a neuropeptide that is (among others) reportedly involved in the pathophysiology of psychiatric disorders. The excitatory role of CCK in negative affective emotions as well as in aversive reactions, antisocial behaviors and memories, has been indicated by numerous electrophysiological, neurochemical and behavioral methodologies on both animal models for anxiety and human studies. The current review article summarizes the existing experimental evidence with regards to the role of CCK in the induction of aggressive behavior, and: (a) synopsizes the anatomical circuits through which it could potentially mediate all types of aggressive behavior, as well as (b) highlights the potential use of these experimental evidence in the current research quest for the clinical treatment of mood and anxiety disorders.

  17. Endogenous elevation of plasma cholecystokinin does not prevent gallstones

    Science.gov (United States)

    Shahid, Rafiq A.; Wang, David Q.-H.; Fee, Brian E.; McCall, Shannon J.; Romac, Joelle M.-J.; Vigna, Steven R.; Liddle, Rodger A.

    2015-01-01

    Background Regular gallbladder contraction reduces bile stasis and prevents gallstone formation. Intraduodenal administration of exogenous pancreatic secretory trypsin inhibitor (PSTI-I, also known as monitor peptide) causes cholecystokinin (CCK) secretion. Design We proposed that stimulation of CCK release by PSTI would produce gallbladder contraction and prevent gallstones in mice fed a lithogenic diet. Therefore, we tested the effect of overexpression of rat PSTI-I in pancreatic acinar cells on plasma CCK levels and gallbladder function in a transgenic mouse line (TgN[Psti1]; known hereafter as PSTI-I tg). Results Importantly, PSTI tg mice had elevated fasting and fed plasma CCK levels compared to wild-type (WT) mice. Only mice fed the lithogenic diet developed gallstones. Both fasting and stimulated plasma CCK levels were substantially reduced in both WT and PSTI-I tg mice on the lithogenic diet. Moreover, despite higher CCK levels PSTI-I tg animals developed more gallstones than WT animals. Conclusions Together with the previously observed decrease in CCK-stimulated gallbladder emptying in mice fed a lithogenic diet, our findings suggest that a lithogenic diet causes gallstone formation by impaired CCK secretion in addition to reduced gallbladder sensitivity to CCK. PMID:25641074

  18. Cholecystokinin as a stimulus in drug discrimination learning.

    Science.gov (United States)

    Melton, P M; Kopman, J A; Riley, A L

    1993-02-01

    Animals were trained to discriminate a relatively low dose of the octapeptide cholecystokinin (CCK) from distilled water within the conditioned taste aversion baseline of drug discrimination learning. Specifically, rats were injected with CCK (5.6 micrograms/kg) prior to the presentation of saccharin-LiCl pairings and with the CCK vehicle prior to the presentation of saccharin alone. After 10 conditioning trials (40 days), subjects acquired the discrimination, avoiding saccharin consumption following administration of CCK and consuming the same saccharin solution following the drug vehicle. Once the discrimination was acquired, a generalization function was determined for doses above and below that of the training stimulus. At doses below the training dose of CCK (i.e., 0, 3.2, and 4.2 micrograms/kg), subjects drank at control levels, whereas at the training dose and above (10 micrograms/kg) subjects significantly reduced consumption. That a relatively low dose of CCK can be used as a discriminative stimulus within a drug discrimination design may be important in that the procedure can now be used in the assessment of the pharmacological characteristics of CCK at a dose similar to that used in other behavioral assessments of the compound.

  19. Radiolabeled CCK/gastrin peptides for imaging and therapy of CCK2 receptor-expressing tumors

    NARCIS (Netherlands)

    Roosenburg, S.; Laverman, P.; Delft, F.L. van; Boerman, O.C.

    2011-01-01

    Cholecystokinin (CCK) receptors are overexpressed in numerous human cancers, like medullary thyroid carcinomas, small cell lung cancers and stromal ovarian cancers. The specific receptor-binding property of the endogenous ligands for these receptors can be exploited by labeling peptides with a radio

  20. Effect of peripheral administration of cholecystokinin on food intake in apolipoprotein AIV knockout mice.

    Science.gov (United States)

    Yoshimichi, Go; Lo, Chunmin C; Tamashiro, Kellie L K; Ma, Liyun; Lee, Dana M; Begg, Denovan P; Liu, Min; Sakai, Randall R; Woods, Stephen C; Yoshimatsu, Hironobu; Tso, Patrick

    2012-06-01

    Apolipoprotein AIV (apo AIV) and cholecystokinin (CCK) are satiation factors secreted by the small intestine in response to lipid meals. Apo AIV and CCK-8 has an additive effect to suppress food intake relative to apo AIV or CCK-8 alone. In this study, we determined whether CCK-8 (1, 3, or 5 μg/kg ip) reduces food intake in fasted apo AIV knockout (KO) mice as effectively as in fasted wild-type (WT) mice. Food intake was monitored by the DietMax food system. Apo AIV KO mice had significantly reduced 30-min food intake following all doses of CCK-8, whereas WT mice had reduced food intake only at doses of 3 μg/kg and above. Post hoc analysis revealed that the reduction of 10-min and 30-min food intake elicited by each dose of CCK-8 was significantly larger in the apo AIV KO mice than in the WT mice. Peripheral CCK 1 receptor (CCK1R) gene expression (mRNA) in the duodenum and gallbladder of the fasted apo AIV KO mice was comparable to that in WT mice. In contrast, CCK1R mRNA in nodose ganglia of the apo AIV KO mice was upregulated relative to WT animals. Similarly, upregulated CCK1R gene expression was found in the brain stem of apo AIV KO mice by in situ hybridization. Although it is possible that the increased satiating potency of CCK in apo AIV KO mice is mediated by upregulation of CCK 1R in the nodose ganglia and nucleus tractus solitarius, additional experiments are required to confirm such a mechanism.

  1. Roles of dorsomedial hypothalamic cholecystokinin signaling in the controls of meal patterns and glucose homeostasis.

    Science.gov (United States)

    Zhu, Guangjing; Yan, Jianqun; Smith, Wanli W; Moran, Timothy H; Bi, Sheng

    2012-01-18

    A role for dorsomedial hypothalamus (DMH) cholecystokinin (CCK) signaling in feeding control has been proposed. Administration of CCK into the DMH reduces food intake and OLETF rats lacking CCK1 receptors (CCK1R) become hyperphagic and obese. We hypothesized that site specific replenishment of CCK1R in the DMH of OLETF rats would attenuate aspects of their feeding deficits. Recombinant vectors of adeno-associated viral (AAV)-mediated expression of CCK1R (AAVCCK1R) were bilaterally delivered into the DMH of OLETF. OLETF rats with AAVCCK1R injections demonstrated a 65% replenishment of Cck1r mRNA expression in the DMH relative to lean LETO control rats. Although this level of replenishment did not significantly affect overall food intake or body weight through 14 weeks following viral injections, meal patterns were partially normalized in OLETF rats receiving AAVCCK1R with a significant decrease in dark cycle meal size and a small but significant decrease in daily food intake in the meal analysis chambers. Importantly, the elevation in blood glucose level of OLETF rats was attenuated by the AAVCCK1R injections (p=0.03), suggesting a role for DMH CCK signaling in glucose homeostasis. In support of this role, administration of CCK into the DMH of intact rats enhanced glucose tolerance, as this occurred through activation of CCK1R but not CCK2R signaling. In conclusion, partial replenishment of CCK1R in the DMH of OLETF rats, although insufficient for altering overall food intake and body weight, normalizes meal pattern changes and reduces blood glucose levels. Our study also shows a novel role of DMH CCK signaling in glucose homeostasis.

  2. Age and nutritional state influence the effects of cholecystokinin on energy balance.

    Science.gov (United States)

    Balaskó, M; Rostás, I; Füredi, N; Mikó, A; Tenk, J; Cséplő, P; Koncsecskó-Gáspár, M; Soós, S; Székely, M; Pétervári, E

    2013-11-01

    Cholecystokinin (CCK) is anorexic, irrespective whether it is applied intraperitoneally (IP) or intracerebroventricularly (ICV) in male Wistar rats. The metabolic effects depend on the route of administration: by the IP route it elicits hypothermia (presumably by type-1 receptors, CCK1R-s), while ICV administration is followed by fever-like hypermetabolism and hyperthermia via activation of CCK2R-s, which latter response seems to be most important in the postprandial (compensatory) hypermetabolism. The efficacy of the IP injected CCK varies with age: it causes strong anorexia in young adult 4 and 6-months old and again in old rats (aged 18-24 months), but the middle-aged (12-month old) ones seem to be resistant to this effect. Such pattern of effects may contribute to the explanation of age-related obesity observed in middle-aged animals as well as to the aging anorexia and loss of body weight in old ones. Diet-induced obesity accelerates the appearance of CCK-resistance as well as the return of high sensitivity to CCK in further aging, while chronic calorie-restriction prevents the development of resistance, as if the speed of the age-related regulatory changes was altered by the nutritional state. The effects of ICV applied CCK also change with age: the characteristic anorexic and hypermetabolic/hyperthermic effects can be observed in young adult rats, but the effects gradually and monotonically decline with age and disappear by the old age of 24 months. These disparate age-related patterns of CCK efficacy upon peripheral or central administration routes may indicate that although both peripheral and central CCKR-s exert anorexic effects, they may have dissimilar roles in the regulation of overall energy balance.

  3. Glucagon-Like Peptide-1 Regulates Cholecystokinin Production in β-Cells to Protect From Apoptosis.

    Science.gov (United States)

    Linnemann, Amelia K; Neuman, Joshua C; Battiola, Therese J; Wisinski, Jaclyn A; Kimple, Michelle E; Davis, Dawn Belt

    2015-07-01

    Cholecystokinin (CCK) is a classic gut hormone that is also expressed in the pancreatic islet, where it is highly up-regulated with obesity. Loss of CCK results in increased β-cell apoptosis in obese mice. Similarly, islet α-cells produce increased amounts of another gut peptide, glucagon-like peptide 1 (GLP-1), in response to cytokine and nutrient stimulation. GLP-1 also protects β-cells from apoptosis via cAMP-mediated mechanisms. Therefore, we hypothesized that the activation of islet-derived CCK and GLP-1 may be linked. We show here that both human and mouse islets secrete active GLP-1 as a function of body mass index/obesity. Furthermore, GLP-1 can rapidly stimulate β-cell CCK production and secretion through direct targeting by the cAMP-modulated transcription factor, cAMP response element binding protein (CREB). We find that cAMP-mediated signaling is required for Cck expression, but CCK regulation by cAMP does not require stimulatory levels of glucose or insulin secretion. We also show that CREB directly targets the Cck promoter in islets from obese (Leptin(ob/ob)) mice. Finally, we demonstrate that the ability of GLP-1 to protect β-cells from cytokine-induced apoptosis is partially dependent on CCK receptor signaling. Taken together, our work suggests that in obesity, active GLP-1 produced in the islet stimulates CCK production and secretion in a paracrine manner via cAMP and CREB. This intraislet incretin loop may be one mechanism whereby GLP-1 protects β-cells from apoptosis.

  4. Up-regulation of cholesterol absorption is a mechanism for cholecystokinin-induced hypercholesterolemia.

    Science.gov (United States)

    Zhou, LiChun; Yang, Hong; Okoro, Emmanuel U; Guo, Zhongmao

    2014-05-09

    Excessive absorption of intestinal cholesterol is a risk factor for atherosclerosis. This report examines the effect of cholecystokinin (CCK) on plasma cholesterol level and intestinal cholesterol absorption using the in vivo models of C57BL/6 wild-type and low density lipoprotein receptor knock-out (LDLR(-/-)) mice. These data were supported by in vitro studies involving mouse primary intestinal epithelial cells and human Caco-2 cells; both express CCK receptor 1 and 2 (CCK1R and CCK2R). We found that intravenous injection of [Thr(28),Nle(31)]CCK increased plasma cholesterol levels and intestinal cholesterol absorption in both wild-type and LDLR(-/-) mice. Treatment of mouse primary intestinal epithelial cells with [Thr(28),Nle(31)]CCK increased cholesterol absorption, whereas selective inhibition of CCK1R and CCK2R with antagonists attenuated CCK-induced cholesterol absorption. In Caco-2 cells, CCK enhanced CCK1R/CCK2R heterodimerization. Knockdown of both CCK1R and CCK2 or either one of them diminished CCK-induced cholesterol absorption to the same extent. CCK also increased cell surface-associated NPC1L1 (Niemann-Pick C1-like 1) transporters but did not alter their total protein expression. Inhibition or knockdown of NPC1L1 attenuated CCK-induced cholesterol absorption. CCK enhanced phosphatidylinositide 3-kinase (PI3K) and Akt phosphorylation and augmented the interaction between NPC1L1 and Rab11a (Rab-GTPase-11a), whereas knockdown of CCK receptors or inhibition of G protein βγ dimer (Gβγ) diminished CCK-induced PI3K and Akt phosphorylation. Inhibition of PI3K and Akt or knockdown of PI3K diminished CCK-induced NPC1L1-Rab11a interaction and cholesterol absorption. Knockdown of Rab11a suppressed CCK-induced NPC1L1 translocation and cholesterol absorption. These data imply that CCK enhances cholesterol absorption by activation of a pathway involving CCK1R/CCK2R, Gβγ, PI3K, Akt, Rab11a, and NPC1L.

  5. Cholecystokinin revisited: CCK and the hunger trap in anorexia nervosa.

    Directory of Open Access Journals (Sweden)

    Ulrich Cuntz

    Full Text Available OBJECTIVE: Despite a number of studies in the past decades, the role of Cholecystokinin (CCK in anorexia nervosa (AN has remained uncertain. In this study a highly specific assay for the biologically active part of CCK was used in patients with bulimic as well as with the restricting type of AN who were followed over the course of weight gain. METHODS: Ten patients with restricting and 13 with bulimic AN were investigated upon admission (T0, after a weight gain of at least 2 kg on two consecutive weighting dates (T1, and during the last week before discharge (T2 from inpatient treatment in a specialized clinic. Blood samples were drawn under fasting conditions and 20 and 60 minutes following a standard meal (250 kcal. Data were compared to those of eight controls matched for sex and age. Gastrointestinal complaints of patients were measured by a questionnaire at each of the follow-up time points. RESULTS: At admission, AN patients exhibited CCK-levels similar to controls both prior to and after a test meal. Pre and post-meal CCK levels increased significantly after an initial weight gain but decreased again with further weight improvement. CCK release was somewhat lower in bulimic than in restricting type AN but both subgroups showed a similar profile. There was no significant association of CCK release to either initial weight or BMI, or their changes, but CCK levels at admission predicted gastrointestinal symptom improvement during therapy. CONCLUSIONS: Normal CCK profiles in AN at admission indicates hormonal responses adapted to low food intake while change of eating habits and weight gain results in initially increased CCK release (counteracting the attempts to alter eating behavior that returns towards normal levels with continuous therapy.

  6. Analysis of interaction of phenolic compounds with the cholecystokinin signaling pathway to explain effects on reducing food intake.

    Science.gov (United States)

    Al Shukor, Nadin; Raes, Katleen; Van Camp, John; Smagghe, Guy

    2014-03-01

    Previous animal experiments demonstrated that phenolic compounds can reduce weight and food intake, but the exact mechanism(s) behind these effects remain unknown. For regulation of food intake, the cholecystokinin (CCK) hormone signaling pathway plays an important role as it induces satiety by binding on its specific receptor (CCK1R), hereby reducing food intake. In this study, we investigated the possible interactions of eight phenolic compounds of different classes (tannic acid, gallic acid, benzoic acid, hydroxybenzoic acid, protocatechuic acid, quercetin, kaempferol and resveratrol) with the CCK1R signaling pathway. As major results, the tested phenolic compounds could not activate the CCK1R in a specific cell-based bioassay. In contrast, we observed an anti-CCK1R activity. This antagonistic action might be explained by blocking of the functioning of the CCK1R receptor, although the exact mechanism of interaction remains unknown. For tannic acid, we also measured a sequestration activity of the CCK hormone in vitro. In conclusion, the reported activity of phenolic compounds against food intake and weight is not based on an activation of the CCK1R. Taking into account the complex regulation of food intake, further work is necessary to unravel other essential mechanisms involved to explain the reported effects of phenolic compounds against food intake.

  7. Gallbladder emptying and cholecystokinin response to fish oil and trioleate ingestion

    DEFF Research Database (Denmark)

    Riber, C; Hojgaard, L; Madsen, J L

    1996-01-01

    The aim of the present study was to compare gallbladder emptying, gastric emptying and release of cholecystokinin (CCK), gastrin and secretin after intragastric administration of fish oil and trioleate. After intravenous injection of 99mTc-HIDA, 30 ml of a lipid labelled with 111In was administer...

  8. An electrophysiological investigation of the effects of cholecystokinin on enteric neurons

    NARCIS (Netherlands)

    Schutte, I.W.M.

    1998-01-01


    Cholecystokinin (CCK) is a peptide, which is present in the gastrointestinat tract in endocrine cells and in the enteric nervous system (ENS). A possible function in the control of motility of the small intestine has been attributed to neuronal CCK. The aim of this thesis was to obtain a

  9. Cholecystokinin-gated currents in neurons of the rat solitary complex in vitro.

    Science.gov (United States)

    Branchereau, P; Champagnat, J; Denavit-Saubié, M

    1993-12-01

    1. Ionic conductances controlled by type A and type B cholecystokinin (CCK) receptors were studied in neurons of the rat nucleus tractus solitarius (NTS) and dorsal motor nucleus of the vagus (DMNV), using intracellular and whole-cell patch clamp recordings in current or voltage clamp configuration during bath application of agonists (CCK8, CCK4, BC 264) and antagonists. 2. CCKA receptor-related inhibition was associated with a membrane hyperpolarization and a decrease in input resistance that developed 2-6 min after the arrival of drug into the extracellular medium. These effects were induced by 5 nM CCK8 but not BC 264 and they were blocked by the CCKA antagonist, L-364,718, but not by the CCKB antagonist, L-365,260. 3. CCKA receptor-related inhibition was generated by a potassium current that reversed at a reversal potential E(rev) of -73 +/- 1 (mean +/- SE) mV with bathing potassium concentration [K+]o = 6 mM and at -88 +/- 1 with [K+]o = 3 mM, in agreement with the Nernst equation for potassium ions. 4. CCKB receptor-related excitation was associated with a membrane depolarization and an increase of the input resistance induced by the following agonists at threshold concentrations: CCK8 (0.2 nM) > or = BC 264 (0.4 nM) > CCK4 (10.9 nM). The increase of input resistance was abolished by L-365,260 and was maintained after blockade of the CCKA current by L-364,718. 5. CCKB receptor-related excitation, in the neurons (30% of cases) in which clear response reversal was observed, appeared to be generated by a decrease of a potassium conductance. Responses showed a reversal potential E(rev) of -68 +/- 4 mV with [K+]o = 6 mM and -89 +/- 1 mV with [K+]o = 3 mM, verifying predictions from the Nernst equation applied to potassium ions. However, in 70% of cases, clear reversal was not observed at membrane potentials negative to the theoretical potassium equilibrium potential EK. 6. In voltage clamp studies, CCK8 induced a 181 +/- 17 pA inward current associated with a 26

  10. Effect of cholecystokinin on cytokines during endotoxic shock in rats

    Institute of Scientific and Technical Information of China (English)

    Yi-Ling Ling; Al-Hong Weng; Xiao-Yun Zhao; Bao-Fn Shan; Jun-Lan Zhang; Xiao-Peng Zhang

    2001-01-01

    AIM To study the effect of cholecystokinin-octapeptide (CCK-8) on systemic hypotension and cytokine production in lipopolysaccharide (LPS)-induced endotoxic shock (ES) rats.``METHODS The changes of blood pressure were observed using physiological record instrument in four groups of rats: LPS (8 mg. kg-1, iv) induced ES; CCK-8 (40 μg.kg- 1 iv) pretreatment 10 min before LPS (8 mg. kg- 1);CCK-8 (40 μg.kg-1, iv) or normal saline (control) groups.Differences in tissue and circulating specificity of the proinflammatory cytokines (TNF-a, IL-l3 and IL-6) were assayed with ELISA kits.``RESULTS CCK-8 reversed LPS-induced decrease of mean artery blood pressure (MABP) in rats. Compared with control, LPS elevated the serum level of IL-6 significantly (3567_-687 ng.L-1 vs 128_+22 ng.L-1, P<0.01), while contents of TNF-a and IL- lβ elevated significantly (277 _± 86ng.L-1 vs not detectable and 43 ± 9 ng.L-1 vs notdetectable, P<0.01) but less extent than IL-6, CCK-8significantly inhibited the LPS-induced increase in serum TNF-a, IL-lβ and IL-6. LPS elevated spleen and lung content of IL-Iβ significantly (5184 ± 85 ng.L-1 vs 1047 ±21 ng.L-1 and 4050 ± 614 ng.L-1 vs not detectable,P<0,01). while levels of TNF-a and IL-6 also rosesignificantly but in less extent than IL-lβ. CCK-8 inhibited the LPS-induced increase of the cytokines in spleen and lung. in the heart, CCK-8 significantly inhibited LPS.induced increase of TNF-a (864 ± 123 ng. L-1 in CCK-8 +LPS group vs 1599_-227 ng-L-1 in LPS group, P<0.01),and IL-lβ (282 ± 93 ng-L-1 in CCK-8 + LPS group vs 621 ±145 ng.L-1 in LPS group, P<0.01).``CONCLUSION CCK-8 reverses ES, which may be relatedto its inhibitory effect on the overproduction of cytokines.``

  11. Time-resolved quantitative analysis of CCK1 receptor-induced intracellular calcium increase.

    NARCIS (Netherlands)

    Staljanssens, D.; Vos, W.H. De; Willems, P.H.; Camp, J. Van; Smagghe, G.

    2012-01-01

    Cholecystokinin (CCK) is a gastrointestinal hormone, which regulates many physiological functions such as satiety by binding to the CCK receptor (CCKR). Molecules, which recognize this receptor can mimic or block CCK signaling and thereby influence CCKR-mediated processes. We have set up a quantitat

  12. Time-resolved quantitative analysis of CCK1 receptor-induced intracellular calcium increase.

    NARCIS (Netherlands)

    Staljanssens, D.; Vos, W.H. De; Willems, P.H.; Camp, J. Van; Smagghe, G.

    2012-01-01

    Cholecystokinin (CCK) is a gastrointestinal hormone, which regulates many physiological functions such as satiety by binding to the CCK receptor (CCKR). Molecules, which recognize this receptor can mimic or block CCK signaling and thereby influence CCKR-mediated processes. We have set up a

  13. Stress-induced enhancement of fear conditioning activates the amygdalar cholecystokinin system in a rat model of post-traumatic stress disorder.

    Science.gov (United States)

    Feng, Ting; Yang, Shengchang; Wen, Di; Sun, Qiming; Li, Yingmin; Ma, Chunling; Cong, Bin

    2014-10-01

    Post-traumatic stress disorder (PTSD), a debilitating psychiatric disease characterized by invasive and persistent fear memories-induced stressful experience, is associated with numerous changes in neuroendocrine function. Here, we investigated whether PTSD-like symptoms are associated with changes in the cholecystokinin (CCK) system in the basolateral amygdala. We developed an animal model of PTSD using multiple foot shocks at 1.1 mA. The resulting conditioned fear response was severe (>80% freezing) and maintained for at least 28 days. The stress-associated neurotransmitters norepinephrine, dopamine, and corticotrophin-releasing hormone were elevated at 1 day after foot shock. CCK immunoreactivity and extracellular concentration as well as the expression of CCK receptors (CCK1R, CCK2R) increased progressively for 28 days following foot shock. Taken together, these results suggest that stress-induced activation of the CCK system in the BLA, which may contribute toward the development of PTSD-like symptoms.

  14. Biodistribution and pharmacokinetics of PEG-10kDa-cholecystokinin-10 in rats after different routes of administration.

    Science.gov (United States)

    León-Tamariz, Fabián; Verbaeys, Isabelle; Van Boven, Maurits; De Cuyper, Marcel; Buyse, Johan; de Witte, Peter; Verbruggen, Alfons; Cokelaere, Marnix

    2010-04-01

    Cholecystokinin, produced in the proximal small intestine, is a short acting satiating peptide hormone. CCK-10, before and after mono-iodination, was previously coupled to 10kDa polyethylene glycol (PEG). The formed conjugates PEG10kDa-CCK-10 and PEG10kDa-[(127)I]-CCK-10 show after i.p. administration to rats a sustained food intake reduction during 8h in comparison to 2h for free CCK-10. The present study examined the blood pharmacokinetics of this pharmacological interesting molecule by means of PEG10kDa-[(123)I]-CCK-10 following intravenous, intraperitoneal, intramuscular and nasal administration and the biodistribution after i.p. administration. HPLC analysis with radiometric detection allowed the differentiation between inorganic iodide and the intact tracer in blood. Blood kinetics after i.v. injection was fitted to a bi-exponential with a distribution half-life of 15 min and with an elimination half-life of 8 hours for intact PEG10kDa-[(123)I]-CCK-10. The biodistribution studies showed a higher accumulation of the tracer for all administration routes in organs expressing CCK receptors localized in the gastrointestinal tract such as pancreas, duodenum and small intestine. No indication of blood brain barrier crossing for the conjugate could be observed independently of the administration route. Main clearance was via the urinary pathway.

  15. Cholecystokinin rapidly stimulates CrkII function in vivo in rat pancreatic acini. Formation of CrkII-protein complexes.

    Science.gov (United States)

    Andreolotti, Alberto G; Bragado, Maria J; Tapia, Jose A; Jensen, Robert T; Garcia-Marin, Luis J

    2003-12-01

    Crk belongs to a family of adapter proteins whose structure allows interaction with tyrosine-phosphorylated proteins and is therefore an important modulator of downstream signals, representing a convergence of the actions of numerous stimuli. Recently, it was demonstrated that cholecystokinin (CCK) induced tyrosine phosphorylation of proteins related to fiber stress formation in rat pancreatic acini. Here, we investigated whether CCK receptor activation signals through CrkII and forms complexes with tyrosine-phosphorylated proteins in rat pancreatic acini. We demonstrated that CCK promoted the transient formation of CrkII-paxillin and CrkII-p130Cas complexes with maximal effect at 1 min. Additionally, CCK decreased the electrophoretic mobility of CrkII. This decrease was time- and concentration-dependent and inversely related with its function. Carbachol and bombesin also decreased CrkII electrophoretic mobility, whereas epidermal growth factor, vasoactive intestinal peptide, secretin or pituitary adenylate cyclase-activating polypeptide had no effect. CCK-induced CrkII electrophoretic shift was dependent on the Src family of tyrosine kinases and occurred in the intact animal, suggesting a physiological role of CrkII mediating CCK actions in the exocrine pancreas in vivo.

  16. Suppressive effect on food intake of a potato extract (Potein®) involving cholecystokinin release in rats.

    Science.gov (United States)

    Chen, Wenya; Hira, Tohru; Nakajima, Shingo; Tomozawa, Hiroshi; Tsubata, Masahito; Yamaguchi, Kazuya; Hara, Hiroshi

    2012-01-01

    We have recently reported that oral gavage of a potato extract (Potein®) suppressed the food intake in rats. The satiating effect of the potato extract was compared in the present study to other protein sources, and the involvement of endogenous cholecystokinin (CCK) secretion was examined. Food consumption was measured in 18-h fasted rats after oral gavage of the potato extract or other protein sources. The CCK-releasing activity of the potato extract was then examined in anesthetized rats with a portal cannula. Oral gavage of the potato extract reduced the food intake in the rats, the effect being greater than with casein and a soybean β-conglycinin hydrolysate. The suppressive effect on appetite of the potato extract was attenuated by treating with a CCK-receptor antagonist (devazepide). The portal CCK concentration was increased after a duodenal administration of the potato extract to anesthetized rats. These results indicate that the potato extract suppressed the food intake in rats through CCK secretion.

  17. Relationship between vulnerability to reinforcing effects of morphine and activity of the endogenous cholecystokinin system in Lewis and Fischer rats.

    Science.gov (United States)

    Noble, Florence; Benturquia, Nadia; Crete, Dominique; Canestrelli, Corinne; Mas Nieto, Magdalena; Wilson, Jodie; Roques, Bernard P

    2012-05-01

    A great number of studies have shown the presence of physiological interactions between brain neurotransmitter systems in behavioural responses. This is the case for opioid, cholecystokinin (CCK) and dopamine systems. However, so far the role that the CCK system may play in vulnerability to consumption of drugs of abuse is not clear. This was investigated in this study using Lewis rats that are more sensitive to the reinforcing properties of drugs of abuse than Fischer rats. The extraneuronal CCK(8) levels and brain CCK(2) receptors were found higher in Fischer than in Lewis rats in the nucleus accumbens, one of the most important structures involved in drug consumption. Moreover, pharmacological modulation of the CCK system by administration of a selective CCK(2) agonist blocked, in the conditioned place preference, the reinforcing effects of morphine in Lewis rats, whereas a selective CCK(2) antagonist revealed reinforcing effects of the alkaloid in Fischer rats. These results obtained following systemic administrations of the CCK ligands were confirmed following microinjection into the nucleus accumbens. Thus, a low level of CCK efflux in the nucleus accumbens could be one of the many factors involved in drug reinforcing effects, whereas a high level of CCK efflux could attenuate it.

  18. Homolateral cerebrocortical changes in neuropeptide and receptor expression after minimal cortical infarction.

    Science.gov (United States)

    Van Bree, L; Zhang, F; Schiffmann, S N; Halleux, P; Mailleux, P; Vanderhaeghen, J J

    1995-12-01

    A cortical infarct of 2 mm diameter was obtained in the parietal cortex after a craniotomy, disruption of the dura mater and topical application of 3 M KCl. It has been shown previously that the presence of a small cortical infarct induces an increase in immediate early gene messenger RNA expression followed by an increase in neuropeptide and glutamic acid decarboxylase messenger RNA expression. Glutamate, acting at N-methyl-D-aspartate receptors, is held responsible for these changes, since they are blocked by pretreatment with dizocilpine. In the present study, we have analysed the consequences of the dramatic changes in messenger RNA expression on the level of immediate early gene products c-fos and zif 268, and on that of neuropeptides by using immunohistochemistry. After just 1 h, an increase in c-fos- and zif 268-like immunoreactivity is observed in the entire cortical hemisphere homolateral to the infarct, and is no longer detected after 6 h. An increase in cholecystokinin octapeptide-, substance P-, neuropeptide Y- and somatostatin-like immunoreactivity is observed in the entire cortical hemisphere homolateral to the infarct after three days, and is no longer detected after 30 days. To investigate if these dramatic increases in neuropeptide immunoreactivities may have functional consequences, we studied the level of cholecystokinin receptors by autoradiographic binding using [125I]cholecystokinin-8S and in situ hybridization for the detection of cholecystokinin-b receptor messenger RNA. A decrease in cholecystokinin binding sites and cholecystokinin-b receptor messenger RNA is observed in the entire cortical hemisphere homolateral to the infarct after three days, and is no longer detected after nine days. This study shows that a topical stimulation has diffuse effects, reaching regions far from the site of the lesion, and some of them are still strongly present after nine days. The increase in neuropeptide messenger RNAs is followed by an increase in the

  19. Cholecystokinin enhances visceral pain-related affective memory via vagal afferent pathway in rats

    Directory of Open Access Journals (Sweden)

    Cao Bing

    2012-06-01

    Full Text Available Abstract Background Pain contains both sensory and affective dimensions. Using a rodent visceral pain assay that combines the colorectal distension (CRD model with the conditioned place avoidance (CPA paradigms, we measured a learned behavior that directly reflects the affective component of visceral pain, and showed that perigenual anterior cingulate cortex (pACC activation is critical for memory processing involved in long-term visceral affective state and prediction of aversive stimuli by contextual cue. Progress has been made and suggested that activation of vagal afferents plays a role in the behavioral control nociception and memory storage processes. In human patients, electrical vagus nerve stimulation enhanced retention of verbal learning performance. Cholecystokinin-octapeptide (CCK, which is a gastrointestinal hormone released during feeding, has been shown to enhance memory retention. Mice access to food immediately after training session enhanced memory retention. It has been well demonstrated that CCK acting on vagal afferent fibers mediates various physiological functions. We hypothesize that CCK activation of vagal afferent enhances visceral pain-related affective memory. Results In the presented study, infusion of CCK-8 at physiological concentration combining with conditional training significantly increased the CRD-induced CPA scores, and enhanced the pain affective memory retention. In contrast, CCK had no effect on CPA induced by non-nociceptive aversive stimulus (U69,593. The physiological implications were further strengthened by the similar effects observed in the rats with duodenal infusion of 5% peptone, which has been shown to induce increases in plasma CCK levels. CCK-8 receptor antagonist CR-1409 or perivagal application of capsaicin abolished the effect of CCK on aversive visceral pain memory, which was consistent with the notion that vagal afferent modulates affective aspects of visceral pain. CCK does not change

  20. Terminal Field and Firing Selectivity of Cholecystokinin-Expressing Interneurons in the Hippocampal CA3 Area

    OpenAIRE

    Lasztóczi, Bálint; Tukker, John J.; Somogyi, Peter; Klausberger, Thomas

    2011-01-01

    Hippocampal oscillations reflect coordinated neuronal activity on many timescales. Distinct types of GABAergic interneuron participate in the coordination of pyramidal cells over different oscillatory cycle phases. In the CA3 area, which generates sharp waves and gamma oscillations, the contribution of identified GABAergic neurons remains to be defined. We have examined the firing of a family of cholecystokinin-expressing interneurons during network oscillations in urethane-anesthetized rats ...

  1. Role of Cholecystokinin in Anxiety-related Disorder%胆囊收缩素在焦虑相关障碍中的作用探讨

    Institute of Scientific and Technical Information of China (English)

    郑伦; 郑希耕

    2013-01-01

    Cholecystokinin ( CCK ) is an abundant and widely distributed neuropeptide that plays a modulatory role in anxiety - related disorder. CCK is co - localized in cell bodies and terminals with many other neurotransmitters in limbic system, such as dopamine ( DA ) and y - aminobutyric acid ( GABA ) . Of the two CCK receptor subtypes, CCK2 receptors are most implicated in the control of anxiety - related behavior. The activation of the CCK2 receptor causes anxiogenic effects while the blockade of it has anxiolytic effect. CCK2 receptor antagonist may provide important therapeutic strategies to treat anxiety - related disorder.%胆囊收缩素(CCK)是广泛分布于中枢神经系统的神经肽,在焦虑相关障碍中发挥重要的调控作用.CCK与多巴胺(DA)、γ-氨基丁酸(GABA)等经典神经递质在边缘系统共存.在CCK的两种受体亚型中,CCK2受体在焦虑行为的控制中起重要作用,激活CCK2受体具有致焦虑作用,封闭CCK2受体则具有抗焦虑作用.CCK2受体拮抗剂在焦虑障碍的临床治疗中具有重要的应用前景.

  2. Parvalbumin, somatostatin and cholecystokinin as chemical markers for specific GABAergic interneuron types in the rat frontal cortex.

    Science.gov (United States)

    Kawaguchi, Yasuo; Kondo, Satoru

    2002-01-01

    It remains to be clarified how many classes of GABAergic nonpyramidal cells exist in the cortical circuit. We have divided GABA cells in the rat frontal cortex into 3 groups, based on their firing characteristics: fast-spiking (FS) cells, late-spiking (LS) cells, and non-FS cells. Expression of calcium-binding proteins and peptides could be shown in separate groups of GABA cells in layers II/III and V of the frontal cortex: (1) parvalbumin cells, (2) somatostatin cells, (3) calretinin and/or vasoactive intestinal polypeptide (VIP) cells [partially positive for cholecystokinin (CCK)] and (4) large CCK cells (almost negative for VIP/calretinin). Combining the physiological and chemical properties of morphologically diverse nonpyramidal cells allows division into several groups, including FS basket cells containing parvalbumin, non-FS somatostatin Martinotti cells with ascending axonal arbors, and non-FS large basket cells positive for CCK. These subtypes show characteristic spatial distributions of axon collaterals and the innervation tendency of postsynaptic elements. With synchronized activity induced by cortical excitatory or inhibitory circuits, firing patterns were also found to differ. Subtype-selective occurrence of electrical coupling, finding for potassium channel Kv3.1 proteins, and cholinergic and serotonergic modulation supports our tentative classification. To clarify the functional architecture in the frontal cortex, it is important to reveal the connectional characteristics of GABA cell subtypes and determine whether they are similar to those in other cortical regions.

  3. Levels of serum leptin, cholecystokinin, plasma lipid and lipoprotein differ between patients with gallstone or/and those with hepatolithiasis

    Institute of Scientific and Technical Information of China (English)

    Zheng-Ming Lei; Ming-Xin Ye; Wen-Guang Fu; Yue Chen; Cheng Fang; Jing Li

    2008-01-01

    BACKGROUND:A signiifcant relationship exists among food intake and nutritional status and cholelithiasis, including gallstone and hepatolithiasis. Leptin is associated with obesity. This study was to investigate the differences in serum leptin levels in patients with gallstone and hepatolithiasis and to evaluate the relationships among leptin, cholecystokinin (CCK), lipid and lipoprotein concentrations. METHODS:Body mass index (BMI), serum leptin, CCK, insulin, lipid and lipoprotein concentrations, and liver function were measured in 382 patients with gallstone (GS group), 83 patients with hepatolithiasis (HS group) and 30 healthy controls (control group). The values of these indices were compared among the groups. In each group, Pearson's product-moment correlation coefifcient among these indices were evaluated. RESULTS:There were notable differences in serum leptin, CCK, total cholesterol, total triglycerides, apolipoprotein-a (APO-a), globulin, direct reacting bilirubin, and BMI between the GS and HS groups (P CONCLUSIONS:Leptin participates in modulating lipid metabolism. There are notable differences in leptin, serum lipid, and CCK between patients with gallstone and those with hepatolithiasis. The role of leptin in the pathophysiological course of cholelithiasis needs further investigation.

  4. Influence of Cholecystokinin Octapeptide on Expression of TNF Receptor mRNA in Rat Synovial Cell Strain RSC-364%八肽胆囊收缩素对大鼠滑膜细胞株RSC-364 TNF受体基因表达的影响

    Institute of Scientific and Technical Information of China (English)

    金玉怀; 赵占胜; 丛斌; 徐锦荣; 姚玉霞; 李淑瑾; 凌亦凌

    2006-01-01

    目的探讨CCK-8对RSC-364细胞株TNF受体基因表达的影响.方法采用RT-PCR法检测不同浓度的八肽胆囊收缩素(CCK-8)对在TNF-α诱导下的大鼠滑膜细胞BSC-364 TNF受体(Tumor necrosisfactor receptor,TNFR)mRNA表达的影响.结果 CCK-8在10-6mol/L和10-7mol/L浓度时可抑制TNF-α诱导的TNFR2 mRNA在RSC-364细胞的表达,且表现了一定的剂量和时间依赖性,CCK受体拮抗剂丙谷胺则可抑制此作用.结论 CCK-8可抑制TNF-α诱导的大鼠滑膜细胞RSC-364株TNFR2基因的表达.

  5. Synergistic effect of CART (cocaine- and amphetamine-regulated transcript peptide and cholecystokinin on food intake regulation in lean mice

    Directory of Open Access Journals (Sweden)

    Kiss Alexander

    2008-10-01

    Full Text Available Abstract Background CART (cocaine- and amphetamine-regulated transcript peptide and cholecystokinin (CCK are neuromodulators involved in feeding behavior. This study is based on previously found synergistic effect of leptin and CCK on food intake and our hypothesis on a co-operation of the CART peptide and CCK in food intake regulation and Fos activation in their common targets, the nucleus tractus solitarii of the brainstem (NTS, the paraventricular nucleus (PVN, and the dorsomedial nucleus (DMH of the hypothalamus. Results In fasted C57BL/6 mice, the anorexigenic effect of CART(61-102 in the doses of 0.1 or 0.5 μg/mouse was significantly enhanced by low doses of CCK-8 of 0.4 or 4 μg/kg, while 1 mg/kg dose of CCK-A receptor antagonist devazepide blocked the effect of CART(61-102 on food intake. After simultaneous administration of 0.1 μg/mouse CART(61-102 and of 4 μg/kg of CCK-8, the number of Fos-positive neurons in NTS, PVN, and DMH was significantly higher than after administration of each particular peptide. Besides, CART(61-102 and CCK-8 showed an additive effect on inhibition of the locomotor activity of mice in an open field test. Conclusion The synergistic and long-lasting effect of the CART peptide and CCK on food intake and their additive effect on Fos immunoreactivity in their common targets suggest a co-operative action of CART peptide and CCK which could be related to synergistic effect of leptin on CCK satiety.

  6. Cholecystokinin but not ghrelin stimulates mucosal bicarbonate secretion in rat duodenum: independence of feeding status and cholinergic stimuli.

    Science.gov (United States)

    Sjöblom, Markus; Lindqvist, Ramin; Bengtsson, Magnus W; Jedstedt, Gunilla; Flemström, Gunnar

    2013-05-10

    Cholecystokinin (CCK) is an important regulator of food digestion but its influence on small intestinal secretion has received little attention. We characterized effects of CCK-8, ghrelin and some related peptides on duodenal HCO3(-) secretion in vivo and demonstrated CCK-induced calcium signaling in acutely isolated enterocytes. A segment of proximal duodenum with intact blood supply was cannulated in situ in anaesthetized rats. Mucosal HCO3(-) secretion was continuously recorded (pH-stat). Peptides were administrated to the duodenum by close intra-arterial infusion. Clusters of duodenal enterocytes were attached to the bottom of a perfusion chamber. The intracellular calcium concentration ([Ca(2+)]i) was examined by dual-wavelength imaging. CCK-8 (3.0, 15 and 60 pmol/kg,h) caused dose-dependent increases (psecretion in both overnight fasted and continuously fed animals. The CCK1R-antagonist devazepide but neither the CCK2R-antagonist YMM022 nor the melatonin MT2-selective antagonist luzindole inhibited the rise in secretion. Atropine decreased sensitivity to CCK-8. The appetite-related peptide ghrelin was without effect on the duodenal secretion in fasted as well as fed animals. Superfusion with CCK-8 (1.0-50 nM) induced [Ca(2+)]i signaling in acutely isolated duodenal enterocytes. After an initial peak response, [Ca(2+)]i returned to near basal values within 3-5min. Devazepide but not YMM022 inhibited this [Ca(2+)]i response. Low doses of CCK-8 stimulate duodenal alkaline secretion and induce enterocyte [Ca(2+)]i signaling by an action at CCK1 receptors. The results point to importance of CCK in the rapid postprandial rise in mucosa-protective duodenal secretion.

  7. Prefrontal cortical circuit for depression- and anxiety-related behaviors mediated by cholecystokinin: role of ΔFosB.

    Science.gov (United States)

    Vialou, Vincent; Bagot, Rosemary C; Cahill, Michael E; Ferguson, Deveroux; Robison, Alfred J; Dietz, David M; Fallon, Barbara; Mazei-Robison, Michelle; Ku, Stacy M; Harrigan, Eileen; Winstanley, Catherine A; Joshi, Tej; Feng, Jian; Berton, Olivier; Nestler, Eric J

    2014-03-12

    Decreased medial prefrontal cortex (mPFC) neuronal activity is associated with social defeat-induced depression- and anxiety-like behaviors in mice. However, the molecular mechanisms underlying the decreased mPFC activity and its prodepressant role remain unknown. We show here that induction of the transcription factor ΔFosB in mPFC, specifically in the prelimbic (PrL) area, mediates susceptibility to stress. ΔFosB induction in PrL occurred selectively in susceptible mice after chronic social defeat stress, and overexpression of ΔFosB in this region, but not in the nearby infralimbic (IL) area, enhanced stress susceptibility. ΔFosB produced these effects partly through induction of the cholecystokinin (CCK)-B receptor: CCKB blockade in mPFC induces a resilient phenotype, whereas CCK administration into mPFC mimics the anxiogenic- and depressant-like effects of social stress. We previously found that optogenetic stimulation of mPFC neurons in susceptible mice reverses several behavioral abnormalities seen after chronic social defeat stress. Therefore, we hypothesized that optogenetic stimulation of cortical projections would rescue the pathological effects of CCK in mPFC. After CCK infusion in mPFC, we optogenetically stimulated mPFC projections to basolateral amygdala or nucleus accumbens, two subcortical structures involved in mood regulation. Stimulation of corticoamygdala projections blocked the anxiogenic effect of CCK, although no effect was observed on other symptoms of social defeat. Conversely, stimulation of corticoaccumbens projections reversed CCK-induced social avoidance and sucrose preference deficits but not anxiogenic-like effects. Together, these results indicate that social stress-induced behavioral deficits are mediated partly by molecular adaptations in mPFC involving ΔFosB and CCK through cortical projections to distinct subcortical targets.

  8. Involvement of cholecystokinin in the opioid tolerance induced by dipyrone (metamizol) microinjections into the periaqueductal gray matter of rats.

    Science.gov (United States)

    Tortorici, Victor; Nogueira, Lourdes; Aponte, Yexica; Vanegas, Horacio

    2004-11-01

    The analgesic effect of non-steroidal anti-inflammatory drugs (NSAIDs) is partly due to an action upon the periaqueductal gray matter (PAG), which triggers the descending pain control system and thus inhibits nociceptive transmission. This action of NSAIDs engages endogenous opioids at the PAG, the nucleus raphe magnus and the spinal cord. Repeated administration of NSAIDs such as dipyrone (metamizol) and acetylsalicylate thus induces tolerance to these compounds and cross-tolerance to morphine. Since cholecystokinin plays a key role in opioid tolerance, the present study in rats investigated whether PAG cholecystokinin is also responsible for tolerance to PAG-microinjected dipyrone. Microinjection of cholecystokinin (1 ng/0.5 microl) into PAG blocked the antinociceptive effect of a subsequent microinjection of dipyrone (150 microg/0.5 microl) into the same site, as evaluated by the tail flick and hot plate tests. Microinjection of proglumide (0.4 microg/0.5 microl), a non-selective cholecystokinin antagonist, into PAG prevented the development of tolerance to subsequent microinjections of dipyrone, as well as cross-tolerance to microinjection of morphine (5 microg/0.5 microl) into the same site. In rats tolerant to PAG dipyrone, a PAG microinjection of proglumide restored the antinociceptive effect of a subsequent microinjection of dipyrone or morphine. These results suggest that PAG-microinjected dipyrone triggers and/or potentiates local opioidergic circuits leading to descending inhibition of nociception, on the one hand, and to a local antiopioid action by cholecystokinin, on the other. Reiteration of these events would then result in an enhancement of cholecystokinin's antiopioid action and thus tolerance to opioids and dipyrone in the PAG.

  9. Gut peptide receptors in pancreata of azaserine-treated and normal control rats

    NARCIS (Netherlands)

    Tang, C.; Biemond, I.; Appel, M.J.; Visser, C.J.T.; Woutersen, R.A.; Lamers, C.B.H.W.

    1995-01-01

    Gut peptides are involved in the growth and carcinogenesis of the exocrine pancreas of rats after treatment with azaserine. However, little is known about the influence of azaserine on expression of gut peptide receptors in the pancreas of the rat. Cholecystokinin, bombesin, somatostatin, secretin a

  10. Impaired intestinal cholecystokinin secretion, a fascinating but overlooked link between coeliac disease and cholesterol gallstone disease.

    Science.gov (United States)

    Wang, Helen H; Liu, Min; Li, Xiaodan; Portincasa, Piero; Wang, David Q-H

    2017-04-01

    Coeliac disease is a chronic, small intestinal, immune-mediated enteropathy caused by a permanent intolerance to dietary gluten in genetically predisposed individuals. Clinical studies have found that intestinal cholecystokinin secretion and gallbladder emptying in response to a fatty meal are impaired before coeliac patients start the gluten-free diet (GFD). However, it was never really appreciated whether coeliac disease is associated with gallstones because there were very few studies investigating the mechanism underlying the impact of coeliac disease on the pathogenesis of gallstones. We summarize recent progress on the relationship between coeliac disease and gallstones and propose that coeliac disease is an important risk factor for gallstone formation because defective intestinal cholecystokinin secretion markedly increases susceptibility to cholesterol gallstones via a mechanism involving dysmotility of both the gallbladder and the small intestine. Because GFD can significantly improve the coeliac enteropathy, early diagnosis and therapy in coeliac patients is crucial for preventing the long-term impact of cholecystokinin deficiency on the biliary and intestinal consequences. When gluten is reintroduced, clinical and histologic relapse often occurs in coeliac patients. Moreover, some of the coeliac patients do not respond well to GFD. It is imperative to routinely examine by ultrasonography whether gallbladder motility function is preserved in coeliac patients and monitor whether biliary sludge (a precursor of gallstones) appears in the gallbladder, regardless of whether they are under the GFD programme. To prevent gallstones in coeliac patients, it is urgently needed to investigate the prevalence and pathogenesis of gallstones in these patients. © 2017 Stichting European Society for Clinical Investigation Journal Foundation.

  11. Characteristics of the Cholecystokinin-Induced Depolarization of Pacemaking Activity in Cultured Interstitial Cells of Cajal from Murine Small Intestine

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    Jae Hwa Lee

    2013-04-01

    Full Text Available Background/Aims: In this study, we studied the effects of cholecystokinin (CCK on pacemaker potentials in cultured interstitial cells of Cajal (ICCs from mouse small intestine using the whole cell patch clamp technique. Methods: ICCs are pacemaker cells that exhibit periodic spontaneous depolarization, which is responsible for the production of slow waves in gastrointestinal smooth muscle, and generate periodic pacemaker potentials in current-clamp mode. Results: Exposure to CCK (100 nM-5 µM decreased the amplitudes of pacemaker potentials and depolarized resting membrane potentials. To identify the type of CCK receptors involved in ICCs, we examined the effects of CCK agonists and found that the addition of CCK1 agonist (A-71323, 1 µM depolarized resting membrane potentials, whereas exposure to CCK2 agonist (gastrin , 1 µM had no effect on pacemaker potentials. To confirm these results, we examined the effects of CCK antagonists and found that pretreatment with CCK1 antagonist (SR 27897, 1 µM blocked CCK-induced effects. However, pretreatment with CCK2 antagonist (LY 225910, 1 µM did not. Furthermore, intracellular GDPβS suppressed CCK-induced effects. To investigate the involvements of phospholipase C (PLC, protein kinase C (PKC, and protein kinase A (PKA in the effects of CCK in cultured ICCs, we used U-73122 (an active PLC inhibitor, chelerythrine (a PKC inhibitor, SQ-22536 (an inhibitor of adenylate cyclase, or mPKAI (an inhibitor of myristoylated PKA. All inhibitors blocked the CCK-mediated effects on pacemaker potentials. In addition, we found that transient receptor potential classical 5 (TRPC5 channel was involved in CCK-activated currents in cultured ICCs. Conclusion: These results suggest that the CCK induced depolarization of pacemaking activity occurs in a G-protein-, PLC-, PKC-, and PKA-dependent manner via CCK1 receptor and TRPC5 channel is a candidate for CCK-activated currents in cultured ICCs in murine small intestine

  12. Synthesis and biological activity of some partially modified retro-inverso analogues of cholecystokinin.

    Science.gov (United States)

    Rodriguez, M; Galas, M C; Lignon, M F; Mendre, C; Laur, J; Aumelas, A; Martinez, J

    1989-10-01

    Syntheses of some partially modified retro-inverso analogues of the C-terminal octa- or heptapeptide of cholecystokinin are described. These analogues (in which the C-terminal carboxamide was deleted or not) were obtained by reverting one or several peptide bonds in the parent molecule. All these compounds were able to inhibit binding of labeled CCK-8 to rat pancreatic acini and guinea pig brain membranes and to stimulate amylase release from rat pancreatic acini with various potencies. Some of these derivatives reproduce only part of the biological response of CCK on amylase release.

  13. Mechanisms of cholecystokinin-induced calcium mobilization in gastric antral interstitial cells of Cajal

    Institute of Scientific and Technical Information of China (English)

    Yao-Yao Gong; Xin-Min Si; Lin Lin; Jia Lu

    2012-01-01

    AIM:To investigate the effect of sulfated cholecystokinin-8 (CCK-8S) on calcium mobilization in cultured murine gastric antral interstitial cells of Cajal (ICC) and its possible mechanisms.METHODS:ICC were isolated from the gastric antrum of mice and cultured.Immunofluorescence staining with a monoclonal antibody for c-Kit was used to identify ICC.The responsiveness of ICC to CCK-8S was measured using Fluo-3/AM based digital microfluorimetric measurement of intracellular Ca2+ concentration ([Ca2+]i).A confocal laser scanning microscope was used to monitor [Ca2+]i changes.The selective CCK1 receptor antagonist lorglumide,the intracellular Ca2+-ATPase inhibitor thapsigargin,the type Ⅲ inositol 1,4,5-triphosphate (InsP3) receptor blocker xestospongin C and the L-type voltage-operated Ca2+ channel inhibitor nifedipine were used to examine the mechanisms of [Ca2+]i elevation caused by CCK-8S.Immunoprecipitation and Western blotting were used to determine the regulatory effect of PKC on phosphorylation of type Ⅲ InsP3 receptor (InsP3R3) in ICC.Protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) and inhibitor chelerythrine were used to assess the role of PKC in the CCK-8S-evoked [Ca2+]i increment of ICC.RESULTS:ICC were successfully isolated from the gastric antrum of mice and cultured.Cultured ICC were identified by immunofluorescence staining.When given 80 nmol/L or more than 80 nmol/L CCK-8S,the [Ca2+]i in ICC increased and 100 nmol/L CCK-8S significantly increased the mean [Ca2+]i by 59.30% ± 4.85% (P <0.01).Pretreatment of ICC with 5 μmol/L lorglumide inhibited 100 nmol/L CCK-8S-induced [Ca2+]i increment from 59.30% ± 4.85% to 14.97% ± 9.05% (P < 0.01),suggesting a CCK1R-mediated event.Emptying of intracellular calcium stores by thapsigargin (5 μmol/L)prevented CCK-8S (100 nmol/L) from inducing a [Ca2+]i increase.Moreover,pretreatment with xestospongin C (1 μmol/L) could also abolish the CCK-8S-induced effect

  14. Discovery of a novel glucagon-like peptide (GCGL) and its receptor (GCGLR) in chickens: evidence for the existence of GCGL and GCGLR genes in nonmammalian vertebrates.

    Science.gov (United States)

    Wang, Yajun; Meng, Fengyan; Zhong, Yu; Huang, Guian; Li, Juan

    2012-11-01

    Glucagon (GCG), glucagon-related peptides, and their receptors have been reported to play important roles including the regulation of glucose homeostasis, gastrointestinal activity, and food intake in vertebrates. In this study, we identified genes encoding a novel glucagon-like peptide (named GCGL) and its receptor (GCGLR) from adult chicken brain using RACE and/or RT-PCR. GCGL was predicted to encode a peptide of 29 amino acids (cGCGL(1-29)), which shares high amino acid sequence identity with mammalian and chicken GCG (62-66%). GCGLR is a receptor of 430 amino acids and shares relatively high amino acid sequence identity (53-55%) with the vertebrate GCG receptor (GCGR). Using a pGL3-CRE-luciferase reporter system, we demonstrated that synthetic cGCGL(1-29), but not its structurally related peptides, i.e. exendin-4 and GCG, could potently activate GCGLR (EC(50): 0.10 nm) expressed in Chinese hamster ovary cells, indicating that GCGLR can function as a GCGL-specific receptor. RT-PCR assay revealed that GCGL expression is mainly restricted to several tissues including various brain regions, spinal cord, and testes, whereas GCGLR mRNA is widely expressed in adult chicken tissues with abundant expression noted in the pituitary, spinal cord, and various brain regions. Using synteny analysis, GCGL and GCGLR genes were also identified in the genomes of fugu, tetraodon, tilapia, medaka, coelacanth, and Xenopus tropicalis. As a whole, the discovery of GCGL and GCGLR genes in chickens and other nonmammalian vertebrates clearly indicates a previously unidentified role of GCGL-GCGLR in nonmammalian vertebrates and provides important clues to the evolutionary history of GCG and GCGL genes in vertebrates.

  15. Spike protein homology between the SARS-associated virus and murine hepatitis virus implies existence of a putative receptor-binding region

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    Coronavirus has been determined to be the cause of the recent outbreak of severe acute respiratory syndrome (SARS). Human coronavirus 229E had been studied well and its receptor-binding domain was restricted to aa417-547 of S protein. However, this region has no homology with the newly separated SARS-associated virus (Hong Kong isolate CUHK-W1). Then we analyzed the phylogenesis of S1 subunit of the coronavirus spike protein (SARS-associated virus, Hong Kong isolate CUHK-W1). Interestingly, the highest homology between murine hepatitis virus (MHV) and SARS-associated coronavirus was found. And the important sites (aa62-65 and aa214-216) on the spike protein of MHV with receptor-binding capacity were highly conservative in comparison with the newly separated SARS-asso- ciated virus (the corresponding sites are aa51-54 and aa195-197). These results from bioinformatics analysis might help us to study the receptor-binding sites of SARS-associ- ated virus and the mechanism of the virus entry into the target cell, and design antiviral drugs and potent vaccines.

  16. Effect of cholecystokinin on learning and memory, neuronal proliferation and apoptosis in the rat hippocampus

    Science.gov (United States)

    Reisi, Parham; Ghaedamini, Ali Reza; Golbidi, Mohammad; Shabrang, Moloud; Arabpoor, Zohreh; Rashidi, Bahman

    2015-01-01

    Background: Cholecystokinin (CCK) has roles in learning and memory, but the cellular mechanism is poorly understood. This study investigated the effect of CCK on spatial learning and memory, neuronal proliferation and apoptosis in the hippocampus in rats. Materials and Methods: Experimental groups were control and CCK. The rats received CKK octapeptide sulfated (CCK-8S, 1.6 μg/kg, i.p.) for 14 days. Spatial learning and memory were tested by Morris water maze and finally immunohistochemical study was performed; neurogenesis by Ki-67 method and apoptosis by Terminal deoxynucleotidyl transferase mediated dUTP Nick End Labeling (TUNEL) assay in hippocampal dentate gyrus (DG). Results: Cholecystokinin increased Ki-67 positive cells and reduced TUNEL positive cells in the granular layer of hippocampal DG. CCK failed to have a significant effect on spatial learning and memory. Conclusion: Results indicate neuroprotective and proliferative effects of CCK in the hippocampus; however, other factors are probably involved until the newly born neurons achieve necessary integrity for behavioral changes. PMID:26623402

  17. Trypsin inhibitor from tamarindus indica L. seeds reduces weight gain and food consumption and increases plasmatic cholecystokinin levels

    Directory of Open Access Journals (Sweden)

    Joycellane Alline do Nascimento Campos Ribeiro

    2015-02-01

    Full Text Available OBJECTIVES: Seeds are excellent sources of proteinase inhibitors, some of which may have satietogenic and slimming actions. We evaluated the effect of a trypsin inhibitor from Tamarindus indica L. seeds on weight gain, food consumption and cholecystokinin levels in Wistar rats. METHODS: A trypsin inhibitor from Tamarindus was isolated using ammonium sulfate (30-60% following precipitation with acetone and was further isolated with Trypsin-Sepharose affinity chromatography. Analyses were conducted to assess the in vivo digestibility, food intake, body weight evolution and cholecystokinin levels in Wistar rats. Histological analyses of organs and biochemical analyses of sera were performed. RESULTS: The trypsin inhibitor from Tamarindus reduced food consumption, thereby reducing weight gain. The in vivo true digestibility was not significantly different between the control and Tamarindus trypsin inhibitor-treated groups. The trypsin inhibitor from Tamarindus did not cause alterations in biochemical parameters or liver, stomach, intestine or pancreas histology. Rats treated with the trypsin inhibitor showed significantly elevated cholecystokinin levels compared with animals receiving casein or water. CONCLUSION: The results indicate that the isolated trypsin inhibitor from Tamarindus reduces weight gain by reducing food consumption, an effect that may be mediated by increased cholecystokinin. Thus, the potential use of this trypsin inhibitor in obesity prevention and/or treatment should be evaluated.

  18. Expression of the cannabinoid receptor CB1 in distinct neuronal subpopulations in the adult mouse forebrain.

    Science.gov (United States)

    Marsicano, G; Lutz, B

    1999-12-01

    Cannabinoids can modulate motor behaviour, learning and memory, cognition and pain perception. These effects correlate with the expression of the cannabinoid receptor 1 (CB1) and with the presence of endogenous cannabinoids in the brain. In trying to obtain further insights into the mechanisms underlying the modulatory effects of cannabinoids, CB1-positive neurons were determined in the murine forebrain at a single cell resolution. We performed a double in situ hybridization study to detect mRNA of CB1 in combination with mRNA of glutamic acid decarboxylase 65k, neuropeptide cholecystokinin (CCK), parvalbumin, calretinin and calbindin D28k, respectively. Our results revealed that CB1-expressing cells can be divided into distinct neuronal subpopulations. There is a clear distinction between neurons containing CB1 mRNA either at high levels or low levels. The majority of high CB1-expressing cells are GABAergic (gamma-aminobutyric acid) neurons belonging mainly to the cholecystokinin-positive and parvalbumin-negative type of interneurons (basket cells) and, to a lower extent, to the calbindin D28k-positive mid-proximal dendritic inhibitory interneurons. Only a fraction of low CB1-expressing cells is GABAergic. In the hippocampus, amygdala and entorhinal cortex area, CB1 mRNA is present at low but significant levels in many non-GABAergic cells that can be considered as projecting principal neurons. Thus, a complex mechanism appears to underlie the modulatory effects of cannabinoids. They might act on principal glutamatergic circuits as well as modulate local GABAergic inhibitory circuits. CB1 is very highly coexpressed with CCK. It is known that cannabinoids and CCK often have opposite effects on behaviour and physiology. Therefore, we suggest that a putative cross-talk between cannabinoids and CCK might exist and will be relevant to better understanding of physiology and pharmacology of the cannabinoid system.

  19. Urotensin II receptor (UTR) exists in hyaline chondrocytes: a study of peripheral distribution of UTR in the African clawed frog, Xenopus laevis.

    Science.gov (United States)

    Konno, Norifumi; Fujii, Yuya; Imae, Haruka; Kaiya, Hiroyuki; Mukuda, Takao; Miyazato, Mikiya; Matsuda, Kouhei; Uchiyama, Minoru

    2013-05-01

    Urotensin II (UII) and UII-related peptide (URP) exhibit diverse physiological actions including vasoconstriction, locomotor activity, osmoregulation, and immune response through UII receptor (UTR), which is expressed in the central nervous system and peripheral tissues of fish and mammals. In amphibians, only UII has been identified. As the first step toward elucidating the actions of UII and URP in amphibians, we cloned and characterized URP and UTR from the African clawed frog Xenopus laevis. Functional analysis showed that treatment of UII or URP with Chinese hamster ovary cells transfected with the cloned receptor increased the intracellular calcium concentration in a concentration-dependent manner, whereas the administration of the UTR antagonist urantide inhibited UII- or URP-induced Ca(2+) mobilization. An immunohistochemical study showed that UTR was expressed in the splenocytes and leukocytes isolated from peripheral blood, suggesting that UII and URP are involved in the regulation of the immune system. UTR was also localized in the apical membrane of the distal tubule of the kidney and in the transitional epithelial cells of the urinary bladder. This result supports the view that the UII/URP-UTR system plays an important role in osmoregulation of amphibians. Interestingly, immunopositive labeling for UTR was first detected in the chondrocytes of various hyaline cartilages (the lung septa, interphalangeal joint and sternum). The expression of UTR was also observed in the costal cartilage, tracheal cartilages, and xiphoid process of the rat. These novel findings probably suggest that UII and URP mediate the formation of the cartilaginous matrix. Copyright © 2013 Elsevier Inc. All rights reserved.

  20. Synthesis and biological activity of 2-phenylethyl ester analogues of C-terminal heptapeptide of cholecystokinin modified in Trp 30 region.

    Science.gov (United States)

    Rolland, M; Rodriguez, M; Lignon, M F; Galas, M C; Laur, J; Aumelas, A; Martinez, J

    1991-08-01

    We have tried to evaluate the significance of the tryptophan side chain residue and of the surrounding peptide bonds in the antagonist activity of cholecystokinin analogues lacking the C-terminal amide function and having a D-tryptophan. In order to perform this study, analogues of the C-terminal heptapeptide of cholecystokinin were synthesized by replacing the C-terminal phenylalanine residue with 2-phenylethyl alcohol and by either replacing the tryptophan residue with an alanine, a norleucine and a phenylalanine residue, or introducing a "reduced peptide bond" in the tryptophan 30 region. Most of these compounds were able to reproduce only part of the response of cholecystokinin in stimulating amylase release from rat pancreatic acini, as was already observed for 2-phenylethyl ester analogues of CCK. These results point out the key role of tryptophan 30 in the biological response of cholecystokinin.

  1. Effects of rizatriptan on the expression of calcitonin gene-related peptide and cholecystokinin in the periaqueductal gray of a rat migraine model.

    Science.gov (United States)

    Yao, Gang; Han, Ximei; Hao, Tingting; Huang, Qian; Yu, Tingmin

    2015-02-05

    Triptans are serotonin 5-hydroxytryptamine receptor 1B/D agonists that are highly effective in the treatment of migraine. We previously found that rizatriptan can reduce the expression of proenkephalin and P substance in the rat midbrain, suggesting that rizatriptan may exert its analgesic effects by influencing the endogenous pain modulatory system. Calcitonin gene-related peptide (CGRP) and cholecystokinin (CCK) are mainly responsible for antagonizing the analgesic effects of opioid peptides in the endogenous pain modulatory system. In this study, we investigated the effects of rizatriptan on the expression of CGRP and CCK in the periaqueductal gray (PAG), a key structure of the endogenous pain modulatory system, in a rat migraine model induced by nitroglycerin. We found that the mRNA and protein levels of CGRP and CCK in the PAG of migraine rats were significantly increased compared to those in control rats, and these levels were significantly reduced upon treatment with rizatriptan in migraine rats (P<0.05). Our results suggest that the expression of CGRP and CCK in the endogenous pain modulatory system may be increased during migraine attacks, which further antagonizes the analgesic effects of endogenous opioid peptides and induces sustained migraine. Rizatriptan, however, significantly reduces the levels of CGRP and CCK to enhance the inhibition of pain signals via the endogenous pain modulatory system, resulting in effective treatment of migraine.

  2. Effects of whisky on plasma gastrin and cholecystokinin in young adult men.

    Science.gov (United States)

    Manabe, T; Sawai, H; Okada, Y; Funahashi, H; Yamamoto, M; Sato, M; Hayakawa, T; Yamaki, K

    2003-01-01

    Whisky (1 g/kg, 21.5% alcohol) was administered orally to healthy young adult male volunteers, and changes in the plasma concentrations of alcohol, acetaldehyde, gastrin, cholecystokinin (CCK) and serum amylase were measured over time. Values for alcohol and acetaldehyde rapidly reached a peak at 30-45 min after alcohol intake, followed by a gradual decline. The plasma gastrin concentration showed a rapid elevation, while the plasma CCK concentration did not exhibit any significant changes in the early phase after alcohol intake. Elevation of CCK was observed after 75 min, however. These results show that intake of whisky stimulates the secretion of gastrin and is associated with a later increase in CCK.

  3. No Correlation Exists between Disease Activity and the Expression of Killer-Cell Immunoglobulin-Like Receptors in Patients with Rheumatoid Arthritis

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    Toshiaki Kogure

    2007-01-01

    Full Text Available Objective. The genes for killer-cell immunoglobulin-like receptors (KIRs have been cloned and their functions and expression in patients with rheumatoid arthritis (RA have been partially clarified. However, the correlation between their expression and disease activity has not been analyzed in patients with RA. Thus, we measured KIR expression on lymphocytes in patients with RA, and assessed the correlation between KIR expression and disease activity. Patients and Methods. In the cross-sectional study, 15 patients (9 females and 6 males who fulfilled the diagnostic criteria for RA were assessed. In the longitudinal study, patients who were followed-up for 3 months were assessed. CD158a/b expression on peripheral blood mononuclear cells (PBMC of RA patients was analyzed using flow cytometry. Results. No significant correlation between KIR expression and CRP, ESR, or IgM-RF was observed. There was no remarkable change in the expression of KIRs between the baseline and after 3 months. Additionally, in the 5 patients whose expression of KIRs particularly changed, the time-related changes in the expression of KIRs were independent from those of inflammation parameters and IgM-RF. Conclusion. There was no correlation between KIR expression and disease activity; therefore, the clinical use of KIR expression should be limited, while unnatural KIR expression may be involved in the pathogenesis of RA, but not a recruitment of chronic inflammation to induce joint damage.

  4. Terminal field and firing selectivity of cholecystokinin-expressing interneurons in the hippocampal CA3 area.

    Science.gov (United States)

    Lasztóczi, Bálint; Tukker, John J; Somogyi, Peter; Klausberger, Thomas

    2011-12-07

    Hippocampal oscillations reflect coordinated neuronal activity on many timescales. Distinct types of GABAergic interneuron participate in the coordination of pyramidal cells over different oscillatory cycle phases. In the CA3 area, which generates sharp waves and gamma oscillations, the contribution of identified GABAergic neurons remains to be defined. We have examined the firing of a family of cholecystokinin-expressing interneurons during network oscillations in urethane-anesthetized rats and compared them with firing of CA3 pyramidal cells. The position of the terminals of individual visualized interneurons was highly diverse, selective, and often spatially coaligned with either the entorhinal or the associational inputs to area CA3. The spike timing in relation to theta and gamma oscillations and sharp waves was correlated with the innervated pyramidal cell domain. Basket and dendritic-layer-innervating interneurons receive entorhinal and associational inputs and preferentially fire on the ascending theta phase, when pyramidal cell assemblies emerge. Perforant-path-associated cells, driven by recurrent collaterals of pyramidal cells fire on theta troughs, when established pyramidal cell assemblies are most active. In the CA3 area, slow and fast gamma oscillations occurred on opposite theta oscillation phases. Perforant-path-associated and some COUP-TFII-positive interneurons are strongly coupled to both fast and slow gamma oscillations, but basket and dendritic-layer-innervating cells are weakly coupled to fast gamma oscillations only. During sharp waves, different interneuron types are activated, inhibited, or remain unaffected. We suggest that specialization in pyramidal cell domain and glutamatergic input-specific operations, reflected in the position of GABAergic terminals, is the evolutionary drive underlying the diversity of cholecystokinin-expressing interneurons.

  5. Retraction: Borroto-Escuela et al., The existence of FGFR1-5-HT1A receptor heterocomplexes in midbrain 5-HT neurons of the rat: relevance for neuroplasticity.

    Science.gov (United States)

    2013-07-10

    The Journal of Neuroscience has received a report describing an investigation by the Karolinska Institutet, which found substantial data misrepresentation in the article "The Existence of FGFR1-5-HT1A Receptor Heterocomplexes in Midbrain 5-HT Neurons of the Rat: Relevance for Neuroplasticity" by Dasiel O. Borroto-Escuela, Wilber Romero-Fernandez, Mileidys Pérez-Alea, Manuel Narvaez, Alexander O. Tarakanov, Giuseppa Mudó , Luigi F. Agnati, Francisco Ciruela, Natale Belluardo, and Kjell Fuxe, which appeared on pages 6295-6303 of the May 2, 2012 issue. Because the results cannot be considered reliable, the editors of The Journal are retracting the paper.

  6. receptores

    Directory of Open Access Journals (Sweden)

    Salete Regina Daronco Benetti

    2006-01-01

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

  7. Connections between 5-HT-containing terminals and 5-HT2A receptor and γ-aminobutyric acid or glycine co-existed neurons in the rat medullary dorsal horn

    Institute of Scientific and Technical Information of China (English)

    LI Hui; LI Yun-qing

    2001-01-01

    Objective: To investigate the connections between serotonin (5-HT)-containing terminals and 5-HT2A receptor (5-HT2AR)/γ-aminobutyric acid (GABA) or 5-HT2AR/glycine co-existed neurons in the rat medullary dorsal horn (MDH).Methods: Immunofluorescence histochemical triple-staining for 5-HT, 5-HT2AR, GABA or glycine. Results: 5-HT-immunoreaetive fibers and terminals were chiefly located in the superficial laminae (laminae Ⅰ and Ⅱ) of the MDH. Neurons exhibiting 5-HT2AR-, GABA- or glycine-immunoreactivities were mainly observed in the superficial laminae. Some 5-HT2AR-immunopositive neurons also exhibited GABA- or glycine-immunoreaetivities. 5-HT-containing terminals made close contacts with 5-HT2AR/GABA or 5-HT2AR/glycine co-existed neurons. Conclusion: 5-HT2AR/GABA or 5-HT2AR /glycine co-exist in some of the neurons in the superficial laminae of the MDH. 5-HT-immunoreactive terminals form close connections with 5-HT2AR/GABA or 5-HT2AR/glycine co-existed neurons.

  8. Cholecystokinin like immunoreactivity in the brains of young Meishan and Duroc pigs(4).

    Science.gov (United States)

    Elmquist, J K; Ross, L R; Hsu, W; Rothschild, M F; Jacobson, C D

    1993-01-12

    Cholecystokinin (CCK), a peptide found in both the gastrointestinal tract and brain, has been shown to be involved in the control of feed intake in a variety of animals including the pig. Chinese breeds of pigs such as the Meishan are noted for slow growth and heavy adipose deposition. In this study we have described the regional cholecystokinin-like immunoreactivity (CCK-IR) concentrations in the brain of young Duroc and Meishan pigs utilizing radioimmunoassay. Brains of days 1, 10, and 20 postnatal pigs from each breed were examined. The CCK-IR increased with age in all three areas examined (cortex, medulla, and hypothalamus). The cortical concentrations rose significantly from days 1 to 10 and from days 10 to 20. The levels in the hypothalamus and medulla increased significantly between days 1 and 20. There were no statistically significant differences in CCK-IR between the breeds at any of the three ages examined. Our results indicate that a rise in CCK-IR in the regions of the brain involved in the control of feed intake may parallel the ability of the young pigs to assimilate nutrients from a solid diet. ZUSAMMENFASSUNG: Cholecystokinin-ähnliche Immunreaktivität in den Gehirnen junger Meishan- und Durocschweine Das Peptid Cholecystokinin (CCK) wird im Gastrointestinaltrakt und im Gehirn gefunden und beeinflußt Futteraufnahme in einer Reihe von Tieren einschließlich Schwein. Chinesische Rassen wie Meishan sind wegen ihres langsamen Wachstums und der starken Fettablagerung bekannt. In dieser Studie beschreiben wir regionale Cholecystokinin-ähnliche Immunreaktivitäts-(CCK-IR)Konzentrationen im Gehirn junger Duroc- und Meishantiere, mittels Radioimmunassay bestimmt. Gehirne von 1, 10 und 20 Tage alten Ferkeln jeder Rasse wurden untersucht. CCK-IR nahm mit dem Alter in allen drei untersuchten Organen zu (Kortex, Medulla und Hypothalamus). Die kortikalen Spiegel stiegen vom Tag 1 bis 10 und vom Tag 10 bis 20 signifikant, die des Hypothalamus und der Medulla

  9. Role of cholecystokinin in anorexia induction following oral exposure to the 8-ketotrichothecenes deoxynivalenol, 15-acetyldeoxynivalenol, 3-acetyldeoxynivalenol, fusarenon X, and nivalenol.

    Science.gov (United States)

    Wu, Wenda; Zhou, Hui-Ren; He, Kaiyu; Pan, Xiao; Sugita-Konishi, Yoshiko; Watanabe, Maiko; Zhang, Haibin; Pestka, James J

    2014-04-01

    Cereal grain contamination by trichothecene mycotoxins is known to negatively impact human and animal health with adverse effects on food intake and growth being of particular concern. The head blight fungus Fusarium graminearum elaborates five closely related 8-ketotrichothecene congeners: (1) deoxynivalenol (DON), (2) 3-acetyldeoxynivalenol (3-ADON), (3) 15-acetyldeoxynivalenol (15-ADON), (4) fusarenon X (FX), and (5) nivalenol (NIV). While anorexia induction in mice exposed intraperitoneally to DON has been linked to plasma elevation of the satiety hormones cholecystokinin (CCK) and peptide YY₃₋₃₆ (PYY₃₋₃₆), the effects of oral gavage of DON or of other 8-keotrichothecenes on release of these gut peptides have not been established. The purpose of this study was to (1) compare the anorectic responses to the aforementioned 8-ketotrichothecenes following oral gavage at a common dose (2.5 mg/kg bw) and (2) relate these effects to changes plasma CCK and PYY₃₋₃₆ concentrations. Elevation of plasma CCK markedly corresponded to anorexia induction by DON and all other 8-ketotrichothecenes tested. Furthermore, the CCK1 receptor antagonist SR 27897 and the CCK2 receptor antagonist L-365,260 dose-dependently attenuated both CCK- and DON-induced anorexia, which was consistent with this gut satiety hormone being an important mediator of 8-ketotrichothecene-induced food refusal. In contrast to CCK, PYY₃₋₃₆ was moderately elevated by oral gavage with DON and NIV but not by 3-ADON, 15-ADON, or FX. Taken together, the results suggest that CCK plays a major role in anorexia induction following oral exposure to 8-ketotrichothecenes, whereas PYY₃₋₃₆ might play a lesser, congener-dependent role in this response.

  10. Synthesis and biological activities of pseudopeptide analogues of the C-terminal heptapeptide of cholecystokinin. On the importance of the peptide bonds.

    Science.gov (United States)

    Rodriguez, M; Lignon, M F; Galas, M C; Fulcrand, P; Mendre, C; Aumelas, A; Laur, J; Martinez, J

    1987-08-01

    A series of pseudopeptide analogues of the C-terminal heptapeptide of cholecystokinin in which each peptide bond, one at a time, has been replaced by a CH2NH bond were synthesized: Z-Tyr(SO3-)-Nle-Gly-Trp-Nle-Asp psi-(CH2NH)Phe-NH2 (1), Z-Tyr(SO3-)-Nle-Gly-Trp-Nle psi (CH2NH)Asp-Phe-NH2 (2), Z-Tyr(SO3-)-Nle-Gly-Trp psi-(CH2NH)Nle-Asp-Phe-NH2 (3), Z-Tyr(SO3-)-Nle-Gly psi(CH2NH)Trp-Nle-Asp-Phe-NH2 (4), Z-Tyr(SO3-)-Nle psi-(CH2NH)Gly-Trp-Nle-Asp-Phe-NH2 (5), Z-Tyr(SO3-)-Met-Gly-Trp-Nle-Asp psi (CH2NH)Phe-NH2 (6), Z-Tyr-(SO3-)-Met-Gly-Trp-Nle psi (CH2NH)Asp-Phe-NH2 (7), Z-Tyr(SO3-)-Met-Gly-Trp psi (CH2NH)Nle-Asp-Phe-NH2 (8). These derivatives were studied for their ability to stimulate amylase release from rat pancreatic acini and to inhibit the binding of labeled CCK-9 to rat pancreatic acini and to guinea pig brain membrane CCK receptors. They were compared to the potent CCK-8 analogue Boc-Asp-Tyr(SO3-)-Nle-Gly-Trp-Nle-Asp-Phe-NH2. All of these pseudopeptides were able to stimulate amylase secretion with the same efficacy as CCK-8 but with varying potencies. These compounds were also potent in inhibiting the binding of labeled CCK-9 to CCK receptors from rat pancreatic acini and from guinea pig brain membranes.

  11. Involvement of cholecystokinin (CCK) in the daily pattern of gastrointestinal regulation of Senegalese sole (Solea senegalensis) larvae reared under different feeding regimes.

    Science.gov (United States)

    Navarro-Guillén, Carmen; Rønnestad, Ivar; Jordal, Ann-Elise Olderbakk; Moyano, Francisco Javier; Yúfera, Manuel

    2017-01-01

    Cholecystokinin (CCK) is an important regulator of pancreatic enzyme secretion in adult mammals and teleosteans. Although some studies have focused on the interaction between CCK and trypsin in marine fish larvae, little is known about the circadian patterns of the regulatory mechanism involving these two digestive components. In this study, we took advantage of the characteristic change from a diurnal to a nocturnal feeding habit that occurs in Senegalese sole (Solea senegalensis) post-larvae, to conduct an experiment where larvae and postlarvae were submitted to three different feeding regimes from mouth opening: continuous feeding, diurnal feeding and nocturnal feeding. The aim was to establish different daily feeding scenarios to uncover the operating mechanisms of CCK and tryptic enzyme activity over the 24-hourcycle to better understand the regulation of digestion in developing fish larvae. Results show a prevalence of simultaneous and opposing trends of CCK level and tryptic activity as a function of the postprandial time. This finding supports the existence of a regulatory loop between these two digestive components in pre- and post-metamorphic Senegal sole larvae. In addition, CCK level was also modulated by the gut content, tending to be lower when the gut is full and higher when is being emptied. Furthermore, larvae were able to synchronize digestive functions to very different feeding regimes, although it seems to be important having a diurnal feeding phase during pre-metamorphic stages for a proper development.

  12. Synergistic relationship between the Columbia University Appetitive Behavior Seminar and the satiating effect of cholecystokinin.

    Science.gov (United States)

    Smith, Gerard P

    2013-12-01

    Synergism between the Columbia University Appetitive Behavior Seminar and the research program of Smith and Gibbs on the satiating effect of cholecystokinin during the past 40 years is described. The Seminar was synergistic with the research program in five ways. First, the steady parade of speakers gave us a window on the varied and interesting work going on in the field. Second, the Seminar was the kind of audience for presentations of the work-in-progress on CCK that scientists hope for and rarely find. Criticism by members of the Seminar was relentless and constructive, and ideas for further experiments or new ways to tackle problematic data poured forth. Third, members of the Seminar did experiments that facilitated the experimental success of the research program. Fourth, members of the Seminar tutored us on topics that we wanted to import into the research program on CCK. Fifth, and probably most important, members of the Seminar gave us the encouragement, good humor, and friendship so necessary for coping with the struggles of the scientific life.

  13. Taraxacum officinale protects against cholecystokinin-induced acute pancreatitis in rats

    Institute of Scientific and Technical Information of China (English)

    Sang-Wan Seo; Hyung-Min Kim; Seung-Heon Hong; Hyun-Na Koo; Hyo-Jin An; Kang-Beom Kwon; Byung-Cheal Lim; Eun-A Seo; Do-Gon Ryu; Goo Moon; Hong-Yeoul Kim

    2005-01-01

    AIM: Taraxacum officinale (TO) has been frequently used as a remedy for inflammatory diseases. The aim of this study was to investigate the effect of TO on cholecystokinin (CCK)-octapeptide-induced acute pancreatitis in rats.METHODS: TO at 10 mg/kg was orally administered, followed by 75 μg/kg CCK octapeptide injected subcutaneously three times after 1, 3 and 5 h. This whole procedure was repeated for 5 d. We determined the pancreatic weight/body weight ratio, the levels of pancreatic HSP60 and HSP72, and the secretion of pro-inflammatory cytokines. Repeated CCK octapeptide treatment resulted in typical laboratory and morphological changes of experimentally-induced pancreatitis.RESULTS: TO significantly decreased the pancreatic weight/body weight ratio in CCK octapeptide-induced acute pancreatitis. TO also increased the pancreatic levels of HSP60 and HSP72. Additionally, the secretion of IL-6 and TNF-α decreased in the animals treated with TO.CONCLUSION: TO may have a protective effect against CCK octapeptide-induced acute pancreatitis.

  14. Effect of weight loss and ketosis on postprandial cholecystokinin and free fatty acid concentrations.

    Science.gov (United States)

    Chearskul, Supornpim; Delbridge, Elizabeth; Shulkes, Arthur; Proietto, Joseph; Kriketos, Adamandia

    2008-05-01

    Weight regain after weight loss may not be due primarily to voluntary return to social habits but may be explained by changes in peripheral hormonal signals activating hunger and encouraging feeding behavior. The objective of this study was to investigate physiologic adaptations to weight loss that may encourage weight regain. The study had a within-subject repeated-measure design [12 healthy, obese men, 33-64 y, body mass index (in kg/m(2)) 30-46] and was a clinical intervention investigation of circulating metabolites and hunger-satiety responses before and after weight loss. Measures included anthropometry (bioelectrical impedance, body weight, and waist circumference), concentrations of circulating hormones and metabolites [ketone bodies, free fatty acids (FFAs), insulin, leptin, glucose, and cholecystokinin (CCK)], and measures of hunger and satiety at baseline, 8 wk after weight loss with a very-low-energy diet, and 1 wk after weight maintenance. Weight loss led to a reduction in postprandial CCK secretion (P = 0.016). However, when subjects were ketotic (elevated circulating beta-hydroxybutyrate concentrations), CCK secretion was sustained at concentrations before weight loss. After weight loss, there were reduced postprandial FFA concentrations (P = 0.0005). The presence of ketosis sustained FFA to concentrations before weight loss (P = 0.60). Rapid weight loss of approximately 10% of initial body weight results in a reduction in postprandial CCK and FFA concentrations.

  15. Sulfated cholecystokinin-8 increases ghrelin secretion but does not affect oxyntomodulin in Holstein steers.

    Science.gov (United States)

    Yannaing, Swe; Thidarmyint, Hnin; Zhao, Hongqiong; Thanthan, Sint; Kitagawa, Kouki; Kuwayama, Hideto

    2012-08-01

    The effect of appetite regulatory hormone cholecystokinin (CCK) on the secretions of oxyntomodulin (OXM) and ghrelin, and the effect of ghrelin on the secretions of CCK and OXM were studied in ruminants. Eight Holstein steers, 7 months old, 243 ± 7 kg body weight (BW), were arranged in an incomplete Latin square design (8 animals × 4 treatments × 4 days of sampling). Steers were intravenously injected with 10 µg of sulfated CCK-8/kg BW, 20 µg of acyl ghrelin/kg BW, 100 µg of des-acyl ghrelin/kg BW or vehicle. Blood samples were collected from -60 min to 120 min relative to time of injection. Plasma concentrations of ghrelin, sulfated CCK and OXM were measured by double-antibody radioimmunoassay. Plasma acyl ghrelin was increased to peak level (428.3 ± 6 pg/mL) at 60 min after injection of CCK compared with pre-injected levels (203.3 ± 1 pg/mL). These results showed for the first time, that intravenous bolus injection of CCK increased ghrelin secretion in ruminants. In contrast, injection of ghrelin did not change CCK secretion. Administration of ghrelin or CCK has no effect on plasma OXM concentrations. In conclusion, our results show that administration of CCK increased ghrelin secretion but did not affect OXM release in ruminants. Ghrelin did not affect the secretions of CCK and OXM.

  16. Purification and characterization of cholecystokinin from the skin of salamander Tylototriton verrucosus.

    Science.gov (United States)

    Jiang, Wen-Bin; Hakim, Ma; Luo, Lei; Li, Bo-Wen; Yang, Shi-Long; Song, Yu-Zhu; Lai, Ren; Lu, Qiu-Min

    2015-05-18

    As a group of intestinal hormones and neurotransmitters, cholecystokinins (CCKs) regulate and affect pancreatic enzyme secretion, gastrointestinal motility, pain hypersensitivity, digestion and satiety, and generally contain a DYMGWMDFG sequence at the C-terminus. Many CCKs have been reported in mammals. However, only a few have been reported in amphibians, such as Hyla nigrovittata, Xenopus laevis, and Rana catesbeiana, with none reported in urodele amphibians like newts and salamanders. Here, a CCK called CCK-TV was identified and characterized from the skin of the salamander Tylototriton verrucosus. This CCK contained an amino acid sequence of DYMGWMDF-NH2 as seen in other CCKs. A cDNA encoding the CCK precursor containing 129 amino acid residues was cloned from the cDNA library of T. verrucosus skin. The CCK-TV had the potential to induce the contraction of smooth muscle strips isolated from porcine gallbladder, eliciting contraction at a concentration of 5.0 x 10⁻¹¹ mol/L and inducing maximal contraction at a concentration of 2.0 x 10⁻⁶ mol/L. The EC50 was 13.6 nmol/L. To the best of our knowledge, this is the first report to identify the presence of a CCK in an urodele amphibian.

  17. Cholecystokinin from the entorhinal cortex enables neural plasticity in the auditory cortex.

    Science.gov (United States)

    Li, Xiao; Yu, Kai; Zhang, Zicong; Sun, Wenjian; Yang, Zhou; Feng, Jingyu; Chen, Xi; Liu, Chun-Hua; Wang, Haitao; Guo, Yi Ping; He, Jufang

    2014-03-01

    Patients with damage to the medial temporal lobe show deficits in forming new declarative memories but can still recall older memories, suggesting that the medial temporal lobe is necessary for encoding memories in the neocortex. Here, we found that cortical projection neurons in the perirhinal and entorhinal cortices were mostly immunopositive for cholecystokinin (CCK). Local infusion of CCK in the auditory cortex of anesthetized rats induced plastic changes that enabled cortical neurons to potentiate their responses or to start responding to an auditory stimulus that was paired with a tone that robustly triggered action potentials. CCK infusion also enabled auditory neurons to start responding to a light stimulus that was paired with a noise burst. In vivo intracellular recordings in the auditory cortex showed that synaptic strength was potentiated after two pairings of presynaptic and postsynaptic activity in the presence of CCK. Infusion of a CCKB antagonist in the auditory cortex prevented the formation of a visuo-auditory association in awake rats. Finally, activation of the entorhinal cortex potentiated neuronal responses in the auditory cortex, which was suppressed by infusion of a CCKB antagonist. Together, these findings suggest that the medial temporal lobe influences neocortical plasticity via CCK-positive cortical projection neurons in the entorhinal cortex.

  18. Protective effects of cholecystokinin-8 on methamphetamine-induced behavioral changes and dopaminergic neurodegeneration in mice.

    Science.gov (United States)

    Gou, Hongyan; Wen, Di; Ma, Chunling; Li, Ming; Li, Yingmin; Zhang, Wenfang; Liu, Li; Cong, Bin

    2015-04-15

    We investigated whether pretreatment with the neuropeptide cholecystokinin-8 affected methamphetamine (METH)-induced behavioral changes and dopaminergic neurodegeneration in male C57/BL6 mice. CCK-8 pretreatment alone had no effect on locomotion and stereotypic behavior and could not induce behavioral sensitization; however, it attenuated, in a dose-dependent manner, hyperlocomotion and behavioral sensitization induced by a low dose of METH (1mg/kg). CCK-8 attenuated METH-induced stereotypic behavior at a dose of 3mg/kg but not at 10mg/kg. CCK-8 pretreatment attenuated METH (10mg/kg)-induced hyperthermia, the decrease of tyrosine hydroxylase (TH) and dopamine transporter (DAT) in the striatum, and TH in the substantia nigra. CCK-8 alone had no effect on rectal temperature, TH and DAT expression in the nigrostriatal region. In conclusion, our study demonstrated that pretreatment with CCK-8 inhibited changes typically induced by repeated exposure to METH, such as hyperlocomotion, behavioral sensitization, stereotypic behavior, and dopaminergic neurotoxicity. These findings make CCK-8 a potential therapeutic agent for the treatment of multiple symptoms associated with METH abuse.

  19. Serum cholecystokinin concentrations in dogs with naturally acquired pituitary-dependent hyperadrenocorticism.

    Science.gov (United States)

    Noh, Sungjun; Kim, Hye-Sun; Chang, Jinhwa; Kang, Ji-Houn; Chang, Dongwoo; Yang, Mhan-Pyo

    2016-10-01

    OBJECTIVE To determine serum cholecystokinin (CCK) concentrations in dogs with pituitary-dependent hyperadrenocorticism (PDH) and to evaluate associations among CCK concentration, PDH, and gallbladder mucocele (GBM). ANIMALS 14 client-owned dogs with PDH and 14 healthy dogs. PROCEDURES Dogs were separated into 4 groups: healthy dogs without gallbladder sludge (group A; n = 7), healthy dogs with gallbladder sludge (group B; 7), dogs with PDH and gallbladder sludge (group C; 8), and dogs with PDH and GBM (group D; 6). Serum CCK concentrations were then measured before and 1, 2, and 4 hours after consumption of a high-fat meal. Concentrations in dogs with PDH were also measured before and after trilostane treatment. Results were compared among groups and assessment points. RESULTS Preprandial serum CCK concentrations in group C were significantly lower than those in groups A, B, and D, but no significant differences in postprandial CCK concentrations were identified among the groups 1, 2, or 4 hours after the meal. With respect to trilostane treatment of dogs with PDH, no significant differences were identified between pre- and post-trilostane serum CCK concentrations in group C or D. Median CCK concentration after trilostane treatment was higher in group D than in group C, but this difference was not significant. CONCLUSIONS AND CLINICAL RELEVANCE The outcomes in this study did not support the hypothesis that a low circulating CCK concentration affects the development of GBM in dogs with PDH.

  20. Flavonoids stimulate cholecystokinin peptide secretion from the enteroendocrine STC-1 cells.

    Science.gov (United States)

    Al Shukor, Nadin; Ravallec, Rozenn; Van Camp, John; Raes, Katleen; Smagghe, Guy

    2016-09-01

    Animal experiments showed that flavonoids might have the potential for an anti-obesity effect by reducing weight and food intake. However, the exact mechanisms that could be involved in these proposed effects are still under investigation. The complex process of food intake is partially regulated by gastrointestinal hormones. Cholecystokinin (CCK) is the best known gastrointestinal hormone to induce satiety signal that plays a key role in food intake regulation. It is released from the endocrine cells (I cell) in response to the ingestion of nutrients into the small intestine. In this study, we investigated the possible effects of flavonoids (quercetin, kaempferol, apigenin, rutin and baicalein) on stimulation of CCK release in vitro using enteroendocrine STC-1 cells. In comparison with the control, quercetin, kaempferol and apigenin resulted in a significant increase in CCK secretion with quercetin showing the highest activity. On the other hand, no significant effect was seen by rutin and baicalein. To our knowledge, this is the first report to study the stimulation of CCK peptide hormone secretion from STC-1 cells by quercetin and kaempferol, rutin, apigenin and baicalein. Based on the cell-based results in this work, it can be suggested that the reported activity of flavonoids against food intake and weight could be mediated by stimulation of CCK signal which in turn is responsible for food intake reduction, but future animal and human studies are needed to confirm this conclusion at organism level.

  1. Action of peripherally administered cholecystokinin on monoaminergic and GABAergic neurons in the rat brain.

    Directory of Open Access Journals (Sweden)

    Kaneyuki,Takao

    1989-06-01

    Full Text Available In an acute study, cholecystokinin octapeptide sulfate (CCK in doses of 1, 10 or 100 micrograms/kg body weight was injected intraperitoneally into rats just prior to the dark cycle. Rats were sacrificed two hours following the CCK injection. Norepinephrine levels were elevated in the dorsal amygdala of rats injected with 10 micrograms of CCK as well as in the septum of rats injected with 1 and 10 micrograms of CCK. The dopamine level in the septum of rats injected with 1 microgram of CCK as well as the gamma-aminobutyric acid (GABA level in the lateral hypothalamus of rats injected with 10 micrograms of CCK were also elevated. In a chronic study, CCK (1 microgram/kg body weight/h was subcutaneously infused into rats with Alzet osmotic minipump for seven consecutive days. The daily food consumption did not change during the 7 days of CCK infusion. The dopamine turnover in the striatum accelerated and the GABA level increased. On the contrary, dopamine metabolism in the substantia nigra and locus coeruleus decreased. Furthermore, the serotonin level in the substantia nigra decreased. Norepinephrine levels decreased in the nucleus paraventricularis, the locus coeruleus and the substantia nigra. The results suggest that peripherally administered CCK may act on the monoaminergic neurons and GABAergic neurons in the brain.

  2. [Changes in the cholecystokinin-synthetizing hypothalamic system during experimental diabetes mellitus in rats].

    Science.gov (United States)

    Abramov, A V; Kolesnik, Iu M; Trzhetsinskiĭ, S D; Orlovskiĭ, M A

    1998-01-01

    The investigation was performed in 96 Wistar rats. Diabetes mellitus was induced by single injection of 50 mg/kg of streptozotocin. Cholecystokinin (CCK) synthesizing neurons were identified in hypothalamic structures using indirect immunofluorescence. In latent period of diabetes (2 wks) number of CCK--immunopositive neurons increases, especially in paraventricular and suprachiasmatic nuclei, while in ventrolateral subnucleus of arcuate nucleus and parvicellular subnucleus of paraventricular nucleus areas occupied by immunoreactive material in neurons and their CCK content are reduced. By the end of wk 5 of the disease increase in number of CCK immunopositive neurons was registered only in medial parvicellular subnucleus of paraventricular nucleus whereas in other structures their number was reduced. The administration of CCK to intact animals causes increase of insulin content in endocrinocytes of pancreatic islets, but does not affect the level of hypoglycemia. The administration of the peptide to animals with diabetes leads to destruction of pancreatic islets, decline in endocrinocyte number and insulin content and marked hypoglycemia. Thus, the data obtained indicate the significant role of hypothalamic peptidergic system and CCK in regulation of beta-endocrinocyte function.

  3. Cholecystokinin acts as an essential factor in the exacerbation of pancreatic bile duct ligation-induced rat pancreatitis model under non-fasting condition.

    Science.gov (United States)

    Yoshinaga, K; Washizuka, M; Segawa, Y

    2000-09-01

    We examined the influence of 2 gut hormones involved in the enhancement of pancreatic exocrine secretion, secretin and cholecystokinin (CCK), in the exacerbation of pancreatitis. We also examined the role of the vagal system, which was considered to be a transmission route for these hormones. Our model of pancreatitis in the rat was prepared by pancreatic bile duct ligation (PBDL), which simultaneously ligated the pancreatic duct and the common bile duct. Serum amylase activity and histopathological changes in the pancreas were used as indices of pancreatitis. We also measured the volume of pancreatic juice, as well as the amylase activity and protein level of the pancreatic juice, as indices of increased pancreatic exocrine secretion. Two gut hormones were given 6 times at 1-h intervals. Administration of secretin (1-3 microg/kg, s.c.) did not influence serum amylase activity in rats with PBDL-induced pancreatitis. However, food stimulation and administration of CCK-8 (1 microg/kg, s.c.) increased serum amylase activity and promoted vacuolation of the pancreatic acinar cells in rats with PBDL-induced pancreatitis. Administration of atropine (3 mg/kg, s.c.) or a CCK1-receptor antagonist, Z-203 (0.1 mg/kg, i.v.), inhibited food-stimulated or CCK-8-induced (1 microg/kg, s.c.) enhancement of pancreatic exocrine secretion and exacerbation after the development of PBDL-induced pancreatitis. These results suggest that not secretin, which regulates the volume of pancreatic juice, but CCK, which regulates the secretion of pancreatic enzymes via the vagal system, plays an essential role in food-stimulated exacerbation after the development of pancreatitis.

  4. The dorsomedial hypothalamus mediates stress-induced hyperalgesia and is the source of the pronociceptive peptide cholecystokinin in the rostral ventromedial medulla.

    Science.gov (United States)

    Wagner, K M; Roeder, Z; Desrochers, K; Buhler, A V; Heinricher, M M; Cleary, D R

    2013-05-15

    While intense or highly arousing stressors have long been known to suppress pain, relatively mild or chronic stress can enhance pain. The mechanisms underlying stress-induced hyperalgesia (SIH) are only now being defined. The physiological and neuroendocrine effects of mild stress are mediated by the dorsomedial hypothalamus (DMH), which has documented connections with the rostral ventromedial medulla (RVM), a brainstem region capable of facilitating nociception. We hypothesized that stress engages both the DMH and the RVM to produce hyperalgesia. Direct pharmacological activation of the DMH increased sensitivity to mechanical stimulation in awake animals, confirming that the DMH can mediate behavioral hyperalgesia. A behavioral model of mild stress also produced mechanical hyperalgesia, which was blocked by inactivation of either the DMH or the RVM. The neuropeptide cholecystokinin (CCK) acts in the RVM to enhance nociception and is abundant in the DMH. Using a retrograde tracer and immunohistochemical labeling, we determined that CCK-expressing neurons in the DMH are the only significant supraspinal source of CCK in the RVM. However, not all neurons projecting from the DMH to the RVM contained CCK, and microinjection of the CCK2 receptor antagonist YM022 in the RVM did not interfere with SIH, suggesting that transmitters in addition to CCK play a significant role in this connection during acute stress. While the RVM has a well-established role in facilitation of nociception, the DMH, with its well-documented role in stress, may also be engaged in a number of chronic or abnormal pain states. Taken as a whole, these findings establish an anatomical and functional connection between the DMH and RVM by which stress can facilitate pain.

  5. Cholecystokinin expression in the β-cell leads to increased β-cell area in aged mice and protects from streptozotocin-induced diabetes and apoptosis.

    Science.gov (United States)

    Lavine, Jeremy A; Kibbe, Carly R; Baan, Mieke; Sirinvaravong, Sirinart; Umhoefer, Heidi M; Engler, Kimberly A; Meske, Louise M; Sacotte, Kaitlyn A; Erhardt, Daniel P; Davis, Dawn Belt

    2015-11-15

    Cholecystokinin (CCK) is a peptide hormone produced in the gut and brain with beneficial effects on digestion, satiety, and insulin secretion. CCK is also expressed in pancreatic β-cells, but only in models of obesity and insulin resistance. Whole body deletion of CCK in obese mice leads to reduced β-cell mass expansion and increased apoptosis. We hypothesized that islet-derived CCK is important in protection from β-cell apoptosis. To determine the specific role of β-cell-derived CCK in β-cell mass dynamics, we generated a transgenic mouse that expresses CCK in the β-cell in the lean state (MIP-CCK). Although this transgene contains the human growth hormone minigene, we saw no expression of human growth hormone protein in transgenic islets. We examined the ability of MIP-CCK mice to maintain β-cell mass when subjected to apoptotic stress, with advanced age, and after streptozotocin treatment. Aged MIP-CCK mice have increased β-cell area. MIP-CCK mice are resistant to streptozotocin-induced diabetes and exhibit reduced β-cell apoptosis. Directed CCK overexpression in cultured β-cells also protects from cytokine-induced apoptosis. We have identified an important new paracrine/autocrine effect of CCK in protection of β-cells from apoptotic stress. Understanding the role of β-cell CCK adds to the emerging knowledge of classic gut peptides in intraislet signaling. CCK receptor agonists are being investigated as therapeutics for obesity and diabetes. While these agonists clearly have beneficial effects on body weight and insulin sensitivity in peripheral tissues, they may also directly protect β-cells from apoptosis.

  6. Endocannabinoids regulate interneuron migration and morphogenesis by transactivating the TrkB receptor

    OpenAIRE

    Berghuis, Paul; Dobszay, Marton B.; Wang, Xinyu; Spano, Sabrina; Ledda, Fernanda; Sousa, Kyle M.; Schulte, Gunnar; Ernfors, Patrik; Mackie, Ken; Paratcha, Gustavo; Hurd, Yasmin L.; Harkany, Tibor

    2005-01-01

    In utero exposure to Δ9-tetrahydrocannabinol (Δ9-THC), the active component from marijuana, induces cognitive deficits enduring into adulthood. Although changes in synaptic structure and plasticity may underlie Δ9-THC-induced cognitive impairments, the neuronal basis of Δ9-THC-related developmental deficits remains unknown. Using a Boyden chamber assay, we show that agonist stimulation of the CB1 cannabinoid receptor (CB1R) on cholecystokinin-expressing interneurons induces chemotaxis that is...

  7. Apelin stimulates both cholecystokinin and glucagon-like peptide 1 secretions in vitro and in vivo in rodents.

    Science.gov (United States)

    Wattez, Jean-Sébastien; Ravallec, Rozenn; Cudennec, Benoit; Knauf, Claude; Dhulster, Pascal; Valet, Philippe; Breton, Christophe; Vieau, Didier; Lesage, Jean

    2013-10-01

    Apelin is an enteric peptide that exerts several digestive functions such as stimulation of cell proliferation and cholecystokinin (CCK) secretion. We investigated using murine enteroendocrine cell line (STC-1) and rats if apelin-13 stimulates both CCK and glucagon-like peptide 1 (GLP-1) secretions. We demonstrated that, in vitro and in vivo, apelin-13 increases the release of these two hormones in a dose-dependent manner. Present data suggest that apelin may modulate digestive functions, food intake behavior and glucose homoeostasis via apelin-induced release of enteric CCK but also through a new incretin-releasing activity on enteric GLP-1.

  8. 2-Phenylethyl ester and 2-phenylethyl amide derivative analogues of the C-terminal hepta- and octapeptide of cholecystokinin.

    Science.gov (United States)

    Fulcrand, P; Rodriguez, M; Galas, M C; Lignon, M F; Laur, J; Aumelas, A; Martinez, J

    1988-11-01

    Syntheses of analogues of the C-terminal octa- and heptapeptide of cholecystokinin are described. These analogues were obtained by replacing the C-terminal phenylalanine residue by 2-phenylethyl alcohol or by 2-phenylethylamine derivatives and by replacing the tryptophan residue by a D-tryptophan. The CCK-derivatives were tested for their ability to inhibit binding of labeled CCK-8 to rat pancreatic acini and to guinea pig brain membranes, and for their action on stimulation of amylase release from rat pancreatic acini. Some of these derivatives appeared to exhibit only part of the CCK-activity on amylase release, the D-Trp analogues behaving as CCK-antagonists.

  9. The type 2 CCK/gastrin receptor antagonist YF476 acutely prevents NSAID-induced gastric ulceration while increasing iNOS expression

    OpenAIRE

    Webb, Dominic-Luc; Rudholm-Feldreich, Tobias; Gillberg, Linda; Halim, Abdul; Theodorsson, Elvar; Sanger, Gareth J.; Campbell, Colin A.; Boyce, Malcolm; Näslund, Erik; Per M Hellström

    2013-01-01

    YF476 differs from the proton pump inhibitor (PPI) esomeprazole in mode of action by antagonizing the type 2 receptor of cholecystokinin/gastrin (CCK-2R). YF476 protection against diclofenac-induced gastric ulcers was compared to esomeprazole and correlated with plasma levels of hormones related to gastric pH (gastrin, ghrelin, and somatostatin), gastric gene expression of these hormones, their receptors, and inducible nitric oxide synthase (iNOS). YF476 or esomeprazole pretreatments were fol...

  10. Ontogeny expression of ghrelin, neuropeptide Y and cholecystokinin in blunt snout bream, Megalobrama amblycephala.

    Science.gov (United States)

    Ping, H-C; Feng, K; Zhang, G-R; Wei, K-J; Zou, G-W; Wang, W-M

    2014-04-01

    Ghrelin, neuropeptide Y (NPY) and cholecystokinin (CCK) all have important roles in the regulation of feeding in fish and mammals. To better understand the role of the three peptides in appetite regulation in the early developmental stages of blunt snout bream (Megalobrama amblycephala), partial cDNA sequences of ghrelin, NPY and CCK genes were cloned. And then, real-time quantitative PCR and RT-PCR were used to detect and quantify the mRNA expressions of these genes from zygotes to larvae of 50 days after hatching (DAH). Ghrelin, NPY and CCK were all expressed throughout the embryonic and larval development stages, and the expression levels were higher in larval stages than in embryonic stages. Ghrelin and NPY mRNA expressions were upregulated at 1, 3, 5 DAH, while CCK mRNA expression was reduced significantly at 3 DAH. The mRNA expression levels of three genes in larvae varied significantly until 30 DAH. In adult fish, all three peptides were detected to be expressed in brain and several peripheral tissues. Ghrelin mRNA was mainly expressed in the intestine, whereas NPY and CCK mRNAs were mainly expressed in the brain. Taken together, these results indicate that ghrelin, NPY and CCK may have roles in early development and participate in the regulation of feeding of larvae in blunt snout bream and will be helpful for further investigation into feed intake regulation in adults of this species. Journal of Animal Physiology and Animal Nutrition © 2013 Blackwell Verlag GmbH.

  11. The antagonism of cholecystokinin octapeptide-8 to the peroxynitrite oxidation on a diabetic cataractal rat model

    Institute of Scientific and Technical Information of China (English)

    HAO Li-na; LING Yi-qun; MAO Qi-yan; LING Yi-ling; HE Shou-zhi

    2006-01-01

    Background Cataracts is considered be formed because of an abnormal glucose metabolic pathway or oxidative stress. We explored the damaging role of ONOO- and antagonism of cholecystokinin octapeptide-8(CCK-8) in diabetic cataractal rat lenses.Methods A diabetic cataractal animal model was established by peritoneal injection of streptozotocine (STZ).Thirty-six normal SD rats were taken as control group; seventy-two were given STZ (45 mg/kg) and then divided into STZ group and CCK-8 group (peritoneal injection CCK-8). STZ induced diabetic rats were treated with CCK-8 for 60 days. Lenses were examined with slit lamp at 20, 40 and 60 days. Immunofluorescent staining and Western blot analysis were used for determining nitrotyrosine (NT, a marker for ONOO-). RT-PCR and gene array analysis were used for determining the expression of inducible nitric oxide synthetase mRNA (iNOS mRNA) in lens epithelium (LEC).Results STZ group rats developed lens opacity by 20 days that reached a high level by 60 days after STZ injection. CCK-8 group rats delayed the cataract formation. There was no distinct expression of NT and iNOS mRNA in control group. In STZ group, there were distinct expression of NT and upregulation of iNOS mRNA;however, CCK-8 group showed weak expression of NT and downregulation of iNOS mRNA.Conclusions NT, which may be a new form of oxidative stress, was expressed in diabetic rat LEC although CCK-8 could reverse NT damage in LEC. The results suggested that CCK-8 might be a useful therapeutic agent against diabetic cataract. The antagonizing mechanism of CCK-8 may be related to direct antagonism of ONOO-as well as its inhibition of the expression of iNOS mRNA for production of NO and therefore decrease in the formation of ONOO-.

  12. Cholecystokinin-33 acutely attenuates food foraging, hoarding and intake in Siberian hamsters.

    Science.gov (United States)

    Teubner, Brett J W; Bartness, Timothy J

    2010-04-01

    Neurochemicals that stimulate food foraging and hoarding in Siberian hamsters are becoming more apparent, but we do not know if cessation of these behaviors is due to waning of excitatory stimuli and/or the advent of inhibitory factors. Cholecystokinin (CCK) may be such an inhibitory factor as it is the prototypic gastrointestinal satiety peptide and is physiologically important in decreasing food intake in several species including Siberian hamsters. Systemic injection of CCK-33 in laboratory rats decreases food intake, doing so to a greater extent than CCK-8. We found minimal effects of CCK-8 on food foraging and hoarding previously in Siberian hamsters, but have not tested CCK-33. Therefore, we asked: Does CCK-33 decrease normal levels or food deprivation-induced increases in food foraging, hoarding and intake? Hamsters were housed in a wheel running-based foraging system with simulated burrows to test the effects of peripheral injections of CCK-33 (13.2, 26.4, or 52.8 microg/kg body mass), with or without a preceding 56 h food deprivation. The highest dose of CCK-33 caused large baseline reductions in all three behaviors for the 1st hour post-injection compared with saline; in addition, the intermediate CCK-33 dose was sufficient to curtail food intake and foraging during the 1st hour. In food-deprived hamsters, we used a 52.8 microg/kg body mass dose of CCK-33 which decreased food intake, hoarding, and foraging almost completely compared with saline controls for 1h. Therefore, CCK-33 appears to be a potent inhibitor of food intake, hoarding, and foraging in Siberian hamsters.

  13. Cholecystokinin activation of central satiety centers changes seasonally in a mammalian hibernator.

    Science.gov (United States)

    Otis, Jessica P; Raybould, Helen E; Carey, Hannah V

    2011-05-01

    Hibernators that rely on lipids during winter exhibit profound changes in food intake over the annual cycle. The mechanisms that regulate appetite changes in seasonal hibernators remain unclear, but likely consist of complex interactions between gut hormones, adipokines, and central processing centers. We hypothesized that seasonal changes in the sensitivity of neurons in the nucleus tractus solitarius (NTS) to the gut hormone cholecystokinin (CCK) may contribute to appetite regulation in ground squirrels. Spring (SPR), late summer (SUM), and winter euthermic hibernating (HIB) 13-lined ground squirrels (Ictidomys tridecemlineatus) were treated with intraperitoneal CCK (100 μg/kg) or vehicle (CON) for 3h and Fos expression in the NTS was quantified. In CON squirrels, numbers of Fos-positive neurons in HIB were low compared to SPR and SUM. CCK treatment increased Fos-positive neurons in the NTS at the levels of the area postrema (AP) and pre AP during all seasons and at the level of the rostral AP in HIB squirrels. The highest absolute levels of Fos-positive neurons were found in SPR CCK squirrels, but the highest relative increase from CON was found in HIB CCK squirrels. Fold-changes in Fos-positive neurons in SUM were intermediate between SPR and HIB. Thus, CCK sensitivity falls from SPR to SUM suggesting that seasonal changes in sensitivity of NTS neurons to vagally-derived CCK may influence appetite in the active phase of the annual cycle in hibernating squirrels. Enhanced sensitivity to CCK signaling in NTS neurons of hibernators indicates that changes in gut-brain signaling may contribute to seasonal changes in food intake during the annual cycle.

  14. Nesfatin-1 stimulates cholecystokinin and suppresses peptide YY expression and secretion in mice.

    Science.gov (United States)

    Ramesh, Naresh; Mortazavi, Sima; Unniappan, Suraj

    2016-03-25

    Nesfatin-1 is an 82 amino acid secreted peptide encoded in the precursor, nucleobindin-2 (NUCB2). It is an insulinotropic anorexigen abundantly expressed in the stomach and hypothalamus. Post-prandial insulin secretion is predominantly regulated by incretins glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Nesfatin-1 was previously reported to modulate GLP-1 and GIP secretion in vitro in an enteroendocrine (STC-1) cell line. Intestine is a source of additional hormones including cholecystokinin (CCK) and peptide YY (PYY) that regulate metabolism. We hypothesized that nesfatin-1 modulates CCK and PYY secretion. Immunofluorescence histochemistry showed NUCB2/nesfatin-1 co-localizing CCK and PYY in the intestinal mucosa of mice. Static incubation of STC-1 cells with nesfatin-1 upregulated both CCK mRNA expression (1 and 10 nM) and secretion (0.1, 1 and 10 nM) at 1 h post-incubation. In contrast, nesfatin-1 treatment for 1 h downregulated PYY mRNA expression (all doses tested) and secretion (0.01 and 0.1 nM) in STC-1 cells. Continuous infusion of nesfatin-1 using osmotic mini-pumps for 12 h upregulated CCK mRNA expression in large intestine, and downregulated PYY mRNA expression in both large and small intestines of male C57BL/6J mice. In these tissues, Western blot analysis found a corresponding increase in CCK and a decrease in PYY content. Collectively, we provide new information on the cell specific localization of NUCB2/nesfatin-1 in the intestinal mucosa, and a novel function for nesfatin-1 in modulating intestinal CCK and PYY expression and secretion in mice.

  15. Cholecystokinin regulates satiation independently of the abdominal vagal nerve in a pig model of total subdiaphragmatic vagotomy.

    Science.gov (United States)

    Ripken, D; van der Wielen, N; van der Meulen, J; Schuurman, T; Witkamp, R F; Hendriks, H F J; Koopmans, S J

    2015-02-01

    The vagal nerve and gut hormones CCK and GLP-1 play important roles in the control of food intake. However, it is not clear to what extent CCK and GLP-1 increase satiation by stimulating receptors located on abdominal vagal nerve endings or via receptors located elsewhere. This study aimed to further explore the relative contribution of the abdominal vagal nerve in mediating the satiating effects of endogenous CCK and GLP-1. Total subdiaphragmatic vagotomy or sham operation was combined with administration of CCK1 and GLP-1 receptor antagonists devazepide and exendin (9-39) in 12 pigs, applying an unbalanced Latin Square within-subject design. Furthermore, effects of vagotomy on preprandial and postprandial acetaminophen absorption, glucose, insulin, GLP-1 and CCK plasma concentrations were investigated. Ad libitum liquid meal intake (mean±SEM) was similar in sham and vagotomized pigs (4180±435 and 3760±810 g/meal). Intake increased by about 20% after blockade of CCK1 receptors, independently of the abdominal vagal nerve. Food intake did not increase after blockade of GLP-1 receptors. Blockade of CCK1 and GLP-1 receptors increased circulating CCK and GLP-1 concentrations in sham pigs only, suggesting the existence of a vagal reflex mechanism in the regulation of plasma CCK1 and GLP-1 concentrations. Vagotomy decreased acetaminophen absorption and changed glucose, insulin, CCK and GLP-1 concentrations indicating a delay in gastric emptying. Our data show that at liquid feeding, satiation is decreased effectively by pharmacological blockade of CCK1 receptors. We conclude that regulation of liquid meal intake appears to be primarily regulated by CCK1 receptors not located on abdominal vagal nerve endings.

  16. Regulation of oxidative stress and somatostatin, cholecystokinin, apelin gene expressions by ghrelin in stomach of newborn diabetic rats.

    Science.gov (United States)

    Coskun, Zeynep Mine; Sacan, Ozlem; Karatug, Ayse; Turk, Neslihan; Yanardag, Refiye; Bolkent, Sehnaz; Bolkent, Sema

    2013-09-01

    The aim of the study was to determine whether ghrelin treatment has a protective effect on gene expression and biochemical changes in the stomach of newborn streptozotocin (STZ) induced diabetic rats. In this study, four groups of Wistar rats were used: control, ghrelin control, diabetic and diabetic+ghrelin. The rats were sacrificed after four weeks of treatment for diabetes. The gene expressions of: somatostatin, cholecystokinin, apelin and the altered active caspase-3, active caspase-8, proliferating cell nuclear antigen, were investigated in the pyloric region of the stomach and antioxidant parameters were measured in all the stomach. Although ghrelin treatment to diabetic rats lowered the stomach lipid peroxidation levels, the stomach glutathione levels were increased. Exogenous ghrelin caused an increased activities of stomach catalase, superoxide dismutase, glutathione reductase and glutathione peroxidase in diabetic rats. Numbers of somatostatin, cholecystokinin and proliferating cell nuclear antigen immunoreactive cells decreased in the diabetic+ghrelin group compared to the diabetic group. Apelin mRNA expressions were remarkably less in the diabetic+ghrelin rats than in diabetic rats. The results may indicate that ghrelin treatment has a protective effect to some extent on the diabetic rats. This protection is possibly accomplished through the antioxidant activity of ghrelin observed in type 2 diabetes. Consequently exogenous ghrelin may be a candidate for therapeutic treatment of diabetes. Copyright © 2013 Elsevier GmbH. All rights reserved.

  17. Changes in messenger RNA of pancreatic enzymes and intestinal cholecystokinin after a 7-day bile-pancreatic juice diversion from the proximal small intestine in rats.

    Science.gov (United States)

    Hara, H; Ochi, Y; Kasai, T

    1997-06-01

    We have previously demonstrated the bile-pancreatic juice (BPJ)-independent stimulation of pancreatic enzyme secretion in chronic BPJ-diverted rats. Pancreatic and intestinal adaptation to 7-day BPJ diversion was next examined. Pancreatic enzyme mRNA and cholecystokinin mRNA in the jejunal mucosa were measured in rats with BPJ diverted into the ileum (PBD rats) in comparison with the figures for rats with BPJ returned to the duodenum (normal rats) or laparotomized (Intact) rats under well-nourished conditions. Amylase mRNA in the pancreas was lower and trypsinogen plus chymotrypsinogen mRNA was higher in the PBD rats than in the intact rats. The change in pancreatic mRNA was similar to that in the specific activities of the enzymes after a chronic BPJ diversion. This finding suggests that these pancreatic enzymes were regulated by the mRNA level. The portal concentration of cholecystokinin in the postabsorptive period (exogenously non-stimulated status) was 4-fold higher in the PBD group than in the normal and intact groups. Cholecystokinin mRNA in the jejunal mucosa of PBD rats was somewhat higher than that of intact rats. These results suggest that intestinal cholecystokinin was predominantly increased at the translational or later stage by chronic BPJ diversion.

  18. Quantification of the Sulfated Cholecystokinin CCK8 in Hamster Plasma Using Immunoprecipitation-Liquid Chromatography-Mass Spectrometry/Mass Spectrometry

    Science.gov (United States)

    Cholecystokinin (CCK) and the different molecular forms of CCK are well established as biomarkers for satiety. CCK hormone and the different biologically active and inactive molecular forms have been shown to influence food intake associated with satiety and are predominately secreted from the gut....

  19. Sulfated cholecystokinin-8 activates phospho-mTOR immunoreactive neurons of the paraventricular nucleus in rats

    Science.gov (United States)

    Frommelt, Lisa; Inhoff, Tobias; Lommel, Reinhardt; Stengel, Andreas; Taché, Yvette; Grötzinger, Carsten; Bannert, Norbert; Wiedenmann, Bertram; Klapp, Burghard F.; Kobelt, Peter

    2014-01-01

    The serin/threonin-kinase, mammalian target of rapamycin (mTOR) was detected in the arcuate nucleus (ARC) and paraventricular nucleus of the hypothalamus (PVN) and suggested to play a role in the integration of satiety signals. Since cholecystokinin (CCK) plays a role in the short-term inhibition of food intake and induces c-Fos in PVN neurons, the aim was to determine whether intraperitoneally injected CCK-8S affects the neuronal activity in cells immunoreactive for phospho-mTOR in the PVN. Ad libitum fed male Sprague-Dawley rats received 6 or 10 μg/kg CCK-8S or 0.15 M NaCl ip (n=4/group). The number of c-Fosimmunoreactive (ir) neurons was assessed in the PVN, ARC and in the nucleus of the solitary tract (NTS). CCK-8S increased the number of c-Fos-ir neurons in the PVN (6 μg: 103 ± 13 vs. 10 μg: 165 ± 14 neurons/section; p<0.05) compared to vehicle treated rats (4 ± 1, p<0.05), but not in the ARC. CCK-8S also dose-dependently increased the number of c-Fos neurons in the NTS. Staining for phospho-mTOR and c-Fos in the PVN showed a dose-dependent increase of activated phospho-mTOR neurons (17 ± 3 vs. 38 ± 2 neurons/section; p<0.05), while no activated phospho-mTOR neurons were observed in the vehicle group. Triple staining in the PVN showed activation of phospho-mTOR neurons co-localized with oxytocin, corresponding to 9.8 ± 3.6% and 19.5 ± 3.3% of oxytocin neurons respectively. Our observations indicate that peripheral CCK-8S activates phospho-mTOR neurons in the PVN and suggest that phospho-mTOR plays a role in the mediation of CCK-8S's anorexigenic effects. PMID:20933028

  20. Insulin is necessary for the hypertrophic effect of cholecystokinin-octapeptide following acute necrotizing experimental pancreatitis

    Institute of Scientific and Technical Information of China (English)

    Péter Hegyi; Zoltán Rakonczay Jr; Réka Sári; László Czakó; Norbert Farkas; Csaba Góg; József Németh; János Lonovics; Tamás Takács

    2004-01-01

    AIM: In previous experiments we have demonstrated that by administering low doses of cholecystokinin-octapeptide (CCK-8), the process of regeneration following L-arginine (Arg)-induced pancreatitis is accelerated. In rats that were also diabetic (induced by streptozotocin, STZ), pancreatic regeneration was not observed. The aim of this study was to deduce whether the administration of exogenous insulin could in fact restore the hypertrophic effect of CCK-8 in diabetic-pancreatitic rats.METHODS: Male Wistar rats were used for the experiments.Diabetes mellitus was induced by administering 60 mg/kg body mass of STZ intraperitoneally (i.p.), then, on d 8,pancreatitis was induced by 200 mg/100 g body mass Arg i.p. twice at an interval of 1 h. The animals were injected subcutaneously twice daily (at 7 a.m. and 7 p.m.) with 1 μg/kg of CCK-8 and/or 2 IU mixed insulin (300 g/L shortaction and 700 g/L intermediate-action insulin) for 14 d after pancreatitis induction. Following this the animals were killed and the serum amylase, glucose and insulin levels as well as the plasma glucagon levels, the pancreatic mass/body mass ratio (pm/bm), the pancreatic contents of DNA, protein, amylase, lipase and trypsinogen were measured. Pancreatic tissue samples were examined by light microscopy on paraffin-embedded sections.RESULTS: In the diabetic-pancreatitic rats treatment with insulin and CCK-8 significantly elevated pw/bm and the pancreatic contents of protein, amylase and lipase vs the rats receiving only CCK-8 treatment. CCK-8 administered in combination with insulin also elevated the number of acinar cells with mitotic activities, whereas CCK-8 alone had no effect on laboratory parameters or the mitotic activities in diabetic-pancreatitic rats.CONCLUSION: Despite the hypertrophic effect of CCK-8 being absent following acute pancreatitis in diabetic-rats,the simultaneous administration of exogenous insulin restored this effect. Our results clearly demonstrate that insulin is

  1. NCBI nr-aa BLAST: CBRC-ETEL-01-0465 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-ETEL-01-0465 ref|NP_000721.1| cholecystokinin A receptor [Homo sapiens] sp|P32238|CCKAR_HUMAN Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (CCK1-R) gb|AAA35659.1| chole...cystokinin A receptor gb|AAA02819.1| cholecystokinin A receptor gb|AAA91123.1| chole...cystokinin type A receptor dbj|BAA90879.1| cholecystokinin type-A receptor [Homo ...sapiens] gb|AAP84362.1| cholecystokinin A receptor [Homo sapiens] gb|AAH74987.1| Cholecystokinin A receptor

  2. NCBI nr-aa BLAST: CBRC-GACU-07-0011 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-GACU-07-0011 ref|NP_000721.1| cholecystokinin A receptor [Homo sapiens] sp|P32238|CCKAR_HUMAN Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (CCK1-R) gb|AAA35659.1| chole...cystokinin A receptor gb|AAA02819.1| cholecystokinin A receptor gb|AAA91123.1| chole...cystokinin type A receptor dbj|BAA90879.1| cholecystokinin type-A receptor [Homo ...sapiens] gb|AAP84362.1| cholecystokinin A receptor [Homo sapiens] gb|AAH74987.1| Cholecystokinin A receptor

  3. NCBI nr-aa BLAST: CBRC-XTRO-01-2768 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-XTRO-01-2768 ref|NP_000721.1| cholecystokinin A receptor [Homo sapiens] sp|P32238|CCKAR_HUMAN Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (CCK1-R) gb|AAA35659.1| chole...cystokinin A receptor gb|AAA02819.1| cholecystokinin A receptor gb|AAA91123.1| chole...cystokinin type A receptor dbj|BAA90879.1| cholecystokinin type-A receptor [Homo ...sapiens] gb|AAP84362.1| cholecystokinin A receptor [Homo sapiens] gb|AAH74987.1| Cholecystokinin A receptor

  4. NCBI nr-aa BLAST: CBRC-OCUN-01-1620 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-OCUN-01-1620 ref|NP_000721.1| cholecystokinin A receptor [Homo sapiens] sp|P32238|CCKAR_HUMAN Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (CCK1-R) gb|AAA35659.1| chole...cystokinin A receptor gb|AAA02819.1| cholecystokinin A receptor gb|AAA91123.1| chole...cystokinin type A receptor dbj|BAA90879.1| cholecystokinin type-A receptor [Homo ...sapiens] gb|AAP84362.1| cholecystokinin A receptor [Homo sapiens] gb|AAH74987.1| Cholecystokinin A receptor

  5. NCBI nr-aa BLAST: CBRC-ETEL-01-1373 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-ETEL-01-1373 ref|NP_000721.1| cholecystokinin A receptor [Homo sapiens] sp|P32238|CCKAR_HUMAN Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (CCK1-R) gb|AAA35659.1| chole...cystokinin A receptor gb|AAA02819.1| cholecystokinin A receptor gb|AAA91123.1| chole...cystokinin type A receptor dbj|BAA90879.1| cholecystokinin type-A receptor [Homo ...sapiens] gb|AAP84362.1| cholecystokinin A receptor [Homo sapiens] gb|AAH74987.1| Cholecystokinin A receptor

  6. NCBI nr-aa BLAST: CBRC-ACAR-01-0438 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-ACAR-01-0438 ref|NP_000721.1| cholecystokinin A receptor [Homo sapiens] sp|P32238|CCKAR_HUMAN Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (CCK1-R) gb|AAA35659.1| chole...cystokinin A receptor gb|AAA02819.1| cholecystokinin A receptor gb|AAA91123.1| chole...cystokinin type A receptor dbj|BAA90879.1| cholecystokinin type-A receptor [Homo ...sapiens] gb|AAP84362.1| cholecystokinin A receptor [Homo sapiens] gb|AAH74987.1| Cholecystokinin A receptor

  7. NCBI nr-aa BLAST: CBRC-HSAP-04-0027 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-HSAP-04-0027 ref|NP_000721.1| cholecystokinin A receptor [Homo sapiens] sp|P32238|CCKAR_HUMAN Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (CCK1-R) gb|AAA35659.1| chole...cystokinin A receptor gb|AAA02819.1| cholecystokinin A receptor gb|AAA91123.1| chole...cystokinin type A receptor dbj|BAA90879.1| cholecystokinin type-A receptor [Homo ...sapiens] gb|AAP84362.1| cholecystokinin A receptor [Homo sapiens] gb|AAH74987.1| Cholecystokinin A receptor

  8. NCBI nr-aa BLAST: CBRC-DRER-07-0072 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-DRER-07-0072 ref|NP_000721.1| cholecystokinin A receptor [Homo sapiens] sp|P32238|CCKAR_HUMAN Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (CCK1-R) gb|AAA35659.1| chole...cystokinin A receptor gb|AAA02819.1| cholecystokinin A receptor gb|AAA91123.1| chole...cystokinin type A receptor dbj|BAA90879.1| cholecystokinin type-A receptor [Homo ...sapiens] gb|AAP84362.1| cholecystokinin A receptor [Homo sapiens] gb|AAH74987.1| Cholecystokinin A receptor

  9. NCBI nr-aa BLAST: CBRC-CBRE-01-0701 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-CBRE-01-0701 ref|NP_000721.1| cholecystokinin A receptor [Homo sapiens] sp|P32238|CCKAR_HUMAN Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (CCK1-R) gb|AAA35659.1| chole...cystokinin A receptor gb|AAA02819.1| cholecystokinin A receptor gb|AAA91123.1| chole...cystokinin type A receptor dbj|BAA90879.1| cholecystokinin type-A receptor [Homo ...sapiens] gb|AAP84362.1| cholecystokinin A receptor [Homo sapiens] gb|AAH74987.1| Cholecystokinin A receptor

  10. NCBI nr-aa BLAST: CBRC-FCAT-01-1015 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-FCAT-01-1015 ref|NP_000721.1| cholecystokinin A receptor [Homo sapiens] sp|P32238|CCKAR_HUMAN Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (CCK1-R) gb|AAA35659.1| chole...cystokinin A receptor gb|AAA02819.1| cholecystokinin A receptor gb|AAA91123.1| chole...cystokinin type A receptor dbj|BAA90879.1| cholecystokinin type-A receptor [Homo ...sapiens] gb|AAP84362.1| cholecystokinin A receptor [Homo sapiens] gb|AAH74987.1| Cholecystokinin A receptor

  11. NCBI nr-aa BLAST: CBRC-MMUS-05-0020 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-MMUS-05-0020 ref|NP_000721.1| cholecystokinin A receptor [Homo sapiens] sp|P32238|CCKAR_HUMAN Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (CCK1-R) gb|AAA35659.1| chole...cystokinin A receptor gb|AAA02819.1| cholecystokinin A receptor gb|AAA91123.1| chole...cystokinin type A receptor dbj|BAA90879.1| cholecystokinin type-A receptor [Homo ...sapiens] gb|AAP84362.1| cholecystokinin A receptor [Homo sapiens] gb|AAH74987.1| Cholecystokinin A receptor

  12. NCBI nr-aa BLAST: CBRC-PTRO-05-0018 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-PTRO-05-0018 ref|NP_000721.1| cholecystokinin A receptor [Homo sapiens] sp|P32238|CCKAR_HUMAN Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (CCK1-R) gb|AAA35659.1| chole...cystokinin A receptor gb|AAA02819.1| cholecystokinin A receptor gb|AAA91123.1| chole...cystokinin type A receptor dbj|BAA90879.1| cholecystokinin type-A receptor [Homo ...sapiens] gb|AAP84362.1| cholecystokinin A receptor [Homo sapiens] gb|AAH74987.1| Cholecystokinin A receptor

  13. NCBI nr-aa BLAST: CBRC-PABE-05-0014 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-PABE-05-0014 ref|NP_000721.1| cholecystokinin A receptor [Homo sapiens] sp|P32238|CCKAR_HUMAN Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (CCK1-R) gb|AAA35659.1| chole...cystokinin A receptor gb|AAA02819.1| cholecystokinin A receptor gb|AAA91123.1| chole...cystokinin type A receptor dbj|BAA90879.1| cholecystokinin type-A receptor [Homo ...sapiens] gb|AAP84362.1| cholecystokinin A receptor [Homo sapiens] gb|AAH74987.1| Cholecystokinin A receptor

  14. NCBI nr-aa BLAST: CBRC-CFAM-03-0027 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-CFAM-03-0027 ref|NP_000721.1| cholecystokinin A receptor [Homo sapiens] sp|P32238|CCKAR_HUMAN Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (CCK1-R) gb|AAA35659.1| chole...cystokinin A receptor gb|AAA02819.1| cholecystokinin A receptor gb|AAA91123.1| chole...cystokinin type A receptor dbj|BAA90879.1| cholecystokinin type-A receptor [Homo ...sapiens] gb|AAP84362.1| cholecystokinin A receptor [Homo sapiens] gb|AAH74987.1| Cholecystokinin A receptor

  15. NCBI nr-aa BLAST: CBRC-OLAT-18-0070 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-OLAT-18-0070 ref|NP_000721.1| cholecystokinin A receptor [Homo sapiens] sp|P32238|CCKAR_HUMAN Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (CCK1-R) gb|AAA35659.1| chole...cystokinin A receptor gb|AAA02819.1| cholecystokinin A receptor gb|AAA91123.1| chole...cystokinin type A receptor dbj|BAA90879.1| cholecystokinin type-A receptor [Homo ...sapiens] gb|AAP84362.1| cholecystokinin A receptor [Homo sapiens] gb|AAH74987.1| Cholecystokinin A receptor

  16. NCBI nr-aa BLAST: CBRC-RMAC-05-0007 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-RMAC-05-0007 ref|NP_000721.1| cholecystokinin A receptor [Homo sapiens] sp|P32238|CCKAR_HUMAN Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (CCK1-R) gb|AAA35659.1| chole...cystokinin A receptor gb|AAA02819.1| cholecystokinin A receptor gb|AAA91123.1| chole...cystokinin type A receptor dbj|BAA90879.1| cholecystokinin type-A receptor [Homo ...sapiens] gb|AAP84362.1| cholecystokinin A receptor [Homo sapiens] gb|AAH74987.1| Cholecystokinin A receptor

  17. NCBI nr-aa BLAST: CBRC-ETEL-01-0940 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-ETEL-01-0940 ref|NP_000721.1| cholecystokinin A receptor [Homo sapiens] sp|P32238|CCKAR_HUMAN Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (CCK1-R) gb|AAA35659.1| chole...cystokinin A receptor gb|AAA02819.1| cholecystokinin A receptor gb|AAA91123.1| chole...cystokinin type A receptor dbj|BAA90879.1| cholecystokinin type-A receptor [Homo ...sapiens] gb|AAP84362.1| cholecystokinin A receptor [Homo sapiens] gb|AAH74987.1| Cholecystokinin A receptor

  18. NCBI nr-aa BLAST: CBRC-CJAC-01-1653 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-CJAC-01-1653 ref|NP_000721.1| cholecystokinin A receptor [Homo sapiens] sp|P32238|CCKAR_HUMAN Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (CCK1-R) gb|AAA35659.1| chole...cystokinin A receptor gb|AAA02819.1| cholecystokinin A receptor gb|AAA91123.1| chole...cystokinin type A receptor dbj|BAA90879.1| cholecystokinin type-A receptor [Homo ...sapiens] gb|AAP84362.1| cholecystokinin A receptor [Homo sapiens] gb|AAH74987.1| Cholecystokinin A receptor

  19. NCBI nr-aa BLAST: CBRC-TGUT-06-0015 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-TGUT-06-0015 ref|NP_000721.1| cholecystokinin A receptor [Homo sapiens] sp|P32238|CCKAR_HUMAN Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (CCK1-R) gb|AAA35659.1| chole...cystokinin A receptor gb|AAA02819.1| cholecystokinin A receptor gb|AAA91123.1| chole...cystokinin type A receptor dbj|BAA90879.1| cholecystokinin type-A receptor [Homo ...sapiens] gb|AAP84362.1| cholecystokinin A receptor [Homo sapiens] gb|AAH74987.1| Cholecystokinin A receptor

  20. NCBI nr-aa BLAST: CBRC-GGAL-04-0036 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-GGAL-04-0036 ref|NP_000721.1| cholecystokinin A receptor [Homo sapiens] sp|P32238|CCKAR_HUMAN Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (CCK1-R) gb|AAA35659.1| chole...cystokinin A receptor gb|AAA02819.1| cholecystokinin A receptor gb|AAA91123.1| chole...cystokinin type A receptor dbj|BAA90879.1| cholecystokinin type-A receptor [Homo ...sapiens] gb|AAP84362.1| cholecystokinin A receptor [Homo sapiens] gb|AAH74987.1| Cholecystokinin A receptor

  1. NCBI nr-aa BLAST: CBRC-CPOR-01-1990 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-CPOR-01-1990 ref|NP_000721.1| cholecystokinin A receptor [Homo sapiens] sp|P32238|CCKAR_HUMAN Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (CCK1-R) gb|AAA35659.1| chole...cystokinin A receptor gb|AAA02819.1| cholecystokinin A receptor gb|AAA91123.1| chole...cystokinin type A receptor dbj|BAA90879.1| cholecystokinin type-A receptor [Homo ...sapiens] gb|AAP84362.1| cholecystokinin A receptor [Homo sapiens] gb|AAH74987.1| Cholecystokinin A receptor

  2. NCBI nr-aa BLAST: CBRC-BTAU-01-2281 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-BTAU-01-2281 ref|NP_000721.1| cholecystokinin A receptor [Homo sapiens] sp|P32238|CCKAR_HUMAN Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (CCK1-R) gb|AAA35659.1| chole...cystokinin A receptor gb|AAA02819.1| cholecystokinin A receptor gb|AAA91123.1| chole...cystokinin type A receptor dbj|BAA90879.1| cholecystokinin type-A receptor [Homo ...sapiens] gb|AAP84362.1| cholecystokinin A receptor [Homo sapiens] gb|AAH74987.1| Cholecystokinin A receptor

  3. NCBI nr-aa BLAST: CBRC-CBRE-01-1028 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-CBRE-01-1028 ref|NP_000721.1| cholecystokinin A receptor [Homo sapiens] sp|P32238|CCKAR_HUMAN Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (CCK1-R) gb|AAA35659.1| chole...cystokinin A receptor gb|AAA02819.1| cholecystokinin A receptor gb|AAA91123.1| chole...cystokinin type A receptor dbj|BAA90879.1| cholecystokinin type-A receptor [Homo ...sapiens] gb|AAP84362.1| cholecystokinin A receptor [Homo sapiens] gb|AAH74987.1| Cholecystokinin A receptor

  4. NCBI nr-aa BLAST: CBRC-LAFR-01-0624 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-LAFR-01-0624 ref|NP_000721.1| cholecystokinin A receptor [Homo sapiens] sp|P32238|CCKAR_HUMAN Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (CCK1-R) gb|AAA35659.1| chole...cystokinin A receptor gb|AAA02819.1| cholecystokinin A receptor gb|AAA91123.1| chole...cystokinin type A receptor dbj|BAA90879.1| cholecystokinin type-A receptor [Homo ...sapiens] gb|AAP84362.1| cholecystokinin A receptor [Homo sapiens] gb|AAH74987.1| Cholecystokinin A receptor

  5. NCBI nr-aa BLAST: CBRC-GACU-16-0038 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-GACU-16-0038 ref|NP_000721.1| cholecystokinin A receptor [Homo sapiens] sp|P32238|CCKAR_HUMAN Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (CCK1-R) gb|AAA35659.1| chole...cystokinin A receptor gb|AAA02819.1| cholecystokinin A receptor gb|AAA91123.1| chole...cystokinin type A receptor dbj|BAA90879.1| cholecystokinin type-A receptor [Homo ...sapiens] gb|AAP84362.1| cholecystokinin A receptor [Homo sapiens] gb|AAH74987.1| Cholecystokinin A receptor

  6. NCBI nr-aa BLAST: CBRC-CBRE-01-1053 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-CBRE-01-1053 ref|NP_000721.1| cholecystokinin A receptor [Homo sapiens] sp|P32238|CCKAR_HUMAN Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (CCK1-R) gb|AAA35659.1| chole...cystokinin A receptor gb|AAA02819.1| cholecystokinin A receptor gb|AAA91123.1| chole...cystokinin type A receptor dbj|BAA90879.1| cholecystokinin type-A receptor [Homo ...sapiens] gb|AAP84362.1| cholecystokinin A receptor [Homo sapiens] gb|AAH74987.1| Cholecystokinin A receptor

  7. NCBI nr-aa BLAST: CBRC-DRER-01-0042 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-DRER-01-0042 ref|NP_000721.1| cholecystokinin A receptor [Homo sapiens] sp|P32238|CCKAR_HUMAN Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (CCK1-R) gb|AAA35659.1| chole...cystokinin A receptor gb|AAA02819.1| cholecystokinin A receptor gb|AAA91123.1| chole...cystokinin type A receptor dbj|BAA90879.1| cholecystokinin type-A receptor [Homo ...sapiens] gb|AAP84362.1| cholecystokinin A receptor [Homo sapiens] gb|AAH74987.1| Cholecystokinin A receptor

  8. NCBI nr-aa BLAST: CBRC-FRUB-02-0257 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-FRUB-02-0257 ref|NP_000721.1| cholecystokinin A receptor [Homo sapiens] sp|P32238|CCKAR_HUMAN Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (CCK1-R) gb|AAA35659.1| chole...cystokinin A receptor gb|AAA02819.1| cholecystokinin A receptor gb|AAA91123.1| chole...cystokinin type A receptor dbj|BAA90879.1| cholecystokinin type-A receptor [Homo ...sapiens] gb|AAP84362.1| cholecystokinin A receptor [Homo sapiens] gb|AAH74987.1| Cholecystokinin A receptor

  9. NCBI nr-aa BLAST: CBRC-CINT-01-0111 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-CINT-01-0111 ref|NP_000721.1| cholecystokinin A receptor [Homo sapiens] sp|P32238|CCKAR_HUMAN Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (CCK1-R) gb|AAA35659.1| chole...cystokinin A receptor gb|AAA02819.1| cholecystokinin A receptor gb|AAA91123.1| chole...cystokinin type A receptor dbj|BAA90879.1| cholecystokinin type-A receptor [Homo ...sapiens] gb|AAP84362.1| cholecystokinin A receptor [Homo sapiens] gb|AAH74987.1| Cholecystokinin A receptor

  10. NCBI nr-aa BLAST: CBRC-TNIG-20-0000 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-TNIG-20-0000 ref|NP_000721.1| cholecystokinin A receptor [Homo sapiens] sp|P32238|CCKAR_HUMAN Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (CCK1-R) gb|AAA35659.1| chole...cystokinin A receptor gb|AAA02819.1| cholecystokinin A receptor gb|AAA91123.1| chole...cystokinin type A receptor dbj|BAA90879.1| cholecystokinin type-A receptor [Homo ...sapiens] gb|AAP84362.1| cholecystokinin A receptor [Homo sapiens] gb|AAH74987.1| Cholecystokinin A receptor

  11. NCBI nr-aa BLAST: CBRC-CINT-01-0193 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-CINT-01-0193 ref|NP_000721.1| cholecystokinin A receptor [Homo sapiens] sp|P32238|CCKAR_HUMAN Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (CCK1-R) gb|AAA35659.1| chole...cystokinin A receptor gb|AAA02819.1| cholecystokinin A receptor gb|AAA91123.1| chole...cystokinin type A receptor dbj|BAA90879.1| cholecystokinin type-A receptor [Homo ...sapiens] gb|AAP84362.1| cholecystokinin A receptor [Homo sapiens] gb|AAH74987.1| Cholecystokinin A receptor

  12. Thylakoids suppress appetite by increasing cholecystokinin resulting in lower food intake and body weight in high-fat fed mice

    DEFF Research Database (Denmark)

    Köhnke, Rickard; Lindqvist, Andreas; Göransson, Nathanael

    2009-01-01

    affect food intake and body weight during long-term feeding in mice. Female apolipoprotein E-deficient mice were fed a high-fat diet containing 41% of fat by energy with and without thylakoids for 100 days. Mice fed the thylakoid-enriched diet had suppressed food intake, body weight gain and body fat...... fat mass. There was no sign of desensitization in the animals treated with thylakoids. The results suggest that thylakoids are useful to suppress appetite and body weight gain when supplemented to a high-fat food during long-term feeding....... compared with the high-fat fed control mice. Reduced serum glucose, serum triglyceride and serum free fatty acid levels were found in the thylakoid-treated animals. The satiety hormone cholecystokinin was elevated, suggesting this hormone mediates satiety. Leptin levels were reduced, reflecting a decreased...

  13. Glucagon-like peptide-1 and cholecystokinin production and signaling in the pancreatic islet as an adaptive response to obesity.

    Science.gov (United States)

    Linnemann, Amelia K; Davis, Dawn Belt

    2016-04-01

    Precise control of blood glucose is dependent on adequate β-cell mass and function. Thus, reductions in β-cell mass and function lead to insufficient insulin production to meet demand, and result in diabetes. Recent evidence suggests that paracrine signaling in the islet might be important in obesity, and disruption of this signaling could play a role in the pathogenesis of diabetes. For example, we recently discovered a novel islet incretin axis where glucagon-like peptide-1 regulates β-cell production of another classic gut hormone, cholecystokinin. This axis is stimulated by obesity, and plays a role in enhancing β-cell survival. In the present review, we place our observations in the wider context of the literature on incretin regulation in the islet, and discuss the potential for therapeutic targeting of these pathways.

  14. Homology of the mesopallium in the adult chicken identified by gene expression of the neocortical marker cholecystokinin.

    Science.gov (United States)

    Atoji, Yasuro; Karim, Mohammad Rabiul

    2014-03-06

    Studies of gene expression and fiber connections have suggested that the primary visual (entopallium) and auditory (field L2) centers in the avian telencephalon are homologous to layer 4 of extrastriate and auditory neocortices of mammals, respectively. In addition, it has been proposed that the arcopallium contains neurons homologous to layers 5/6 and that the mesopallium may be homologous to superficial neocortical layers, but gene expression evidence for the latter is lacking in adult birds. In the present study using adult chickens we have examined the gene expression of cholecystokinin (CCK) mRNA, a selective marker for layers 2/3 of mammalian neocortex. CCK mRNA was expressed in neurons of the entire mesopallium, but not in any part of the nidopallium. Together with hodological evidence of connections between the mesopallium and the two primary sensory areas, our results are consistent with the suggestion that the mesopallium is comparable to certain superficial layers of mammalian neocortex.

  15. The effect of cholecystokinin on intracellular Ca2+, membrane-associated protein kinase-C activity, and progesterone production in chicken granulosa cells.

    Science.gov (United States)

    Morley, P; Wang, J; Vanderhyden, B C; Chakravarthy, B; Durkin, J; Whitefield, J F

    1993-11-01

    Nerve fibers immunoreactive for cholecystokinin (CCK) have been observed in the rat ovary, but the function of this gut peptide in the ovary is not known. These studies were designed to investigate the effects of the CCK C-terminal octapeptide (CCK-8) on the intracellular calcium ion concentration ([Ca2+]i), protein kinase-C (PKC) activity, and progesterone secretion in granulosa cells obtained from the two largest preovulatory follicles (F1 and F2) of hens. [Ca2+]i was measured in cells loaded with the Ca(2+)-responsive fluorescent dye fura-2. The resting [Ca2+]i in these cells was 96 +/- 5 nM. There was a rapid (i.e. within 5-10 sec) 2- to 4-fold increase in [Ca2+]i in 70% of the cells examined after the addition of 10(-7) M CCK-8. The CCK-8-triggered [Ca2+]i transient was not affected by incubating the cells in Ca(2+)-free medium containing 2 mM EGTA or by pretreating the cells with a Ca2+ channel blocker, such as La3+ (1 mM) or D600 (100 microM). The CCK-8-triggered [Ca2+]i surge was abolished by pretreating the cells with the inhibitor of inositol phospholipid hydrolysis, neomycin (1.5 mM), the CCK antagonists proglumide (1 mM) and benzotript (1 mM), or pertussis toxin (50 ng/ml for 12 h). Incubating granulosa cells with CCK-8 (2 x 10(-7) M) for 10 min stimulated a 1.60 +/- 0.04-fold increase in membrane-associated PKC activity over control levels. In 3-h incubations, CCK-8 (10(-6)-10(-8) M) did not affect basal or LH (20 or 100 ng/ml-stimulated progesterone production. These studies demonstrate that CCK-8 causes a transient increase in chicken granulosa cell [Ca2+]i through the release of Ca2+ from intracellular stores and activates membrane-associated PKC activity, but does not affect progesterone production. These results suggest the presence of G-protein-coupled phospholipase-C-activating CCK receptors on the surface of these cells.

  16. CCK-58 prolongs the intermeal interval, whereas CCK-8 reduces this interval: not all forms of cholecystokinin have equal bioactivity.

    Science.gov (United States)

    Sayegh, Ayman I; Washington, Martha C; Raboin, Shannon J; Aglan, Amnah H; Reeve, Joseph R

    2014-05-01

    It has been accepted for decades that "all forms of cholecystokinin (CCK) have equal bioactivity," despite accumulating evidence to the contrary. To challenge this concept, we compared two feeding responses, meal size (MS, 10% sucrose) and intermeal interval (IMI), in response to CCK-58, which is the major endocrine form of CCK, and CCK-8, which is the most abundantly utilized form. Doses (0, 0.1, 0.5, 0.75, 1, 3 and 5 nmol/kg) were administered intraperitoneally over a 210-min test to Sprague Dawley rats that had been food-deprived overnight. We found that (1) all doses of CCK-58, except the lowest dose, and all doses of CCK-8, except the lowest two doses, reduced food intake more than vehicle did; (2) at two doses, 0.75 and 3 nmol/kg, CCK-58 increased the IMI, while CCK-8 failed to alter this feeding response; and (3) CCK-58, at all but the lowest two doses, increased the satiety ratio (IMI between first and second meals (min) divided by first MS (ml)) relative to vehicle, while CCK-8 did not affect this value. These findings demonstrate that the only circulating form of CCK in rats, CCK-58, prolongs the IMI more than CCK-8, the peptide generally utilized in feeding studies. Taken together, these results add to a growing list of functions where CCK-8 and CCK-58 express qualitatively different bioactivities. In conclusion, the hypothesis that "all forms of cholecystokinin (CCK) have equal bioactivity" is not supported.

  17. [Morphological and laminar distribution of cholecystokinin-immunoreactive neurons in cortex of human inferior parietal lobe and their clinical significance].

    Science.gov (United States)

    Puskas, Laslo; Draganić-Gajić, Saveta; Malobabić, Slobodan; Puskas, Nela; Krivokuća, Dragan; Stanković, Gordana

    2008-01-01

    Cholecystocinine is a neuropeptide whose function in the cortex has not yet been clarified, although its relation with some psychic disorders has been noticed. Previous studies have not provided detailed data about types, or arrangement of neurons that contain those neuropeptide in the cortex of human inferior parietal lobe. The aim of this study was to examine precisely the morphology and typography of neurons containing cholecytocinine in the human cortex of inferior parietal lobule. There were five human brains on which we did the immunocystochemical research of the shape and laminar distribution of cholecystocinine immunoreactive neurons on serial sections of supramarginal gyrus and angular gyrus. The morphological analysis of cholecystocinine-immunoreactive neurons was done on frozen sections using avidin-biotin technique, by antibody to cholecystocinine diluted in the proportion 1:6000 using diamine-benzedine. Cholecystocinine immunoreactive neurons were found in the first three layers of the cortex of inferior parietal lobule, and their densest concentration was in the 2nd and 3rd layer. The following types of neurons were found: bipolar neurons, then its fusiform subtype, Cajal-Retzius neurons (in the 1st layer), reverse pyramidal (triangular) and unipolar neurons. The diameters of some types of neurons were from 15 to 35 microm, and the diameters of dendritic arborization were from 85-207 microm. A special emphasis is put on the finding of Cajal-Retzius neurons that are immunoreactive to cholecystocinine, which demands further research. Bearing in mind numerous clinical studies pointing out the role of cholecystokinine in the pathogenesis of schizophrenia, the presence of a great number of cholecystokinine immunoreactive neurons in the cortex of inferior parietal lobule suggests their role in the pathogenesis of schizophrenia.

  18. Requirements for existing buildings

    DEFF Research Database (Denmark)

    Thomsen, Kirsten Engelund; Wittchen, Kim Bjarne

    2012-01-01

    This report collects energy performance requirements for existing buildings in European member states by June 2012.......This report collects energy performance requirements for existing buildings in European member states by June 2012....

  19. Requirements for existing buildings

    DEFF Research Database (Denmark)

    Thomsen, Kirsten Engelund; Wittchen, Kim Bjarne

    2012-01-01

    This report collects energy performance requirements for existing buildings in European member states by June 2012.......This report collects energy performance requirements for existing buildings in European member states by June 2012....

  20. Robotic tele-existence

    Science.gov (United States)

    Tachi, Susumu; Arai, Hirohiko; Maeda, Taro

    1989-01-01

    Tele-existence is an advanced type of teleoperation system that enables a human operator at the controls to perform remote manipulation tasks dexterously with the feeling that he or she exists in the remote anthropomorphic robot in the remote environment. The concept of a tele-existence is presented, the principle of the tele-existence display method is explained, some of the prototype systems are described, and its space application is discussed.

  1. Existence of magnetic charge

    Science.gov (United States)

    Akers, David

    1990-10-01

    A status report is presented on the existence of quarks carrying the Dirac unit of magnetic charge g = (137/2) e. The Paschen-Back effect in dyonium is discussed. From the dyonium model, Akers predicted the existence of a new η meson at 1814 MeV with I G(JPC) = 0+(0-+). Experimental evidence now confirms the existence of the meson resonance.

  2. Changes of Serotonin (5-HT), 5-HT2A Receptor, and 5-HT Transporter in the Sprague-Dawley Rats of Depression,Myocardial Infarction and Myocardial Infarction Co-exist with Depression

    Institute of Scientific and Technical Information of China (English)

    Mei-Yan Liu; Yah-Ping Ren; Wan-Lin Wei; Guo-Xiang Tian; Guo Li

    2015-01-01

    Background:To evaluate whether serotonin (5-HT),5-HT2A receptor (5-HT2AR),and 5-HT transporter (serotonin transporter [SERT]) are associated with different disease states of depression,myocardial infarction (MI) and MI co-exist with depression in Sprague-Dawley rats.Methods:After established the animal model of four groups include control,depression,MI and MI with depression,we measured 5-HT,5-HT2AR and SERT from serum and platelet lysate.Results:The serum concentration of 5-HT in depression rats decreased significantly compared with the control group (303.25 ± 9.99 vs.352.98 ± 13.73;P =0.000),while that in MI group increased (381.78 ± 14.17 vs.352.98 ± 13.73;P =0.000).However,the depression + MI group had no change compared with control group (360.62 ± 11.40 vs.352.98 ± 13.73;P =0.036).The changes of the platelet concentration of 5-HT in the depression,MI,and depression + MI group were different from that of serum.The levels of 5-HT in above three groups were lower than that in the control group (380.40 ± 17.90,387.75 ± 22.28,246.40 ± 18.99 vs.500.29 ± 20.91;P =0.000).The platelet lysate concentration of 5-HT2AR increased in depression group,MI group,and depression + MI group compared with the control group (370.75 ± 14.75,393.47 ± 15.73,446.66 ± 18.86 vs.273.66 ± 16.90;P =0.000).The serum and platelet concentration of SERT in the depression group,MI group and depression + MI group were all increased compared with the control group (527.51 ± 28.32,602.02 ± 23.32,734.76 ± 29.59 vs.490.56 ± 16.90;P =0.047,P =0.000,P =0.000 in each and 906.38 ± 51.84,897.33 ± 60.34,1030.17 ± 58.73 vs.708.62 ± 51.15;P =0.000 in each).Conclusions:The concentration of 5-HT2AR in platelet lysate and SERT in serum and platelet may be involved in the pathway of MI with depression.Further studies should examine whether elevated 5-HT2AR and SERT may contribute to the biomarker in MI patients with depression.

  3. Effect of cholecystokinin-8 on in vitro cultured rat cortical neurons against apoptosis

    Institute of Scientific and Technical Information of China (English)

    Ying Liu; Jiangbao Zhou

    2006-01-01

    BACKGROUND: Cholecystokinin (CCK-8) can regulate the synthesis of NO, release of amino acid substance and suppress Ca2+ inflow. It is unknown about neuroprotection of CCK-8 on neuronal apoptosis and its relationship with nerve growth factor (NGF).OBJECTryE: To investigate the protective effect of CCK-8 on in vitro cultured rat cortical neurons against apoptosis induced by glutamate, and explore its effect on expression of NGF in the neurons during apoptosis.DESIGN: Randomized controlled experiment on the basis of cells.SETTING: Children's Research Institute Affiliated to Children Hospital of Chongqing Medical University.MATERIALS: Eighty SD rats of 1-day old; DMEM/F12 culture medium (Biochrom Company, Germany);Fetal bovine serum (TBD Company, Tianjin); CCK-8 (Sigma Company, USA). Glutamate (Bioengineering Company, Shanghai); TUNEL kit and NGF- in situ hybridization kit (Boster Bioengineering Company,Wuhan); anti-NGF polyclonal antibody (Santa-Cluz Company); NGF immunocytochemistry kit (Zhongshan Company, Beijing).METHODS: The experiments were carried out in Children's Research Institute Affiliated to Children Hospital of Chongqing Medical University from December 2004 to September 2005. Primary cultured cortical neurons from SD rats of 1-day oldwere incubated for 7 days. The cultured cells were divided randomly into 3 groups:experimental group, model group and control group. Neurons in experimental groups were added CCK-8 of 1 ×10-6, 1 ×10-7, 1 ×10-8 μ mol/L respectively, and then added 50 μmol/L glutamate solution a hour later. Neurons in model groups were treated with 50 μ mol/L glutamate solution. In the control group, cells were treated with normal medium. Apoptosis of cultured cortical neurons were observed by fluorescent microscope, the expression of NGF protein and mRNA were determined respectively by immunocytochemistry and in situ hybridization, and apoptosis of cortical neurons was detected with terminal deoxynucleotidyl transferase-mediated nick

  4. NCBI nr-aa BLAST: CBRC-OCUN-01-0005 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-OCUN-01-0005 ref|NP_795344.1| cholecystokinin B receptor [Homo sapiens] sp|P32...239|GASR_HUMAN Gastrin/cholecystokinin type B receptor (CCK-B receptor) (CCK-BR) (Cholecystokinin-2 receptor...) (CCK2-R) gb|AAA35660.1| cholecystokinin receptor gb|AAA35657.1| cholecystokinin-B/gastrin receptor gb|AAC3...7528.1| gastrin receptor dbj|BAA02564.1| cholecystokinin receptor [Homo sapiens] gb|AAH00740.1| Chole...cystokinin B receptor [Homo sapiens] dbj|BAA04759.2| cholecystokinin-B receptor/gastrin

  5. NCBI nr-aa BLAST: CBRC-CFAM-21-0204 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-CFAM-21-0204 ref|NP_795344.1| cholecystokinin B receptor [Homo sapiens] sp|P32...239|GASR_HUMAN Gastrin/cholecystokinin type B receptor (CCK-B receptor) (CCK-BR) (Cholecystokinin-2 receptor...) (CCK2-R) gb|AAA35660.1| cholecystokinin receptor gb|AAA35657.1| cholecystokinin-B/gastrin receptor gb|AAC3...7528.1| gastrin receptor dbj|BAA02564.1| cholecystokinin receptor [Homo sapiens] gb|AAH00740.1| Chole...cystokinin B receptor [Homo sapiens] dbj|BAA04759.2| cholecystokinin-B receptor/gastrin

  6. Reutilizing Existing Library Space.

    Science.gov (United States)

    Davis, Marlys Cresap

    1987-01-01

    This discussion of the reutilization of existing library space reviews the decision process and considerations for implementation. Two case studies of small public libraries which reassigned space to better use are provided, including floor plans. (1 reference) (MES)

  7. Transcriptional activation of the cholecystokinin gene by DJ-1 through interaction of DJ-1 with RREB1 and the effect of DJ-1 on the cholecystokinin level in mice.

    Science.gov (United States)

    Yamane, Takuya; Suzui, Sayaka; Kitaura, Hirotake; Takahashi-Niki, Kazuko; Iguchi-Ariga, Sanae M M; Ariga, Hiroyoshi

    2013-01-01

    DJ-1 is an oncogene and also causative gene for familial Parkinson's disease. DJ-1 has multiple functions, including transcriptional regulation. DJ-1 acts as a coactivator that binds to various transcription factors, resulting in stimulation or repression of the expression of their target genes. In this study, we found that the cholecystokinin (CCK) gene is a transcriptional target gene for DJ-1. CCK is a peptide hormone and plays roles in contraction of the gallbladder and in promotion of secretion of pancreatic fluid. CCK is co-localized with dopamine in the substantia nigra to regulate release of dopamine. Reduced expression of CCK mRNA was observed in DJ-1-knockdown cells. The Ras-responsive element (RRE) and Sp1 site were essential for promoter activity, and DJ-1 stimulated promoter activity by binding to RRE-binding protein 1 (RREBP1). The complex of DJ-1 with RREB1 but not with Sp1 bound to the RRE. Furthermore, the reduced CCK level in the serum from DJ-1-knockout mice compared to that from wild-type mice was observed. This is the first report showing that DJ-1 participates in peptide hormone synthesis.

  8. Transcriptional Activation of the Cholecystokinin Gene by DJ-1 through Interaction of DJ-1 with RREB1 and the Effect of DJ-1 on the Cholecystokinin Level in Mice

    Science.gov (United States)

    Yamane, Takuya; Suzui, Sayaka; Kitaura, Hirotake; Takahashi-Niki, Kazuko; Iguchi-Ariga, Sanae M. M.; Ariga, Hiroyoshi

    2013-01-01

    DJ-1 is an oncogene and also causative gene for familial Parkinson’s disease. DJ-1 has multiple functions, including transcriptional regulation. DJ-1 acts as a coactivator that binds to various transcription factors, resulting in stimulation or repression of the expression of their target genes. In this study, we found that the cholecystokinin (CCK) gene is a transcriptional target gene for DJ-1. CCK is a peptide hormone and plays roles in contraction of the gallbladder and in promotion of secretion of pancreatic fluid. CCK is co-localized with dopamine in the substantia nigra to regulate release of dopamine. Reduced expression of CCK mRNA was observed in DJ-1-knockdown cells. The Ras-responsive element (RRE) and Sp1 site were essential for promoter activity, and DJ-1 stimulated promoter activity by binding to RRE-binding protein 1 (RREBP1). The complex of DJ-1 with RREB1 but not with Sp1 bound to the RRE. Furthermore, the reduced CCK level in the serum from DJ-1-knockout mice compared to that from wild-type mice was observed. This is the first report showing that DJ-1 participates in peptide hormone synthesis. PMID:24348900

  9. Transcriptional activation of the cholecystokinin gene by DJ-1 through interaction of DJ-1 with RREB1 and the effect of DJ-1 on the cholecystokinin level in mice.

    Directory of Open Access Journals (Sweden)

    Takuya Yamane

    Full Text Available DJ-1 is an oncogene and also causative gene for familial Parkinson's disease. DJ-1 has multiple functions, including transcriptional regulation. DJ-1 acts as a coactivator that binds to various transcription factors, resulting in stimulation or repression of the expression of their target genes. In this study, we found that the cholecystokinin (CCK gene is a transcriptional target gene for DJ-1. CCK is a peptide hormone and plays roles in contraction of the gallbladder and in promotion of secretion of pancreatic fluid. CCK is co-localized with dopamine in the substantia nigra to regulate release of dopamine. Reduced expression of CCK mRNA was observed in DJ-1-knockdown cells. The Ras-responsive element (RRE and Sp1 site were essential for promoter activity, and DJ-1 stimulated promoter activity by binding to RRE-binding protein 1 (RREBP1. The complex of DJ-1 with RREB1 but not with Sp1 bound to the RRE. Furthermore, the reduced CCK level in the serum from DJ-1-knockout mice compared to that from wild-type mice was observed. This is the first report showing that DJ-1 participates in peptide hormone synthesis.

  10. The Relativity of Existence

    CERN Document Server

    Heinrich, Stuart

    2012-01-01

    Despite the success of physics in formulating mathematical theories that can predict the outcome of experiments, we have made remarkably little progress towards answering some of the most basic questions about our existence, such as: why does the universe exist? Why is the universe apparently fine-tuned to be able to support life? Why are the laws of physics so elegant? Why do we have three dimensions of space and one of time? How is it that the universe can be non-local and non-causal at the quantum scale, and why is there quantum randomness? In this paper, it is shown that all of these questions are answered if existence is relative, and moreover, it seems that we are logically bound to accept it.

  11. This elusive objective existence

    CERN Document Server

    Mohrhoff, U

    2004-01-01

    Zurek's existential interpretation of quantum mechanics suffers from three classical prejudices, including the belief that space and time are intrinsically and infinitely differentiated. They compel him to relativize the concept of objective existence in two ways. The elimination of these prejudices makes it possible to recognize the quantum formalism's ontological implications - the relative and contingent reality of spatiotemporal distinctions and the extrinsic and finite spatiotemporal differentiation of the physical world - which in turn makes it possible to arrive at an unqualified objective existence. Contrary to a widespread misconception, viewing the quantum formalism as being fundamentally a probability algorithm does not imply that quantum mechanics is concerned with states of knowledge rather than states of Nature. On the contrary, it makes possible a complete and strongly objective description of the physical world that requires no reference to observers. What objectively exists, in a sense that r...

  12. Fatty acid transduction of nitric oxide signaling: multiple nitrated unsaturated fatty acid derivatives exist in human blood and urine and serve as endogenous peroxisome proliferator-activated receptor ligands.

    Science.gov (United States)

    Baker, Paul R S; Lin, Yiming; Schopfer, Francisco J; Woodcock, Steven R; Groeger, Alison L; Batthyany, Carlos; Sweeney, Scott; Long, Marshall H; Iles, Karen E; Baker, Laura M S; Branchaud, Bruce P; Chen, Yuqing E; Freeman, Bruce A

    2005-12-23

    Mass spectrometric analysis of human plasma and urine revealed abundant nitrated derivatives of all principal unsaturated fatty acids. Nitrated palmitoleic, oleic, linoleic, linolenic, arachidonic and eicosapentaenoic acids were detected in concert with their nitrohydroxy derivatives. Two nitroalkene derivatives of the most prevalent fatty acid, oleic acid, were synthesized (9- and 10-nitro-9-cis-octadecenoic acid; OA-NO2), structurally characterized and determined to be identical to OA-NO2 found in plasma, red cells, and urine of healthy humans. These regioisomers of OA-NO2 were quantified in clinical samples using 13C isotope dilution. Plasma free and esterified OA-NO2 concentrations were 619 +/- 52 and 302 +/- 369 nm, respectively, and packed red blood cell free and esterified OA-NO2 was 59 +/- 11 and 155 +/- 65 nm. The OA-NO2 concentration of blood is approximately 50% greater than that of nitrated linoleic acid, with the combined free and esterified blood levels of these two fatty acid derivatives exceeding 1 microm. OA-NO2 is a potent ligand for peroxisome proliferator activated receptors at physiological concentrations. CV-1 cells co-transfected with the luciferase gene under peroxisome proliferator-activated receptor (PPAR) response element regulation, in concert with PPARgamma, PPARalpha, or PPARdelta expression plasmids, showed dose-dependent activation of all PPARs by OA-NO2. PPARgamma showed the greatest response, with significant activation at 100 nm, while PPARalpha and PPARdelta were activated at approximately 300 nm OA-NO2. OA-NO2 also induced PPAR gamma-dependent adipogenesis and deoxyglucose uptake in 3T3-L1 preadipocytes at a potency exceeding nitrolinoleic acid and rivaling synthetic thiazo-lidinediones. These data reveal that nitrated fatty acids comprise a class of nitric oxide-derived, receptor-dependent, cell signaling mediators that act within physiological concentration ranges.

  13. [Study of the Effect of Cholecystokinin-Induced Acute Pancreatitis on the Free-Running Rhythm of Mouse].

    Science.gov (United States)

    Li, Yonghong; Yang, Xiaoping; Guo, Panpan; Liu, Yanyou; Yan, Hongli; Li, Shuaizhen; Guan, Junwen

    2016-02-01

    The present paper reports the effect of pancreatitis induced by cholecystokinin (CCK) on free-running rhythm of locomotor activity of the ICR mice, and analyzes the interaction of inflammatory diseases and acute pancreatitis with circadian rhythm system. In the study, the mice were modeled under different phases of acute pancreatitis in DD status (Double Dark, constant dark condition). By comparing of the inflammatory status and the indicators of rhythm before and after modeling of the running wheel activity group and the rest group, it was observed that the rest group showed more possibility of inflammation than the activity group did in ICR mice model of acute pancreatitis. In the rest phase model, the extension of the period is particularly longer. The results presented indicated that CCK-induced acute pancreatitis impacted free activity rhythm of ICR mice. Also in a free running model under different phase, the inflammation severity was proved significantly different. This study provides possible clues for the research of the pathogenesis of acute pancreatitis severe tendency.

  14. Cholecystokinin in white sea bream: molecular cloning, regional expression, and immunohistochemical localization in the gut after feeding and fasting.

    Directory of Open Access Journals (Sweden)

    Valeria Micale

    Full Text Available BACKGROUND: The peptide hormone cholecystokinin (CCK, secreted by the midgut, plays a key role in digestive physiology of vertebrates including teleosts, by stimulating pancreatic secretion, gut motility, and gallbladder contraction, as well as by delaying gastric emptying. Moreover, CCK is involved in the regulation of food intake and satiation. Secretion of CCK by the hindgut is controversial, and its biological activity remains to be elucidated. The present paper addresses the regional distribution of intestinal CCK in the white sea bream, Diplodus sargus, as well as the possible involvement of hindgut CCK in digestive processes. METHODOLOGY/PRINCIPAL FINDINGS: Full-lengths mRNAs encoding two CCK isoforms (CCK-1 and CCK-2 were sequenced and phylogenetically analyzed. CCK gene and protein expression levels in the different gut segments were measured 3 h and 72 h after feeding, by quantitative real-time RT-PCR and Western blot, respectively. Moreover, endocrine CCK cells were immunoistochemically detected. Fasting induced a significant decrease in CCK-2 in all intestinal segments, including the hindgut. On the other hand, no significant difference was induced by fasting on hindgut CCK-1. CONCLUSIONS/SIGNIFICANCE: The results demonstrated two CCK isoforms in the hindgut of D.sargus, one of which (CCK-2 may be involved in the feedback control of uncompleted digestive processes. On the other hand, a functional role alternative to regulation of digestive processes may be inferred for D.sargus CCK-1, since its expression was unaffected by feeding or fasting.

  15. An important role for cholecystokinin, a CLOCK target gene, in the development and treatment of manic-like behaviors.

    Science.gov (United States)

    Arey, R N; Enwright, J F; Spencer, S M; Falcon, E; Ozburn, A R; Ghose, S; Tamminga, C; McClung, C A

    2014-03-01

    Mice with a mutation in the Clock gene (ClockΔ19) have been identified as a model of mania; however, the mechanisms that underlie this phenotype, and the changes in the brain that are necessary for lithium's effectiveness on these mice remain unclear. Here, we find that cholecystokinin (Cck) is a direct transcriptional target of CLOCK and levels of Cck are reduced in the ventral tegmental area (VTA) of ClockΔ19 mice. Selective knockdown of Cck expression via RNA interference in the VTA of wild-type mice produces a manic-like phenotype. Moreover, chronic treatment with lithium restores Cck expression to near wild-type and this increase is necessary for the therapeutic actions of lithium. The decrease in Cck expression in the ClockΔ19 mice appears to be due to a lack of interaction with the histone methyltransferase, MLL1, resulting in decreased histone H3K4me3 and gene transcription, an effect reversed by lithium. Human postmortem tissue from bipolar subjects reveals a similar increase in Cck expression in the VTA with mood stabilizer treatment. These studies identify a key role for Cck in the development and treatment of mania, and describe some of the molecular mechanisms by which lithium may act as an effective antimanic agent.

  16. Beneficial effect of the bioflavonoid quercetin on cholecystokinin-induced mitochondrial dysfunction in isolated rat pancreatic acinar cells.

    Science.gov (United States)

    Weber, Heike; Jonas, Ludwig; Wakileh, Michael; Krüger, Burkhard

    2014-03-01

    The pathogenesis of acute pancreatitis (AP) is still poorly understood. Thus, a reliable pharmacological therapy is currently lacking. In recent years, an impairment of the energy metabolism of pancreatic acinar cells, caused by Ca(2+)-mediated depolarization of the inner mitochondrial membrane and a decreased ATP supply, has been implicated as an important pathological event. In this study, we investigated whether quercetin exerts protection against mitochondrial dysfunction. Following treatment with or without quercetin, rat pancreatic acinar cells were stimulated with supramaximal cholecystokinin-8 (CCK). CCK caused a decrease in the mitochondrial membrane potential (MMP) and ATP concentration, whereas the mitochondrial dehydrogenase activity was significantly increased. Quercetin treatment before CCK application exerted no protection on MMP but increased ATP to a normal level, leading to a continuous decrease in the dehydrogenase activity. The protective effect of quercetin on mitochondrial function was accompanied by a reduction in CCK-induced changes to the cell membrane. Concerning the molecular mechanism underlying the protective effect of quercetin, an increased AMP/ATP ratio suggests that the AMP-activated protein kinase system may be activated. In addition, quercetin strongly inhibited CCK-induced trypsin activity. The results indicate that the use of quercetin may be a therapeutic strategy for reducing the severity of AP.

  17. Synthesis and biological evaluation of cholecystokinin analogs in which the Asp-Phe-NH2 moiety has been replaced by a 3-amino-7-phenylheptanoic acid or a 3-amino-6-(phenyloxy)hexanoic acid.

    Science.gov (United States)

    Amblard, M; Rodriguez, M; Lignon, M F; Galas, M C; Bernad, N; Artis-Noël, A M; Hauad, L; Laur, J; Califano, J C; Aumelas, A

    1993-10-01

    Boc-Tyr(SO3H)-Nle-Gly-Trp-Nle-Asp-2-phenylethyl ester (JMV180), an analog of the C-terminal octapeptide of cholecystokinin (CCK-8), shows interesting biological activities behaving as an agonist at the high-affinity CCK binding sites and as an antagonist at the low-affinity CCK binding sites in rat pancreatic acini. Although we did not observe any major hydrolysis of the ester bond of Boc-Tyr(SO3H)-Nle-Gly-Trp-Nle-Asp-2-phenylethyl ester in our in vitro studies, we were aware of a possible and rapid cleavage of this ester bond during in vivo studies. To improve the stability of Boc-Tyr(SO3H)-Nle-Gly-Trp-Nle-Asp-2-phenylethyl ester, we decided to synthesize analogs in which the ester bond would be replaced by a carba (CH2-CH2) linkage. We synthesized the 3-amino-7-phenylheptanoic acid (beta-homo-Aph) with the R configuration in order to mimic the Asp-2-phenylethyl ester moiety and the 3-amino-6-(phenyloxy)hexanoic acid (H-beta-homo-App-OH), an analog of H-beta-homo-Aph-OH in which a methylene group has been replaced by an oxygen. (R)-beta-Homo-Aph and (R)-H-beta-homo-App-OH were introduced in the CCK-8 sequence to produce Boc-Tyr(SO3H)-Nle-Gly-Trp-Nle-(R)-beta-homo-Aph-OH and Boc-Tyr(SO3H)-Nle-Gly-Trp-Nle-(R)-beta-homo-App-OH. Both compounds were able to recognize the CCK receptor on rat pancreatic acini (IC50 = 12 +/- 8 nM and 13 +/- 5 nM, respectively), on brain membranes (IC50 = 32 +/- 2 nM and 57 +/- 5 nM, respectively), and on Jurkat T cells (IC50 = 75 +/- 15 nM and 65 +/- 21 nM, respectively). Like Boc-Tyr(SO3H)-Nle-Gly-Trp-Nle-Asp-2-phenylethyl ester, both compounds produced maximal stimulation of amylase secretion (EC50 = 6 +/- 2 nM and 4 +/- 2 nM, respectively) with no decrease of the secretion at high concentration indicating that these compounds probably act as agonists at the high-affinity peripheral CCK-receptor and as antagonists at the low-affinity CCK-receptor. Replacing the tryptophan by a D-tryptophan in such analogs produced full CCK-receptor

  18. Relativity, Dimensionality, and Existence

    Science.gov (United States)

    Petkov, Vesselin

    A 100 years have passed since the advent of special relativity and 2008 will mark another important to all relativists anniversary - 100 years since Minkowski gave his talk "Space and Time" on September 21, 1908 in which he proposed the unifi- cation of space and time into an inseparable entity - space-time. Although special relativity has been an enormously successful physical theory no progress has been made in clarifying the question of existence of the objects represented by two of its basic concepts - space-time and world lines (or worldtubes in the case of extended bodies). The major reason for this failure appears to be the physicists' tradition to call such questions of existence philosophical. This tradition, however, is not quite consistent. In Newtonian mechanics physicists believe that they describe real objects whenever they talk about particles - one of the basic concepts of Newtonian physics. The situation is the same in quantum physics - no one questions the existence of electrons, protons, etc. Then why should the question of existence of worldtubes (representing particles in relativity) be regarded as a philosophical question?

  19. Synthesis and evaluation of cholecystokinin trimers: a multivalent approach to pancreatic cancer detection and treatment.

    Science.gov (United States)

    Brabez, Nabila; Nguyen, Kevin L; Saunders, Kara; Lacy, Ryan; Xu, Liping; Gillies, Robert J; Lynch, Ronald M; Chassaing, Gerard; Lavielle, Solange; Hruby, Victor J

    2013-04-15

    In the quest for novel tools for early detection and treatment of cancer, we propose the use of multimers targeting overexpressed receptors at the cancer cell surface. Indeed, multimers are prone to create multivalent interactions, more potent and specific than their corresponding monovalent versions, thus enabling the potential for early detection. There is a lack of tools for early detection of pancreatic cancer, one of the deadliest forms of cancer, but CCK2-R overexpression on pancreatic cancer cells makes CCK based multimers potential markers for these cells. In this Letter, we describe the synthesis and evaluation of CCK trimers targeting overexpressed CCK2-R.

  20. The Problem of Existence

    Science.gov (United States)

    1985-01-01

    envisionment ) produced by GIZMO . ? In the envisionment , I s indicates the set of quantity—conditioned individuals that exists during a situa- tion... envisionment step by step . In START, the initial state, GIZMO deduces that heat flow occurs, since there is assumed to be a temperature difference between the...stov e GIZMO implements the basic operations of qualitative process theory, including an envisioner for makin g predictions and a program for

  1. Hermeneutics as Embodied Existence

    Directory of Open Access Journals (Sweden)

    Marja Schuster RN, PhD

    2013-02-01

    Full Text Available This article explores the possibilities and limits of a hermeneutic way of being in the world, more specifically being a researcher as a part of human, embodied existence. Understanding existence as embodied highlights the subjectivity of a researcher. For a hermeneutic researcher this subjectivity is both a precondition for interpretation and something that might endanger the scientific endeavour. In this article, I examine the possibilities of combining Hans-Georg Gadamer's empathetic hermeneutics with Paul Ricoeur's critical hermeneutics as a means of both recognizing and, to some extent, controlling my subjectivity in the research process. With Gabriel Marcel I also argue for hermeneutics as an embodied experience. This is exemplified by my study with a focus on the existential dimensions of the nursing profession. The first part of the article introduces Marcel and his philosophical anthropology concerning our bodily existence as essential for shared lives with others. In the second part, this understanding of self and others is further developed by means of the hermeneutics of Gadamer and Ricoeur. In the third part, I present a way of applying hermeneutics in procedures for interviews, transcription, and analysis of data.

  2. Distinct interneuron types express m2 muscarinic receptor immunoreactivity on their dendrites or axon terminals in the hippocampus.

    Science.gov (United States)

    Hájos, N; Papp, E C; Acsády, L; Levey, A I; Freund, T F

    1998-01-01

    In previous studies m2 muscarinic acetylcholine receptor-immunoreactive interneurons and various types of m2-positive axon terminals have been described in the hippocampal formation. The aim of the present study was to identify the types of interneurons expressing m2 receptor and to examine whether the somadendritic and axonal m2 immunostaining labels the same or distinct cell populations. In the CA1 subfield, neurons immunoreactive for m2 have horizontal dendrites, they are located at the stratum oriens/alveus border and have an axon that project to the dendritic region of pyramidal cells. In the CA3 subfield and the hilus, m2-positive neurons are multipolar and are scattered in all layers except stratum lacunosum-moleculare. In stratum pyramidale of the CA1 and CA3 regions, striking axon terminal staining for m2 was observed, surrounding the somata and axon initial segments of pyramidal cells in a basket-like manner. The co-localization of m2 with neurochemical markers and GABA was studied using the "mirror" technique and fluorescent double-immunostaining at the light microscopic level and with double-labelling using colloidal gold-conjugated antisera and immunoperoxidase reaction (diaminobenzidine) at the electron microscopic level. GABA was shown to be present in the somata of most m2-immunoreactive interneurons, as well as in the majority of m2-positive terminals in all layers. The calcium-binding protein parvalbumin was absent from practically all m2-immunoreactive cell bodies and dendrites. In contrast, many of the terminals synapsing on pyramidal cell somata and axon initial segments co-localized parvalbumin and m2, suggesting a differential distribution of m2 receptor immunoreactivity on the axonal and somadendritic membrane of parvalbumin-containing basket and axo-axonic cells. The co-existence of m2 receptors with the calcium-binding protein calbindin and the neuropeptides cholecystokinin and vasoactive intestinal polypeptide was rare throughout the

  3. Vagal afferent neurons in high fat diet-induced obesity; intestinal microflora, gut inflammation and cholecystokinin.

    Science.gov (United States)

    de Lartigue, Guillaume; de La Serre, Claire Barbier; Raybould, Helen E

    2011-11-30

    The vagal afferent pathway is the major neural pathway by which information about ingested nutrients reaches the CNS and influences both GI function and feeding behavior. Vagal afferent neurons (VAN) express receptors for many of the regulatory peptides and molecules released from the intestinal wall, pancreas, and adipocytes that influence GI function, glucose homeostasis, and regulate food intake and body weight. As such, they play a critical role in both physiology and pathophysiology, such as obesity, where there is evidence that vagal afferent function is altered. This review will summarize recent findings on changes in vagal afferent function in response to ingestion of high fat diets and explore the hypothesis that changes in gut microbiota and integrity of the epithelium may not only be important in inducing these changes but may be the initial events that lead to dysregulation of food intake and body weight in response to high fat, high energy diets.

  4. Existing chemicals: international activities.

    Science.gov (United States)

    Purchase, J F

    1989-01-01

    The standards of care used in the protection of the health and safety of people exposed to chemicals has increased dramatically in the last decade. Standards imposed by regulation and those adopted by industry have required a greater level of knowledge about the hazards of chemicals. In the E.E.C., the 6th amendment of the dangerous substances directive imposed the requirement that al new chemicals should be tested according to prescribed programme before introduction on to the market. The development of a European inventory of existing chemicals was an integral part of the 6th amendment. It has now become clear that increased standards of care referred to above must be applied to the chemicals on the inventory list. There is, however, a considerable amount of activity already under way in various international agencies. The OECD Chemicals Programme has been involved in considering the problem of existing chemicals for some time, and is producing a priority list and action programme. The International Programme on Chemical Safety produces international chemical safety cards, health and safety guides and environmental health criteria documents. The international register of potentially toxic compounds (part of UNEP) has prepared chemical data profiles on 990 compounds. The International Agency for Research on Cancer prepared monographs on the carcinogenic risk of chemicals to man. So far 42 volumes have been prepared covering about 900 substances. IARC and IPCS also prepare periodic reports on ongoing research on carcinogenicity or toxicity (respectively) of chemicals. The chemical industry through ECETOC (the European Chemical Industry Ecology and Toxicology Centre) has mounted a major initiative on existing chemicals. Comprehensive reviews of the toxicity of selected chemicals are published (Joint Assessment of Commodity Chemicals). In its technical report no. 30 ECETOC lists reviews and evaluations by major national and international organisations, which provides

  5. Hinged Dissections Exist

    CERN Document Server

    Abbott, Timothy G; Charlton, David; Demaine, Erik D; Demaine, Martin L; Kominers, Scott D

    2007-01-01

    We prove that any finite collection of polygons of equal area has a common hinged dissection. That is, for any such collection of polygons there exists a chain of polygons hinged at vertices that can be folded in the plane continuously without self-intersection to form any polygon in the collection. This result settles the open problem about the existence of hinged dissections between pairs of polygons that goes back implicitly to 1864 and has been studied extensively in the past ten years. Our result generalizes and indeed builds upon the result from 1814 that polygons have common dissections (without hinges). We also extend our common dissection result to edge-hinged dissections of solid 3D polyhedra that have a common (unhinged) dissection, as determined by Dehn's 1900 solution to Hilbert's Third Problem. Our proofs are constructive, giving explicit algorithms in all cases. For a constant number of planar polygons, both the number of pieces and running time required by our construction are pseudopolynomial...

  6. Peripheral injected cholecystokinin-8S modulates the concentration of serotonin in nerve fibers of the rat brainstem.

    Science.gov (United States)

    Engster, Kim-Marie; Frommelt, Lisa; Hofmann, Tobias; Nolte, Sandra; Fischer, Felix; Rose, Matthias; Stengel, Andreas; Kobelt, Peter

    2014-09-01

    Serotonin and cholecystokinin (CCK) play a role in the short-term inhibition of food intake. It is known that peripheral injection of CCK increases c-Fos-immunoreactivity (Fos-IR) in the nucleus of the solitary tract (NTS) in rats, and injection of the serotonin antagonist ondansetron decreases the number of c-Fos-IR cells in the NTS. This supports the idea of serotonin contributing to the effects of CCK. The aim of the present study was to elucidate whether peripherally injected CCK-8S modulates the concentration of serotonin in brain feeding-regulatory nuclei. Ad libitum fed male Sprague-Dawley rats received 5.2 and 8.7 nmol/kg CCK-8S (n=3/group) or 0.15M NaCl (n=3-5/group) injected intraperitoneally (ip). The number of c-Fos-IR neurons, and the fluorescence intensity of serotonin in nerve fibers were assessed in the paraventricular nucleus (PVN), arcuate nucleus (ARC), NTS and dorsal motor nucleus of the vagus (DMV). CCK-8S increased the number of c-Fos-ir neurons in the NTS (mean±SEM: 72±4, and 112±5 neurons/section, respectively) compared to vehicle-treated rats (7±2 neurons/section, Pserotonin-immunoreactivity 90 min after injection of CCK-8S (46±2 and 49±8 pixel/section, respectively) compared to vehicle (81±8 pixel/section, Pserotonin-immunoreactivity were observed in the PVN and ARC. Our results suggest that serotonin is involved in the mediation of CCK-8's effects in the brainstem.

  7. Effect of cholecystokinin and secretin on contractile activity of isolated gastric muscle strips in guinea pigs

    Institute of Scientific and Technical Information of China (English)

    Wei Li; Tian Zhen Zheng; Song Yi Qu

    2000-01-01

    AIM To study the effect of cholecystokininoctapeptide (CCK-8) and secretin on contractile activity of isolated gastric muscle strips in guinea pigs.METHODS Each isolated gastric muscle strip was suspended in a tissue chamber containing5 mL Krebs solution constantly warmed by water jacked at 37℃ and supplied with a mixed gas of 95% O2 and 5% CO2. After incubating for 1 h under 1 g tension, varied concentrations of CCK-8 and secretin were added respectively in the tissue chamber and the contractile response was measured isometrically on ink-writing recorders.circular and longitudinal muscular tension at rest (fundus LM 19.7%±2.1%, P<0.01; fundus CM 16.7%±2.2%, P<0.01; gastric body LM 16.8% ± 2.3%, P<0.01; body CM 12.7% ± 2.6%,P<0.01; antrum LM 12.3%±1.3%, P<0.01;antrum CM 16.7%±4.5%, P<0.01; pylous CM frequencies of body LM, both LM and CM of antrum and pylorus CM (5.1/min ± 0.2/min to 5.6/min ± 0.2/min, 5.9/min ± 0.2/min to 6.6/min ±0.1/min, 5.4/min ± 0.3/min to 6.3/min ± 0.4/min, 1.3/min ± 0.2/min to 2.3/min ± 0.3/min,amplitude of antral circular muscle (58.6%±pylorus CM (145.0% ± 23.8%, P<0.01), but decrease the mean contractile amplitude of gastric body and antral LM ( - 10.3% ± 3.3%, -10.5% ±4.6%, respectively, P<0.05). All the CCK-8 effects were not blocked by atropine or indomethacin. Secretin had no effect on gastric smooth muscle activity.CONCLUSION CCK-8 possessed both excitatory and inhibitory action on contractile activity of different regions of stomach in guinea pigs. Its action was not mediated via cholinergic M receptor and endogenous prostaglandin receptor.

  8. Lebesgue Sets Immeasurable Existence

    Directory of Open Access Journals (Sweden)

    Diana Marginean Petrovai

    2012-12-01

    Full Text Available It is well known that the notion of measure and integral were released early enough in close connection with practical problems of measuring of geometric figures. Notion of measure was outlined in the early 20th century through H. Lebesgue’s research, founder of the modern theory of measure and integral. It was developed concurrently a technique of integration of functions. Gradually it was formed a specific area todaycalled the measure and integral theory. Essential contributions to building this theory was made by a large number of mathematicians: C. Carathodory, J. Radon, O. Nikodym, S. Bochner, J. Pettis, P. Halmos and many others. In the following we present several abstract sets, classes of sets. There exists the sets which are not Lebesgue measurable and the sets which are Lebesgue measurable but are not Borel measurable. Hence B ⊂ L ⊂ P(X.

  9. Existence of Minkowski space

    CERN Document Server

    Wagner, Serge

    2016-01-01

    Physics textbooks present Minkowski space as an almost pure mathematical construct, without any explicit restriction on a domain where it is applicable in physics. Meanwhile, its physical meaning cannot but follow the same premises as those which underlies the special relativity theory: motion of free point particles and propagation of electromagnetic waves. However, the common formalism of coordinate transformations between any two inertial frames appears too ponderous to infer the existence of Minkowski space. For this reason, the time dilation and retardation, the contraction of the length along and the spatial invariance across the direction of relative motion of two frames are presented in a coordinate-free manner. This results in the transformation between two frames in the form of relationships between the time moments and the components of the position vector of a given event, along and across the directions of the frames' motion. The obtained transformation rules for the components of the position ve...

  10. Endocannabinoids regulate interneuron migration and morphogenesis by transactivating the TrkB receptor.

    Science.gov (United States)

    Berghuis, Paul; Dobszay, Marton B; Wang, Xinyu; Spano, Sabrina; Ledda, Fernanda; Sousa, Kyle M; Schulte, Gunnar; Ernfors, Patrik; Mackie, Ken; Paratcha, Gustavo; Hurd, Yasmin L; Harkany, Tibor

    2005-12-27

    In utero exposure to Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the active component from marijuana, induces cognitive deficits enduring into adulthood. Although changes in synaptic structure and plasticity may underlie Delta(9)-THC-induced cognitive impairments, the neuronal basis of Delta(9)-THC-related developmental deficits remains unknown. Using a Boyden chamber assay, we show that agonist stimulation of the CB(1) cannabinoid receptor (CB(1)R) on cholecystokinin-expressing interneurons induces chemotaxis that is additive with brain-derived neurotrophic factor (BDNF)-induced interneuron migration. We find that Src kinase-dependent TrkB receptor transactivation mediates endocannabinoid (eCB)-induced chemotaxis in the absence of BDNF. Simultaneously, eCBs suppress the BDNF-dependent morphogenesis of interneurons, and this suppression is abolished by Src kinase inhibition in vitro. Because sustained prenatal Delta(9)-THC stimulation of CB(1)Rs selectively increases the density of cholecystokinin-expressing interneurons in the hippocampus in vivo, we conclude that prenatal CB(1)R activity governs proper interneuron placement and integration during corticogenesis. Moreover, eCBs use TrkB receptor-dependent signaling pathways to regulate subtype-selective interneuron migration and specification.

  11. The role of genetic variation in peroxisome proliferator-activated receptors in the polycystic ovary syndrome (PCOS): an original case-control study followed by systematic review and meta-analysis of existing evidence.

    Science.gov (United States)

    San-Millán, José L; Escobar-Morreale, Héctor F

    2010-03-01

    To study the association of polymorphisms in the genes encoding peroxisome proliferator-activated receptors (PPARs) with the polycystic ovary syndrome (PCOS). Case-control study and meta-analysis of published evidence. One hundred and sixty-one polycystic ovary syndrome patients and 113 non-hyperandrogenic women. Genotyping for PPAR-gamma coactivator-1 gene (PPARGC1A) Gly482Ser, PPAR-alpha Leu162Val, PPAR-delta rs2267668A/G, PPAR-delta-87T/C, PPAR-gamma2 Pro12Ala and PPAR-gamma2 -681C/G variants and systematic review of the literature using the Entrez-PubMed search engine, followed by meta-analysis whenever possible. Polycystic ovary syndrome patients carried the Gly482Ser variant in PPARGC1A more frequently than controls (72%vs. 58%, chi(2 )=( )5.54 P = 0.019), whereas carriers of the PPAR-alpha Leu162Val, PPAR-delta rs2267668A/G, PPAR-delta-87T/C, PPAR-gamma2 Pro12Ala and PPAR-gamma2 -681C/G variants were distributed similarly among both groups. The interaction between the PPARGC1A Gly482Ser and PPAR-delta-87T/C variants was also associated with PCOS (OR = 1.24, 95% CI 1.05-1.50, P = 0.008). The systematic review identified 31 studies addressing associations between PPARs variants and PCOS; meta-analysis was possible for nine studies focusing on the PPAR-gamma2 Pro12Ala variant. Although the individual studies did not reveal any statistically significant association, meta-analysis uncovered that carrying the PPAR-gamma2 Pro12Ala variant was associated with a reduced probability of having PCOS (OR = 0.77, 95% CI 0.61-0.96, P = 0.025), and that this association may be mediated by an effect on insulin sensitivity. Common polymorphisms in the PPARGC1A, PPAR-delta and PPAR-gamma2 loci are associated with PCOS.

  12. [Effects of Yanggan Lidan Granule on rate of gallstone formation and content of plasma cholecystokinin in guinea pigs with induced cholesterol gallstones].

    Science.gov (United States)

    Zhang, Si-bo; Fang, Bang-jiang

    2008-04-01

    To explore the effects of Yanggan Lidan Granule (YGLDG), a compound traditional Chinese herbal medicine for nourishing liver and improving choleresis, on the rate of gallstone formation and content of plasma cholecystokinin in guinea pigs with induced cholesterol gallstones. Eighty guinea pigs were randomly divided into 4 groups, which were normal control group, untreated group, YGLDG-treated group and ursodeoxycholic acid (UDCA)-treated group (n=20). Except the normal control group, gallstones were induced by high-cholesterol diet in the guinea pigs. YGLDG (1.81 g/kg daily) and UDCA (30.12 mg/kg daily) were given orally to guinea pigs in the corresponding group respectively for seven weeks; however, the guinea pigs of normal control group and untreated group were administered with normal saline. The physical signs of the guinea pigs and the rates of gallstone formation were examined, and the content of cholecystokinin (CCK) in the plasma was detected by radio-immunoassay. YGLDG could obviously improve the ethological signs of the guinea pigs. Gallstone formation rate of the untreated group (82.35%) was significantly increased as compared with that of the normal control group (5.26%) (Pgallstone formation rates of the YGLDG-treated group (27.28%) and UDCA-treated group (38.89%) were lower than that of the untreated group (P0.05). YGLDG can significantly decrease the rate of gallstone formation in guinea pigs. It may be related to elevating the content of CCK in the plasma.

  13. Plumes Do Not Exist

    Science.gov (United States)

    Hamilton, W. B.; Anderson, D. L.; Foulger, G. R.; Winterer, E. L.

    conjectures are made ever more complex and implausible to encompass contrary data, and have no predictive value. The inescapable conclusion is that deep-mantle thermal plumes not only are unneces- sary but that they do not exist.

  14. Synaptic cross talk between perisomatic-targeting interneuron classes expressing cholecystokinin and parvalbumin in hippocampus.

    Science.gov (United States)

    Karson, Miranda A; Tang, Ai-Hui; Milner, Teresa A; Alger, Bradley E

    2009-04-01

    Cholescystokinin (CCK)- or parvalbumin (PV)-containing interneurons are the major perisomatic-targeting interneurons in the cerebral cortex, including hippocampus, and are thought to form mutually exclusive networks. We used several techniques to test the alternative hypothesis that CCK and PV cells are coupled by chemical synapses. Triple immunofluorescence confocal microscopy revealed numerous axosomatic, axodendritic, and axoaxonic contacts stained for CCK, PV, and the presynaptic marker synaptophysin. The existence of mutual CCK and PV synapses was supported by dual EM immunolabeling. Paired whole-cell recordings detected unitary GABA(A)ergic synaptic transmission between identified CCK and PV cells, and single CCK cells could transiently inhibit action potential firing of synaptically coupled PV cells. We conclude that the major hippocampal perisomatic-targeting interneurons communicate synaptically. This communication should affect neuronal network activity, including neuronal oscillations, in which the CCK and PV cells have well established roles. The prevalence of CCK and PV networks in other brain regions suggests that internetwork interactions could be generally important.

  15. Effects of +G_z exposure on gallbladder emptying function,cholecystokinin,and somatostatin in rabbits with high cholesterol diets

    Directory of Open Access Journals (Sweden)

    Guo-feng XIAO

    2011-12-01

    Full Text Available Objective The present study explores the effects of +Gz exposure on the gallbladder emptying function,cholecystokinin(CCK,and somatostatin(SS in rabbits with high cholesterol diets and investigates its mechanism in the occurrence of cholecystolithiasis.Methods Twenty-four male New Zealand rabbits were randomly divided into the high cholesterol diet(control group,n=8 and high cholesterol diet plus +Gz exposure groups.The latter was divided into the four-and six-week +Gz exposure groups(n=8 based on the exposure time.Radioimmunoassay was used to determine the CCK and SS contents of the gallbladder at the end of the experiment in the fourth and sixth weeks and to calculate the gallbladder volume and maximum emptying ratio.A microcomputer biodynamic pressure monitor was used to record the hydrostatic pressure in the gallbladder to measure its capacity.Moreover,the bile properties and formation of concretion were observed with the naked eye,and polarized light microscopy was used to observe cholesterin crystallization on the gallbladder wall.Results The gallbladder capacity increased upon +Gz exposure for four and six weeks,indicating that the maximum emptying ratio(E% decreased,the empty and residual volumes improved,and the pressure increased(P < 0.05.After +Gz exposure for four and six weeks,the CCK contents in the experimental groups were evidently lower than that in the control group and gradually decreased(P < 0.05 as the +Gz exposure time increased.On the other hand,after +Gz exposure for four and six weeks,the SS contents in the experimental groups were higher than that in the control group and gradually improved(P < 0.05 as the +Gz exposure time increased.After +Gz exposure for four and six weeks,bile was turbid and sticky with cholesterol crystals and without visible concretion.Conclusions Therefore,+Gz exposure may cause abnormal gallbladder emptying functions,decrease CCK content,increase SS content,and thus cause bile stasis

  16. Cholecystokinin regulates satiation independently of the abdominal vagal nerve in a pig model of total subdiaphragmatic vagotomy

    NARCIS (Netherlands)

    Ripken, D.; Wielen, N. van der; Meulen, J. van der; Schuurman, T.; Witkamp, R.F.; Hendriks, H.F.J.; Koopmans, S.J.

    2015-01-01

    The vagal nerve and gut hormones CCK and GLP-1 play important roles in the control of food intake. However, it is not clear to what extent CCK and GLP-1 increase satiation by stimulating receptors located on abdominal vagal nerve endings or via receptors located elsewhere. This study aimed to furthe

  17. Cholecystokinin regulates satiation independently of the abdominal vagal nerve in a pig model of total subdiaphragmatic vagotomy

    NARCIS (Netherlands)

    Ripken, D.; Wielen, N. van der; Meulen, J. van der; Schuurman, T.; Witkamp, R.F.; Hendriks, H.F.J.; Koopmans, S.J.

    2015-01-01

    The vagal nerve and gut hormones CCK and GLP-1 play important roles in the control of food intake. However, it is not clear to what extent CCK and GLP-1 increase satiation by stimulating receptors located on abdominal vagal nerve endings or via receptors located elsewhere. This study aimed to furthe

  18. Beta-adrenergic receptors are differentially expressed in distinct interneuron subtypes in the rat hippocampus.

    Science.gov (United States)

    Cox, David J; Racca, Claudia; LeBeau, Fiona E N

    2008-08-20

    Noradrenaline (NA) acting via beta-adrenergic receptors (betaARs) plays an important role in the modulation of memory in the hippocampus. betaARs have been shown to be expressed in principal cells, but their distribution across different interneuron classes is unknown. We have used specific interneuron markers including calcium binding proteins (parvalbumin, calbindin, and calretinin) and neuropeptides (somatostatin, neuropeptide Y, and cholecystokinin) together with either beta1AR or beta2AR to determine the distribution of these receptors in all major subfields of the hippocampus. We found that beta1AR-expressing interneurons were more prevalent in the CA3 and CA1 regions of the hippocampus than in the dentate gyrus, where they were relatively sparse. beta2AR-expressing interneurons were more uniformly distributed between all three regions of the hippocampus. A high proportion of neuropeptide Y-containing interneurons in the dentate gyrus co-expressed beta2AR. beta1AR labeling was common in interneurons expressing somatostatin and parvalbumin in the CA3 and CA1 regions, particularly in the stratum oriens of these regions. beta2AR labeling was more likely to be found than beta1AR labeling in cholecystokinin-expressing interneurons. In contrast, calretinin-containing interneurons were virtually devoid of beta1AR or beta2AR labeling. These regional and interneuron type-specific differences suggest functionally distinct roles for NA in modulating hippocampal activity via activation of betaARs.

  19. Melanocortin-4 receptor expression in a vago-vagal circuitry involved in postprandial functions.

    Science.gov (United States)

    Gautron, Laurent; Lee, Charlotte; Funahashi, Hisayuki; Friedman, Jeffrey; Lee, Syann; Elmquist, Joel

    2010-01-01

    Vagal afferents regulate energy balance by providing a link between the brain and postprandial signals originating from the gut. In the current study, we investigated melanocortin-4 receptor (MC4R) expression in the nodose ganglion, where the cell bodies of vagal sensory afferents reside. By using a line of mice expressing green fluorescent protein (GFP) under the control of the MC4R promoter, we found GFP expression in approximately one-third of nodose ganglion neurons. By using immunohistochemistry combined with in situ hybridization, we also demonstrated that approximately 20% of GFP-positive neurons coexpressed cholecystokinin receptor A. In addition, we found that the GFP is transported to peripheral tissues by both vagal sensory afferents and motor efferents, which allowed us to assess the sites innervated by MC4R-GFP neurons. GFP-positive efferents that co-expressed choline acetyltransferase specifically terminated in the hepatic artery and the myenteric plexus of the stomach and duodenum. In contrast, GFP-positive afferents that did not express cholinergic or sympathetic markers terminated in the submucosal plexus and mucosa of the duodenum. Retrograde tracing experiments confirmed the innervation of the duodenum by GFP-positive neurons located in the nodose ganglion. Our findings support the hypothesis that MC4R signaling in vagal afferents may modulate the activity of fibers sensitive to satiety signals such as cholecystokinin, and that MC4R signaling in vagal efferents may contribute to the control of the liver and gastrointestinal tract.

  20. Localization of GABA(B) (R1) receptors in the rat hippocampus by immunocytochemistry and high resolution autoradiography, with specific reference to its localization in identified hippocampal interneuron subpopulations.

    Science.gov (United States)

    Sloviter, R S; Ali-Akbarian, L; Elliott, R C; Bowery, B J; Bowery, N G

    1999-11-01

    Immunocytochemical and autoradiographic methods were used to localize the GABA(B) receptor in the normal rat hippocampus. GABA(B) receptor 1-like immunoreactivity (GBR1-LI) was most intense in presumed GABAergic interneurons of all hippocampal subregions. It was also present throughout the hippocampal neuropil, where it was most intense in the dendritic strata of the dentate gyrus, which are innervated by the perforant pathway and inhibitory dentate hilar cells, and in strata oriens and radiatum of area CA3. The dendritic regions of area CA1 exhibited less GBR1-LI than area CA3. GBR1-LI was detectable in the somata of CA1 pyramidal cells, but was minimal or undetectable within the somata of dentate granule cells and CA3 pyramidal cells. GBR1-LI was similarly minimal in the dentate hilar neuropil, and in stratum lucidum, the two regions that contain granule cell axons and terminals. Nor was GBR1-LI detectable in the inhibitory basket cell fiber systems that surround hippocampal principal cell somata. Fluorescence co-localization studies indicated that significant proportions of interneurons expressing somatostatin, neuropeptide Y, cholecystokinin, calbindin, or calretinin also expressed GBR1-LI constitutively. Conversely, parvalbumin-positive GABAergic basket cells of the dentate gyrus and hippocampus, which form GABA(A) receptor-mediated inhibitory axo-somatic synapses, rarely contained detectable GBR1-LI. High resolution autoradiography with the GABA(B) receptor antagonist CGP 62349 revealed a close correspondence between receptor ligand binding and GBR1-LI, with several notable exceptions. Ligand binding closely matched GBR1-LI throughout the hippocampal, cortical, thalamic, and cerebellar neuropil. However, the hippocampal interneuron somata and dendrites that exhibited the most intense GBR1-LI, and the GBR1-positive somata of CA1 pyramidal cells, did not exhibit a similar density of [3H]-CGP 62349 binding. These data clarify the relationship between

  1. Changes in ghrelin, CCK, GLP-1, and peroxisome proliferator-activated receptors in a hypoxia-induced anorexia rat model.

    Science.gov (United States)

    Duraisamy, Arul Joseph; Bayen, Susovan; Saini, Supriya; Sharma, Alpesh Kumar; Vats, Praveen; Singh, Shashi Bala

    2015-01-01

    A high-altitude environment causes appetite loss in unacclimatised humans, leading to weight reduction. Ghrelin, cholecystokinin (CCK), and glucagon like peptide-1 (GLP-1), are gut hormones involved in the regulation of food intake and energy metabolism. The liver is an important site of metabolic regulation, and together with the gut it plays a role in food intake regulation. This study intends to study the time-dependent changes occurring in plasma gut hormones, PPARα, PPARδ, and PGC1α, in the stomach and liver during hypoxia. Male Sprague Dawley rats were exposed to hypobaric hypoxia in a decompression chamber at 7620 m for different durations up to seven days. Hypoxia increased circulating ghrelin from the third day onwards while CCK and GLP-1 decreased immediately. An increase in ghrelin, ghrelin receptor protein levels, and GOAT mRNA levels in the stomach was observed. Stomach cholecystokinin receptor (CCKAR), PPARα, and PPARδ decreased. Liver CCKAR decreased during the first day of hypoxia and returned to normal levels from the third day onwards. PPARα and PGC1α expression increased while PPARδ protein levels reduced in the liver on third day. Hypoxia alters the expression of ghrelin and ghrelin receptor in the stomach, CCKAR in the liver, and PPAR and its cofactors, which might be possible role players in the contribution of gut and liver to anorexia at high altitude.

  2. NCBI nr-aa BLAST: CBRC-PABE-05-0014 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-PABE-05-0014 ref|NP_036820.1| cholecystokinin A receptor [Rattus norvegicus] sp|P30551|CCKAR_RAT Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (C...CK1-R) gb|AAA40899.1| cholecystokinin receptor dbj|BAA09170.1| cholecystokinin type-A receptor [Rattus norvegicus] NP_036820.1 0.0 92% ...

  3. NCBI nr-aa BLAST: CBRC-ETEL-01-0940 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-ETEL-01-0940 ref|NP_036820.1| cholecystokinin A receptor [Rattus norvegicus] sp|P30551|CCKAR_RAT Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (C...CK1-R) gb|AAA40899.1| cholecystokinin receptor dbj|BAA09170.1| cholecystokinin type-A receptor [Rattus norvegicus] NP_036820.1 3e-32 92% ...

  4. NCBI nr-aa BLAST: CBRC-MMUS-05-0020 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-MMUS-05-0020 ref|NP_036820.1| cholecystokinin A receptor [Rattus norvegicus] sp|P30551|CCKAR_RAT Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (C...CK1-R) gb|AAA40899.1| cholecystokinin receptor dbj|BAA09170.1| cholecystokinin type-A receptor [Rattus norvegicus] NP_036820.1 0.0 94% ...

  5. NCBI nr-aa BLAST: CBRC-CJAC-01-1653 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-CJAC-01-1653 ref|NP_036820.1| cholecystokinin A receptor [Rattus norvegicus] sp|P30551|CCKAR_RAT Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (C...CK1-R) gb|AAA40899.1| cholecystokinin receptor dbj|BAA09170.1| cholecystokinin type-A receptor [Rattus norvegicus] NP_036820.1 0.0 91% ...

  6. NCBI nr-aa BLAST: CBRC-ETEL-01-1373 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-ETEL-01-1373 ref|NP_036820.1| cholecystokinin A receptor [Rattus norvegicus] sp|P30551|CCKAR_RAT Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (C...CK1-R) gb|AAA40899.1| cholecystokinin receptor dbj|BAA09170.1| cholecystokinin type-A receptor [Rattus norvegicus] NP_036820.1 1e-77 81% ...

  7. NCBI nr-aa BLAST: CBRC-LAFR-01-0624 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-LAFR-01-0624 ref|NP_036820.1| cholecystokinin A receptor [Rattus norvegicus] sp|P30551|CCKAR_RAT Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (C...CK1-R) gb|AAA40899.1| cholecystokinin receptor dbj|BAA09170.1| cholecystokinin type-A receptor [Rattus norvegicus] NP_036820.1 1e-83 86% ...

  8. NCBI nr-aa BLAST: CBRC-CBRE-01-1028 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-CBRE-01-1028 ref|NP_036820.1| cholecystokinin A receptor [Rattus norvegicus] sp|P30551|CCKAR_RAT Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (C...CK1-R) gb|AAA40899.1| cholecystokinin receptor dbj|BAA09170.1| cholecystokinin type-A receptor [Rattus norvegicus] NP_036820.1 5e-40 33% ...

  9. NCBI nr-aa BLAST: CBRC-RMAC-05-0007 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-RMAC-05-0007 ref|NP_036820.1| cholecystokinin A receptor [Rattus norvegicus] sp|P30551|CCKAR_RAT Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (C...CK1-R) gb|AAA40899.1| cholecystokinin receptor dbj|BAA09170.1| cholecystokinin type-A receptor [Rattus norvegicus] NP_036820.1 0.0 92% ...

  10. NCBI nr-aa BLAST: CBRC-HSAP-04-0027 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-HSAP-04-0027 ref|NP_036820.1| cholecystokinin A receptor [Rattus norvegicus] sp|P30551|CCKAR_RAT Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (C...CK1-R) gb|AAA40899.1| cholecystokinin receptor dbj|BAA09170.1| cholecystokinin type-A receptor [Rattus norvegicus] NP_036820.1 0.0 91% ...

  11. NCBI nr-aa BLAST: CBRC-CFAM-03-0027 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-CFAM-03-0027 ref|NP_036820.1| cholecystokinin A receptor [Rattus norvegicus] sp|P30551|CCKAR_RAT Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (C...CK1-R) gb|AAA40899.1| cholecystokinin receptor dbj|BAA09170.1| cholecystokinin type-A receptor [Rattus norvegicus] NP_036820.1 0.0 87% ...

  12. NCBI nr-aa BLAST: CBRC-PTRO-05-0018 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-PTRO-05-0018 ref|NP_036820.1| cholecystokinin A receptor [Rattus norvegicus] sp|P30551|CCKAR_RAT Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (C...CK1-R) gb|AAA40899.1| cholecystokinin receptor dbj|BAA09170.1| cholecystokinin type-A receptor [Rattus norvegicus] NP_036820.1 0.0 92% ...

  13. NCBI nr-aa BLAST: CBRC-BTAU-01-2281 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-BTAU-01-2281 ref|NP_036820.1| cholecystokinin A receptor [Rattus norvegicus] sp|P30551|CCKAR_RAT Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (C...CK1-R) gb|AAA40899.1| cholecystokinin receptor dbj|BAA09170.1| cholecystokinin type-A receptor [Rattus norvegicus] NP_036820.1 0.0 87% ...

  14. NCBI nr-aa BLAST: CBRC-ETEL-01-0465 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-ETEL-01-0465 ref|NP_036820.1| cholecystokinin A receptor [Rattus norvegicus] sp|P30551|CCKAR_RAT Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (C...CK1-R) gb|AAA40899.1| cholecystokinin receptor dbj|BAA09170.1| cholecystokinin type-A receptor [Rattus norvegicus] NP_036820.1 1e-77 81% ...

  15. NCBI nr-aa BLAST: CBRC-FCAT-01-1015 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-FCAT-01-1015 ref|NP_036820.1| cholecystokinin A receptor [Rattus norvegicus] sp|P30551|CCKAR_RAT Chole...cystokinin type A receptor (CCK-A receptor) (CCK-AR) (Cholecystokinin-1 receptor) (C...CK1-R) gb|AAA40899.1| cholecystokinin receptor dbj|BAA09170.1| cholecystokinin type-A receptor [Rattus norvegicus] NP_036820.1 0.0 90% ...

  16. Characterization of basal hepatic bile flow and the effects of intravenous cholecystokinin on the liver, sphincter, and gallbladder in patients with sphincter of Oddi spasm

    Energy Technology Data Exchange (ETDEWEB)

    Krishnamurthy, Gerbail T.; Krishnamurthy, Shakuntala [Department of Nuclear Medicine, Tuality Community Hospital, 335 SE 8th Avenue, OR 97123, Hillsboro (United States); Watson, Randy D. [Department of Gastroenterology, Tuality Community Hospital, Hillsboro, OR (United States)

    2004-01-01

    The major objectives of this project were to establish the pattern of basal hepatic bile flow and the effects of intravenous administration of cholecystokinin on the liver, sphincter of Oddi, and gallbladder, and to identify reliable parameters for the diagnosis of sphincter of Oddi spasm (SOS). Eight women with clinically suspected sphincter of Oddi spasm (SOS group), ten control subjects (control group), and ten patients who had recently received an opioid (opioid group) were selected for quantitative cholescintigraphy with cholecystokinin. Each patient was studied with 111-185 MBq (3-5 mCi) technetium-99m mebrofenin after 6-8 h of fasting. Hepatic phase images were obtained for 60 min, followed by gallbladder phase images for 30 min. During the gallbladder phase, 10 ng/kg octapeptide of cholecystokinin (CCK-8) was infused over 3 min through an infusion pump. Hepatic extraction fraction, excretion half-time, basal hepatic bile flow into the gallbladder, gallbladder ejection fraction, and post-CCK-8 paradoxical filling (>30% of basal counts) were identified. Seven of the patients with SOS were treated with antispasmodics (calcium channel blockers), and one underwent endoscopic sphincterotomy. Mean ({+-}SD) hepatic bile entry into the gallbladder (versus GI tract) was widely variable: it was lower in SOS patients (32%{+-}31%) than in controls (61%{+-}36%) and the opioid group (61%{+-}25%), but the difference was not statistically significant. Hepatic extraction fraction, excretion half-time, and pattern of bile flow through both intrahepatic and extrahepatic ducts were normal in all three groups. Gallbladder mean ejection fraction was 9%{+-}4% in the opioid group; this was significantly lower (P<0.0001) than the values in the control group (54%{+-}18%) and the SOS group (48%{+-}29%). Almost all of the bile emptied from the gallbladder refluxed into intrahepatic ducts; it reentered the gallbladder after cessation of CCK-8 infusion (paradoxical gallbladder filling

  17. Orlistat inhibition of intestinal lipase acutely increases appetite and attenuates postprandial glucagon-like peptide-1-(7-36)-amide-1, cholecystokinin, and peptide YY concentrations

    DEFF Research Database (Denmark)

    Ellrichmann, Mark; Kapelle, Mario; Ritter, Peter R;

    2008-01-01

    INTRODUCTION: Intestinal lipase inhibition using tetrahydrolipstatin (Orlistat) has been widely used in the pharmacotherapy of morbid obesity. However, the effects of Orlistat on the secretion of appetite regulating gastrointestinal hormones and appetite sensations are still debated. We addressed...... whether Orlistat alters the secretion of glucagon-like peptide-1-(7-36)-amide (GLP-1), cholecystokinin (CCK), peptide YY (PYY), and ghrelin as well as postprandial appetite sensations. METHODS: Twenty-five healthy human volunteers were examined with a solid-liquid test meal after the oral administration...... of Orlistat or placebo. Gastric emptying, gallbladder volume and the plasma levels of CCK, PYY, GLP-1, and ghrelin were determined and appetite sensations were measured using visual analogue scales. RESULTS: Gastric emptying was accelerated by Orlistat administration (P

  18. Cholecystokinin expression in tumors

    DEFF Research Database (Denmark)

    Rehfeld, Jens F

    2016-01-01

    in different neuroendocrine tumors; cerebral gliomas and astrocytomas and specific pediatric tumors. Tumor hypersecretion of CCK was recently reported in a patient with a metastatic islet cell tumor and hypercholecystokininemia resulting in a novel tumor syndrome, the cholecystokininoma syndrome. This review...... presents an overview of the cell-specific biogenesis of CCK peptides, and a description of the CCK expression in tumors and of the cholecystokininoma syndrome. Finally, assays for the diagnosis of CCK-producing tumors are reviewed....

  19. Measurement of nonsulfated cholecystokinins

    DEFF Research Database (Denmark)

    Agersnap, Mikkel; Rehfeld, Jens F

    2014-01-01

    at a defined processing site in proCCK (R₇₅-D₇₆) followed by monospecific RIA-measurement of the then exposed nonsulfated N-terminal sequence of CCK-8 (DYMGW…). The analysis shows that endocrine cells in the gut synthesize nonsulfated CCK peptides (-58, -33, -22, and -8) in the order of 20...

  20. Enkephalin levels and the number of neuropeptide Y-containing interneurons in the hippocampus are decreased in female cannabinoid-receptor 1 knock-out mice.

    Science.gov (United States)

    Rogers, Sophie A; Kempen, Tracey A Van; Pickel, Virginia M; Milner, Teresa A

    2016-05-04

    Drug addiction requires learning and memory processes that are facilitated by activation of cannabinoid-1 (CB1) and opioid receptors in the hippocampus. This involves activity-dependent synaptic plasticity that is partially regulated by endogenous opioid (enkephalin and dynorphin) and non-opioid peptides, specifically cholecystokinin, parvalbumin and neuropeptide Y, the neuropeptides present in inhibitory interneurons that co-express CB1 or selective opioid receptors. We tested the hypothesis that CB1 receptor expression is a determinant of the availability of one or more of these peptide modulators in the hippocampus. This was achieved by quantitatively analyzing the immunoperoxidase labeling for each of these neuropeptide in the dorsal hippocampus of female wild-type (CB1+/+) and cannabinoid receptor 1 knockout (CB1-/-) C57/BL6 mice. The levels of Leu(5)-enkephalin-immunoreactivity were significantly reduced in the hilus of the dentate gyrus and in stratum lucidum of CA3 in CB1-/- mice. Moreover, the numbers of neuropeptide Y-immunoreactive interneurons in the dentate hilus were significantly lower in the CB1-/- compared to wild-type mice. However, CB1+/+ and CB1-/- mice did not significantly differ in expression levels of either dynorphin or cholecystokinin, and showed no differences in numbers of parvalbumin-containing interneurons. These findings suggest that the cannabinoid and opioid systems have a nuanced, regulatory relationship that could affect the balance of excitation and inhibition in the hippocampus and thus processes such as learning that rely on this balance.

  1. Dopamine receptors and hypertension.

    Science.gov (United States)

    Banday, Anees Ahmad; Lokhandwala, Mustafa F

    2008-08-01

    Dopamine plays an important role in regulating renal function and blood pressure. Dopamine synthesis and dopamine receptor subtypes have been shown in the kidney. Dopamine acts via cell surface receptors coupled to G proteins; the receptors are classified via pharmacologic and molecular cloning studies into two families, D1-like and D2-like. Two D1-like receptors cloned in mammals, the D1 and D5 receptors (D1A and D1B in rodents), are linked to adenylyl cyclase stimulation. Three D2-like receptors (D2, D3, and D4) have been cloned and are linked mainly to adenylyl cyclase inhibition. Activation of D1-like receptors on the proximal tubules inhibits tubular sodium reabsorption by inhibiting Na/H-exchanger and Na/K-adenosine triphosphatase activity. Reports exist of defective renal dopamine production and/or dopamine receptor function in human primary hypertension and in genetic models of animal hypertension. In humans with essential hypertension, renal dopamine production in response to sodium loading is often impaired and may contribute to hypertension. A primary defect in D1-like receptors and an altered signaling system in proximal tubules may reduce dopamine-mediated effects on renal sodium excretion. The molecular basis for dopamine receptor dysfunction in hypertension is being investigated, and may involve an abnormal posttranslational modification of the dopamine receptor.

  2. Kierkegaardovo pojetí existence

    OpenAIRE

    Janatová, Kristýna

    2016-01-01

    The topic of the bachelor thesis is "Kierkegaard's conception of existence". There are both the life of the Danish philosopher Søren Kierkegaard and his philosophy discussed. The issue of human existence is analysed with its main three stages which are focused on aesthetics, ethics and religion. These stages of existence are at first described and afterwards compared with each other. The aesthetic represents the first stage of life and the religious stage is considered to be the highest aim o...

  3. Plasma cholecystokinin in obese patients before and after jejunoileal bypass with 3:1 or 1:3 jejunoileal ratio--no role in the increased risk of gallstone formation

    DEFF Research Database (Denmark)

    Sørensen, T I; Toftdahl, D B; Højgaard, L

    1994-01-01

    BACKGROUND AND AIM: Jejunoileal bypass surgery for obesity increases the risk of gallstone formation, and, contrary to expectations, the incidence is greater in patients with a long as compared to a short ileum left in continuity. Impaired gallbladder motility due to reduced cholecystokinin (CCK...... in plasma CCK levels neither explain the increased risk of gallstone formation after bypass surgery nor the higher incidence with a long compared to a short ileum left in continuity in the bypass....

  4. Gastrin and D1 dopamine receptor interact to induce natriuresis and diuresis.

    Science.gov (United States)

    Chen, Yue; Asico, Laureano D; Zheng, Shuo; Villar, Van Anthony M; He, Duofen; Zhou, Lin; Zeng, Chunyu; Jose, Pedro A

    2013-11-01

    Oral NaCl produces a greater natriuresis and diuresis than the intravenous infusion of the same amount of NaCl. Gastrin is the major gastrointestinal hormone taken up by renal proximal tubule (RPT) cells. We hypothesized that renal gastrin and dopamine receptors interact to synergistically increase sodium excretion, an impaired interaction of which may be involved in the pathogenesis of hypertension. In Wistar-Kyoto rats, infusion of gastrin induced natriuresis and diuresis, which was abrogated in the presence of a gastrin (cholecystokinin B receptor [CCKBR]; CI-988) or a D1-like receptor antagonist (SCH23390). Similarly, the natriuretic and diuretic effects of fenoldopam, a D1-like receptor agonist, were blocked by SCH23390, as well as by CI-988. However, the natriuretic effects of gastrin and fenoldopam were not observed in spontaneously hypertensive rats. The gastrin/D1-like receptor interaction was also confirmed in RPT cells. In RPT cells from Wistar-Kyoto but not spontaneously hypertensive rats, stimulation of either D1-like receptor or gastrin receptor inhibited Na(+)-K(+)-ATPase activity, an effect that was blocked in the presence of SCH23390 or CI-988. In RPT cells from Wistar-Kyoto and spontaneously hypertensive rats, CCKBR and D1 receptor coimmunoprecipitated, which was increased after stimulation of either D1 receptor or CCKBR in RPT cells from Wistar-Kyoto rats; stimulation of one receptor increased the RPT cell membrane expression of the other receptor, effects that were not observed in spontaneously hypertensive rats. These data suggest that there is a synergism between CCKBR and D1-like receptors to increase sodium excretion. An aberrant interaction between the renal CCK BR and D1-like receptors (eg, D1 receptor) may play a role in the pathogenesis of hypertension.

  5. THE EXISTENCE OF CONNECTING ORBITS

    Institute of Scientific and Technical Information of China (English)

    2011-01-01

    In this paper,using the notion of an isolating block and Conley's attractor theory,an existence criterion of trajectories connecting a pair of invariant sets of ordinary differential equations is given.

  6. Expression of messenger RNAs for glutamic acid decarboxylase, preprotachykinin, cholecystokinin, somatostatin, proenkephalin and neuropeptide Y in the adult rat superior colliculus.

    Science.gov (United States)

    Harvey, A R; Heavens, R P; Yellachich, L A; Sirinathsinghji, D J

    2001-01-01

    The mammalian superior colliculus is an important subcortical integrator of sensorimotor behaviours. It is multi-layered, each layer containing specific neuronal types and possessing distinct input/output relationships. Here we use in situ hybridisation methods to map the distribution of seven neurotransmitters/neuromodulator systems in adult rat superior colliculus. Coronal sections were probed for preprotachykinin, cholecystokinin, somatostatin, proenkephalin, neuropeptide Y and the enzymes glutamic acid decarboxylase and choline acetyltransferase, markers for GABA and acetylcholine respectively. Cells expressing glutamic acid decarboxylase messenger RNA were the most abundant, the highest density being found in the superficial layers. Many cells containing proprotachykinin messenger RNA were found in stratum zonale and the upper two-thirds of stratum griseum superficiale; cells were also located in deeper tectal laminae, particularly caudomedially. Most cholecystokinin messenger RNA expressing cells were located in the superficial layers with a prominent band in the middle third of stratum griseum superficiale. Cells expressing moderate to high levels of somatostatin messenger RNA formed a dense band in the lower third of stratum griseum superficiale/upper stratum opticum; two less distinct tiers of labelling were seen in deeper layers. These in situ hybridisation data reveal three distinct sub-laminae in rat stratum griseum superficiale. Cells expressing moderate to low levels of proenkephalin messenger RNA were located in lower stratum griseum superficiale/upper stratum opticum and intermediate laminae. A cluster of enkephalinergic cells was located medially in the deep tectal laminae. Expression of neuropeptide Y messenger RNA was relatively low and mostly confined to cells in stratum griseum superficiale and stratum opticum. No choline acetyltransferase messenger RNA was detected. This in situ analysis of seven different neurotransmitters

  7. Possible Relevance of Receptor-Receptor Interactions between Viral- and Host-Coded Receptors for Viral-Induced Disease

    Directory of Open Access Journals (Sweden)

    Luigi F. Agnati

    2007-01-01

    Full Text Available It has been demonstrated that some viruses, such as the cytomegalovirus, code for G-protein coupled receptors not only to elude the immune system, but also to redirect cellular signaling in the receptor networks of the host cells. In view of the existence of receptor-receptor interactions, the hypothesis is introduced that these viral-coded receptors not only operate as constitutively active monomers, but also can affect other receptor function by interacting with receptors of the host cell. Furthermore, it is suggested that viruses could also insert not single receptors (monomers, but clusters of receptors (receptor mosaics, altering the cell metabolism in a profound way. The prevention of viral receptor-induced changes in host receptor networks may give rise to novel antiviral drugs that counteract viral-induced disease.

  8. Poesia e existência

    Directory of Open Access Journals (Sweden)

    Wladimir Antônio da Costa Garcia

    2006-06-01

    Full Text Available Temas como aquilo que há; o ser na sua singularidade (independentemente dos seus atributos ou das contingências; a relação entre escolha, necessidade e acaso; a relação entre possibilidade e impossibilidade (ou mesmo possíveis impossibilidades; e, por fim, neste ensaio, a relação entre caos e sistemas de ordem, sempre estiveram presentes, tanto na criação lírica como na reflexão filosófica. Logo, a existência não é privilégio do existencialismo. A noção de existência forma-se a partir daqueles temas: ela é secundária em relação aos pensamentos que a determinam. Trata-se, portanto, de uma “longa história, esta do sentido da existência” (DELEUZE, 1985. Desde o pensamento que se forma de uma culpa, desde o ressentimento e da vingança em torno da injustiça permanente do devir (quando a existência torna-se modificada pelos predicados, ou seja, niilista, à negação do todo e à absolvição da existência pela sua inocência (isto é, a afirmação do devir, o eterno retorno do ser do devir, etc., a noção de existência se desdobra. Sendo assim, o título deste trabalho, ao suspender aqueles sentidos estabelecidos, busca capturar a existência desde a potencialidade de suas relações com as configurações do poético.

  9. Existing Steel Railway Bridges Evaluation

    Science.gov (United States)

    Vičan, Josef; Gocál, Jozef; Odrobiňák, Jaroslav; Koteš, Peter

    2016-12-01

    The article describes general principles and basis of evaluation of existing railway bridges based on the concept of load-carrying capacity determination. Compared to the design of a new bridge, the modified reliability level for existing bridges evaluation should be considered due to implementation of the additional data related to bridge condition and behaviour obtained from regular inspections. Based on those data respecting the bridge remaining lifetime, a modification of partial safety factors for actions and materials could be respected in the bridge evaluation process. A great attention is also paid to the specific problems of determination of load-caring capacity of steel railway bridges in service. Recommendation for global analysis and methodology for existing steel bridge superstructure load-carrying capacity determination are described too.

  10. Interaction between gastric and upper small intestinal hormones in the regulation of hunger and satiety: ghrelin and cholecystokinin take the central stage.

    Science.gov (United States)

    Stengel, Andreas; Taché, Yvette

    2011-06-01

    Several peptides are produced and released from endocrine cells scattered within the gastric oxyntic and the small intestinal mucosa. These peptide hormones are crucially involved in the regulation of gastrointestinal functions and food intake by conveying their information to central regulatory sites located in the brainstem as well as in the forebrain, such as hypothalamic nuclei. So far, ghrelin is the only known hormone that is peripherally produced in gastric X/A-like cells and centrally acting to stimulate food intake, whereas the suppression of feeding seems to be much more redundantly controlled by a number of gut peptides. Cholecystokinin produced in the duodenum is a well established anorexigenic hormone that interacts with ghrelin to modulate food intake indicating a regulatory network located at the first site of contact with nutrients in the stomach and upper small intestine. In addition, a number of peptides including leptin, urocortin 2, amylin and glucagon-like peptide 1 interact synergistically with CCK to potentiate its satiety signaling effect. New developments have led to the identification of additional peptides in X/A-like cells either derived from the pro-ghrelin gene by alternative splicing and posttranslational processing (obestatin) or a distinct gene (nucleobindin2/nesfatin-1) which have been investigated for their influence on food intake.

  11. Dietary unsaturated fatty acids increase plasma glucagon-like peptide-1 and cholecystokinin and may decrease premeal ghrelin in lactating dairy cows.

    Science.gov (United States)

    Bradford, B J; Harvatine, K J; Allen, M S

    2008-04-01

    Previous reports have indicated that dietary unsaturated fat can decrease energy intake of lactating dairy cattle. However, the mechanism for this response is unclear. To evaluate the potential role of gut peptides, periprandial concentrations of cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1), and ghrelin were measured. From a replicated 4 x 4 Latin square experiment, 4 cows from a single square were selected for analysis of responses to 3 treatments: a control diet (5.5% total fatty acids, 65% unsaturated), a diet with added saturated fat (SAT, 8.3% fatty acids, 47% unsaturated), and a diet with added unsaturated fat (UNS, 7.8% fatty acids, 63% unsaturated). The SAT treatment increased duodenal flow of saturated fatty acids compared with UNS and control and, despite the fact that ruminal biohydrogenation altered fatty acid profiles of digesta, UNS increased duodenal flow of unsaturated fatty acids compared with SAT and control. Blood samples were collected at 8-min intervals through the first 2 meals of the day and analyzed by commercial radioimmunoassays. The UNS treatment increased plasma CCK concentration relative to SAT and control, and increased plasma GLP-1 concentration compared with control. Furthermore, fat treatments tended to suppress the prandial ghrelin surge that was evident for control. Suppression of feed intake by unsaturated fats is likely mediated in part by increased secretion of CCK and GLP-1, and dietary fat may also inhibit ghrelin release before conditioned meals.

  12. Capsaicin in adult frogs: effects on nociceptive responses to cutaneous stimuli and on nervous tissue concentrations of immunoreactive substance P, somatostatin and cholecystokinin.

    Science.gov (United States)

    Chéry-Croze, S; Godinot, F; Jourdan, G; Bernard, C; Chayvialle, J A

    1985-11-01

    Adult frogs (Rana esculenta) were given subcutaneous injections of 10, 20, 30, 50 and 100 mg/kg capsaicin in sequential order over 5 days, or the vehicle only. The nociceptive thresholds to electrical, thermal and chemical stimuli were measured before, and 1, 5 and 24 h after each injection. Capsaicin was followed by a dose-related reduction of nociceptive responses to all stimuli, but these effects lasted for only 1-5 h after the given injection. Water/acetic extracts of undivided brains and spinal cords were prepared at the corresponding time periods for the radioimmunoassay of peptides. Spinal cord concentrations of immunoreactive substance P were essentially unaffected by capsaicin, while those of immunoreactive somatostatin were significantly increased after the second for fourth injections (20, 30 and 50 mg/kg) of capsaicin. Brain extracts showed an increase of somatostatin and substance P concentrations after the dose of 50 mg/kg. In an additional experiment, immunoreactive substance P, somatostatin and cholecystokinin were measured in tissue samples taken at 2 and 10 min, and 1, 5 and 24 h after a single dose of either 50 mg/kg capsaicin or the vehicle. The only significant effect of capsaicin was an increase of immunoreactive somatostatin concentration in brain homogenates at 5 h, while the vehicle in itself elicited major variations of all three peptides in spinal cord and/or brain. These results indicate that capsaicin reduces the nociceptive responses to cutaneous stimuli in adult frogs.(ABSTRACT TRUNCATED AT 250 WORDS)

  13. Effects of peripherally administered cholecystokinin-8 and secretin on feeding/drinking and oxytocin-mRFP1 fluorescence in transgenic rats.

    Science.gov (United States)

    Motojima, Yasuhito; Kawasaki, Makoto; Matsuura, Takanori; Saito, Reiko; Yoshimura, Mitsuhiro; Hashimoto, Hirofumi; Ueno, Hiromichi; Maruyama, Takashi; Suzuki, Hitoshi; Ohnishi, Hideo; Sakai, Akinori; Ueta, Yoichi

    2016-08-01

    Peripheral administration of cholecystokinin (CCK)-8 or secretin activates oxytocin (OXT)-secreting neurons in the hypothalamus. Although OXT is involved in the regulation of feeding behavior, detailed mechanism remains unclear. In the present study, we examined the central OXTergic pathways after intraperitoneally (i.p.) administration of CCK-8 and secretin using male OXT-monomeric red fluorescent protein 1 (mRFP1) transgenic rats and male Wistar rats. I.p. administration of CCK-8 (50μg/kg) and secretin (100μg/kg) decreased food intake in these rats. While i.p. administration of CCK-8 decreased water intake, i.p. administration of secretin increased water intake. Immunohistochemical study revealed that Fos-Like-Immunoreactive cells were observed abundantly in the brainstem and in the OXT neurons in the dorsal division of the parvocellular paraventricular nucleus (dpPVN). We could observe marked increase of mRFP1 fluorescence, as an indicator for OXT, in the dpPVN and mRFP1-positive granules in axon terminals of the dpPVN OXT neurons in the nucleus tractus solitarius (NTS) after i.p. administration of CCK-8 and secretin. These results provide us the evidence that, at least in part, i.p. administration of CCK-8 or secretin might be involved in the regulation of feeding/drinking via a OXTergic pathway from the dpPVN to the NTS.

  14. Involvement of myristoylated alanine-rich C kinase substrate phosphorylation and translocation in cholecystokinin-induced amylase release in rat pancreatic acini.

    Science.gov (United States)

    Satoh, Keitaro; Narita, Takanori; Katsumata-Kato, Osamu; Sugiya, Hiroshi; Seo, Yoshiteru

    2016-03-15

    Cholecystokinin (CCK) is a gastrointestinal hormone that induces exocytotic amylase release in pancreatic acinar cells. The activation of protein kinase C (PKC) is involved in the CCK-induced pancreatic amylase release. Myristoylated alanine-rich C kinase substrate (MARCKS) is a ubiquitously expressed substrate of PKC. MARCKS has been implicated in membrane trafficking in several cell types. The phosphorylation of MARCKS by PKC results in the translocation of MARCKS from the membrane to the cytosol. Here, we studied the involvement of MARCKS in the CCK-induced amylase release in rat pancreatic acini. Employing Western blotting, we detected MARCKS protein in the rat pancreatic acini. CCK induced MARCKS phosphorylation. A PKC-δ inhibitor, rottlerin, inhibited the CCK-induced MARCKS phosphorylation and amylase release. In the translocation assay, we also observed CCK-induced PKC-δ activation. An immunohistochemistry study showed that CCK induced MARCKS translocation from the membrane to the cytosol. When acini were lysed by a detergent, Triton X-100, CCK partially induced displacement of the MARCKS from the GM1a-rich detergent-resistant membrane fractions (DRMs) in which Syntaxin2 is distributed. A MARCKS-related peptide inhibited the CCK-induced amylase release. These findings suggest that MARCKS phosphorylation by PKC-δ and then MARCKS translocation from the GM1a-rich DRMs to the cytosol are involved in the CCK-induced amylase release in pancreatic acinar cells.

  15. A1-adenosine acute withdrawal response and cholecystokinin-8 induced contractures are regulated by Ca(2+)- and ATP-activated K(+) channels.

    Science.gov (United States)

    Cascio, Maria Grazia; Valeri, Daniela; Tucker, Steven J; Marini, Pietro

    2015-01-01

    In isolated guinea-pig ileum (GPI), the A1-adenosine acute withdrawal response is under the control of several neuronal signalling systems, including the μ/κ-opioid and the cannabinoid CB1 systems. It is now well established that after the stimulation of the A1-adenosine system, the indirect activation of both μ/κ-opioid and CB1 systems is prevented by the peptide cholecystokinin-8 (CCk-8). In the present study, we have investigated the involvement of the Ca(2+)/ATP-activated K(+) channels in the regulation of both acute A1-withdrawal and CCk-8-induced contractures in the GPI preparation. Interestingly, we found that: (a) the A1-withdrawal contracture is inhibited by voltage dependent Ca(2+)-activated K(+) channels, Kv, while it is enhanced by the voltage independent Ca(2+)-activated K(+) channels, SKCa; (b) in the presence of CCk-8, the inhibitory effect of the A1 agonist, CPA, on the peptide induced contracture is significantly enhanced by the voltage independent Ca(2+)-activated K(+) channel, SKCa; and (c) the A1-withdrawal contracture precipitated in the presence of CCk-8 is controlled by the ATP-sensitive potassium channels, KATP. Our data suggest, for the first time, that both Ca(2+)- and ATP-activated K(+) channels are involved in the regulation of both A1-withdrawal precipitated and CCk-8 induced contractures.

  16. The peptide hormone cholecystokinin modulates the tonus and compliance of the bulbus arteriosus and pre-branchial vessels of the rainbow trout (Oncorhynchus mykiss).

    Science.gov (United States)

    Seth, Henrik; Axelsson, Michael; Gräns, Albin

    2014-12-01

    The bulbus arteriosus is a compliant structure between the ventricle and ventral aorta of teleost fish. It serves as a "wind-kessel" that dampens pressure variations during the cardiac cycle allowing a continuous flow of blood into the gills. The bulbus arteriosus receives sympathetic innervation and is affected by several circulating substances, indicating neurohumoral control. We have previously shown that the peptide hormone, cholecystokinin (CCK), affects the hemodynamics of the cardiovascular system in rainbow trout (Oncorhynchus mykiss) by increasing flow pulse amplitude without affecting cardiac output. We hypothesized that this could be explained by an altered tonus or compliance/distensibility of the bulbus arteriosus. Our results show that there is a substantial effect of CCK on the bulbus arteriosus. Concentrations of CCK that altered the cardiac function of in situ perfused hearts also contracted the bulbus arteriosus in vitro. Pressure-volume curves revealed a change in both the tonus and the compliance/distensibility of this structure. Furthermore, the stimulatory (constricting) effect of CCK was also evident in the ventricle and vasculature leading to the gills, but absent in the atrium, efferent branchial arteries and dorsal aorta. In conclusion, CCK alters the mechanical properties of the ventricle, bulbus arteriosus, ventral aorta and afferent gill vasculature, thus maintaining adequate branchial and systemic blood flow and pressure when cardiorespiratory demands change, such as after feeding.

  17. Leptin and cholecystokinin in Schizothorax prenanti: molecular cloning, tissue expression, and mRNA expression responses to periprandial changes and fasting.

    Science.gov (United States)

    Yuan, Dengyue; Wang, Tao; Zhou, Chaowei; Lin, Fangjun; Chen, Hu; Wu, Hongwei; Wei, Rongbin; Xin, Zhiming; Li, Zhiqiong

    2014-08-01

    In the present study, full-length cDNA sequences of leptin and cholecystokinin (CCK) were cloned from Schizothorax prenanti (S. prenanti), and applied real-time quantitative PCR to characterize the tissue distribution, and appetite regulatory effects of leptin and CCK in S. prenanti. The S. prenanti leptin and CCK full-length cDNA sequences were 1121 bp and 776 bp in length, encoding the peptide of 171 and 123 amino acid residues, respectively. Tissue distribution analysis showed that leptin mRNA was mainly expressed in the liver of S. prenanti. CCK was widely expressed, with the highest levels of expression in the hypothalamus, myelencephalon, telencephalon and foregut of S. prenanti. The CCK mRNA expression was highly elevated after feeding, whereas the leptin mRNA expression was not affected by single meal. These results suggested that CCK is a postprandial satiety signal in S. prenanti, but leptin might not be. In present study, leptin and CCK gene expression were both decreased after fasting and increased after refeeding, which suggested leptin and CCK might be involved in regulation of appetite in S. prenanti. This study provides an essential groundwork to further elucidate the appetite regulatory systems of leptin and CCK in S. prenanti as well as in other teleosts.

  18. Preparation and application of a novel molecularly imprinted solid-phase microextraction monolith for selective enrichment of cholecystokinin neuropeptides in human cerebrospinal fluid.

    Science.gov (United States)

    Ji, Xiang; Li, Dan; Li, Hua

    2015-08-01

    A novel molecularly imprinted polymer (MIP) monolith for highly selective extraction of cholecystokinin (CCK) neuropeptides was prepared in a micropipette tip. The MIPs were synthesized by epitope imprinting technique and the polymerization conditions were investigated and optimized. The synthesized MIPs were characterized by infrared spectroscopy, elemental analyzer and scanning electron microscope. A molecularly imprinted solid-phase microextraction (MI-μ-SPE) method was developed for the extraction of CCK neuropeptides in aqueous solutions. The parameters affecting MI-μ-SPE were optimized. The results indicated that this MIP monolith exhibited specific recognition capability and high enrichment efficiency for CCK neuropeptides. In addition, it showed excellent reusability. This MIP monolith was used for desalting and enrichment of CCK4, CCK5 and CCK8 from human cerebrospinal fluid prior to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analysis, and the results show that this MIP monolith can be a useful tool for effective purification and highly selective enrichment of multiple homologous CCK neuropeptides in cerebrospinal fluid simultaneously. By employing MI-μ-SPE combined with HPLC-ESI-MS/MS analysis, endogenous CCK4 in human cerebrospinal fluid was quantified.

  19. Persistently active cannabinoid receptors mute a subpopulation of hippocampal interneurons.

    Science.gov (United States)

    Losonczy, Attila; Biró, Agota A; Nusser, Zoltan

    2004-02-03

    Cortical information processing requires an orchestrated interaction between a large number of pyramidal cells and albeit fewer, but highly diverse GABAergic interneurons (INs). The diversity of INs is thought to reflect functional and structural specializations evolved to control distinct network operations. Consequently, specific cortical functions may be selectively modified by altering the input-output relationship of unique IN populations. Here, we report that persistently active cannabinoid receptors, the site of action of endocannabinoids, and the psychostimulants marijuana and hashish, switch off the output (mute) of a unique class of hippocampal INs. In paired recordings between cholecystokinin-immunopositive, mossy fiber-associated INs, and their target CA3 pyramidal cells, no postsynaptic currents could be evoked with single presynaptic action potentials or with repetitive stimulations at frequencies <25 Hz. Cannabinoid receptor antagonists converted these "mute" synapses into high-fidelity ones. The selective muting of specific GABAergic INs, achieved by persistent presynaptic cannabinoid receptor activation, provides a state-dependent switch in cortical networks.

  20. [Does Stendhal's syndrome exist really?].

    Science.gov (United States)

    Valtueña Borque, Oscar

    2009-01-01

    The author, Medical Doctor and Master in Art History, dicusses the real existence of the so called by the Florentine MD Magherini Stendhal syndrome, first time published in 1980 to put out the sickness that some tourists in their Florentia visit suffered, because the big beauty they founded in the city, as the French writter Stendahl suffered two centuries ago.

  1. Physiological impact of CB1 receptor expression by hippocampal GABAergic interneurons.

    Science.gov (United States)

    Albayram, Önder; Passlick, Stefan; Bilkei-Gorzo, Andras; Zimmer, Andreas; Steinhäuser, Christian

    2016-04-01

    A subset of hippocampal GABAergic neurons, which are cholecystokinin-positive, highly express cannabinoid type 1 (CB1) receptors. Activation of these receptors inhibits GABA release and thereby limits inhibitory control. While genetic deletion of CB1 receptors from GABAergic neurons led to behavioural alterations and neuroinflammatory reactions, it remained unclear whether these changes in the knockout animals were a direct consequence of the enhanced transmitter release or reflected developmental deficits. The hippocampus is vital for the generation of spatial, declarative and working memory. Here, we addressed the question how CB1 receptors in GABAergic neurons influence hippocampal function. Patch clamp and field potential recordings in mice devoid of CB1 receptors in GABAergic neurons revealed an enhanced frequency and faster kinetics of spontaneous inhibitory postsynaptic currents in CA1 pyramidal neurons while tonic inhibition, paired-pulse facilitation and long-term potentiation in the hippocampus were not affected. Evaluation of cognitive functions demonstrated impaired acquisition of spatial memory and deficits in novel object recognition and partner recognition in the knockout mice, while working memory and spatial memory remained intact. The density of GABAergic neurons was also similar in knockout mice and their littermates, which argues against global deficits in hippocampal development. Together, these results suggest that CB1 receptors in GABAergic neurons influence specific aspects of neuronal excitability and hippocampal learning.

  2. The EXIST Mission Concept Study

    Science.gov (United States)

    Fishman, Gerald J.; Grindlay, J.; Hong, J.

    2008-01-01

    EXIST is a mission designed to find and study black holes (BHs) over a wide range of environments and masses, including: 1) BHs accreting from binary companions or dense molecular clouds throughout our Galaxy and the Local Group, 2) supermassive black holes (SMBHs) lying dormant in galaxies that reveal their existence by disrupting passing stars, and 3) SMBHs that are hidden from our view at lower energies due to obscuration by the gas that they accrete. 4) the birth of stellar mass BHs which is accompanied by long cosmic gamma-ray bursts (GRBs) which are seen several times a day and may be associated with the earliest stars to form in the Universe. EXIST will provide an order of magnitude increase in sensitivity and angular resolution as well as greater spectral resolution and bandwidth compared with earlier hard X-ray survey telescopes. With an onboard optical-infra red (IR) telescope, EXIST will measure the spectra and redshifts of GRBs and their utility as cosmological probes of the highest z universe and epoch of reionization. The mission would retain its primary goal of being the Black Hole Finder Probe in the Beyond Einstein Program. However, the new design for EXIST proposed to be studied here represents a significant advance from its previous incarnation as presented to BEPAC. The mission is now less than half the total mass, would be launched on the smallest EELV available (Atlas V-401) for a Medium Class mission, and most importantly includes a two-telescope complement that is ideally suited for the study of both obscured and very distant BHs. EXIST retains its very wide field hard X-ray imaging High Energy Telescope (HET) as the primary instrument, now with improved angular and spectral resolution, and in a more compact payload that allows occasional rapid slews for immediate optical/IR imaging and spectra of GRBs and AGN as well as enhanced hard X-ray spectra and timing with pointed observations. The mission would conduct a 2 year full sky survey in

  3. Cluster pre-existence probability

    Energy Technology Data Exchange (ETDEWEB)

    Rajeswari, N.S.; Vijayaraghavan, K.R.; Balasubramaniam, M. [Bharathiar University, Department of Physics, Coimbatore (India)

    2011-10-15

    Pre-existence probability of the fragments for the complete binary spectrum of different systems such as {sup 56}Ni, {sup 116}Ba, {sup 226}Ra and {sup 256}Fm are calculated, from the overlapping part of the interaction potential using the WKB approximation. The role of reduced mass as well as the classical hydrodynamical mass in the WKB method is analysed. Within WKB, even for negative Q -value systems, the pre-existence probability is calculated. The calculations reveal rich structural information. The calculated results are compared with the values of preformed cluster model of Gupta and collaborators. The mass asymmetry motion is shown here for the first time as a part of relative separation motion. (orig.)

  4. Existence of undiscovered Uranian satellites

    Energy Technology Data Exchange (ETDEWEB)

    Boice, D.C.

    1986-04-01

    Structure in the Uranian ring system as observed in recent occultations may contain indirect evidence for the existence of undiscovered satellites. Using the Alfven and Arrhenius (1975, 1976) scenario for the formation of planetary systems, the orbital radii of up to nine hypothetical satellites interior to Miranda are computed. These calculations should provide interesting comparisons when the results from the Voyager 2 encounter with Uranus are made public. 15 refs., 1 fig., 1 tab.

  5. Receptor binding peptides for target-selective delivery of nanoparticles encapsulated drugs

    Directory of Open Access Journals (Sweden)

    Accardo A

    2014-03-01

    Full Text Available Antonella Accardo,1 Luigi Aloj,2 Michela Aurilio,2 Giancarlo Morelli,1 Diego Tesauro11Centro interuniversitario di Ricerca sui Peptidi Bioattivi (CIRPeB, Department of Pharmacy and Istituto di Biostrutture e Bioimmagini - Consiglio Nazionale delle Ricerche (IBB CNR, University of Naples “Federico II”, 2Department of Nuclear Medicine, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione “G. Pascale”, Napoli, ItalyAbstract: Active targeting by means of drug encapsulated nanoparticles decorated with targeting bioactive moieties represents the next frontier in drug delivery; it reduces drug side effects and increases the therapeutic index. Peptides, based on their chemical and biological properties, could have a prevalent role to direct drug encapsulated nanoparticles, such as liposomes, micelles, or hard nanoparticles, toward the tumor tissues. A considerable number of molecular targets for peptides are either exclusively expressed or overexpressed on both cancer vasculature and cancer cells. They can be classified into three wide categories: integrins; growth factor receptors (GFRs; and G-protein coupled receptors (GPCRs. Therapeutic agents based on nanovectors decorated with peptides targeting membrane receptors belonging to the GPCR family overexpressed by cancer cells are reviewed in this article. The most studied targeting membrane receptors are considered: somatostatin receptors; cholecystokinin receptors; receptors associated with the Bombesin like peptides family; luteinizing hormone-releasing hormone receptors; and neurotensin receptors. Nanovectors of different sizes and shapes (micelles, liposomes, or hard nanoparticles loaded with doxorubicin or other cytotoxic drugs and externally functionalized with natural or synthetic peptides are able to target the overexpressed receptors and are described based on their formulation and in vitro and in vivo behaviors.Keywords: receptors binding peptides, drug delivery

  6. Incretin physiology beyond glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide: cholecystokinin and gastrin peptides

    DEFF Research Database (Denmark)

    Rehfeld, J F

    2011-01-01

    and neonatal islets express significant amounts of gastrin, and human as well as porcine islet cells express the gastrin/CCK-B receptor abundantly. Therefore, exogenous gastrin and CCK peptides stimulate insulin and glucagon secretion in man. Accordingly, endogenous hypergastrinaemia is accompanied by islet...... cell hyperplasia and increased insulin secretion. Conventionally, the effect of gastrointestinal hormones on insulin secretion (the incretin effect) has been defined and quantified in relation to oral versus intravenous glucose loadings. Under these unphysiological conditions, the release of gastrin...... and CCK and, hence, their effect on insulin secretion are modest in comparison with the effects of glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 (GLP-1). Consequently, the interest of CCK and gastrin in incretin research has for decades been limited. A few years ago, however...

  7. Saddle scars Existence and applications

    CERN Document Server

    Mendes, R V

    1998-01-01

    A quantum scar is a wave function which displays an high intensity in the region of a classical unstable periodic orbit. Saddle scars are states related to the unstable harmonic motions along the stable manifold of a saddle point of the potential. Using a semiclassical method it is shown that, independently of the overall structure of the potential, the local dynamics of the saddle point is sufficient to insure the general existence of this type of scars and their factorized structure is obtained. Potentially useful situations are identified, where these states appear (directly or in disguise) and might be used for quantum control purposes.

  8. Turbulence: does energy cascade exist?

    CERN Document Server

    Josserand, Christophe; Lehner, Thierry; Pomeau, Yves

    2016-01-01

    To answer the question whether a cascade of energy exists or not in turbulence, we propose a set of correlation functions able to test if there is an irreversible transfert of energy, step by step, from large to small structures. These tests are applied to real Eulerian data of a turbulent velocity flow, taken in the wind grid tunnel of Modane, and also to a prototype model equation for wave turbulence. First we demonstrate the irreversible character of the flow by using multi-time correlation function at a given point of space. Moreover the unexpected behavior of the test function leads us to connect irreversibility and finite time singularities (intermittency). Secondly we show that turbulent cascade exists, and is a dynamical process, by using a test function depending on time and frequency. The cascade shows up only in the inertial domain where the kinetic energy is transferred more rapidly (on average) from the wavenumber $k_{1}$ to $k_{2}$ than from $k_{1}$ to $k'_{2}$ larger than $k_{2}$.

  9. Effects of lauric acid on upper gut motility, plasma cholecystokinin and peptide YY, and energy intake are load, but not concentration, dependent in humans.

    Science.gov (United States)

    Feltrin, Kate L; Little, Tanya J; Meyer, James H; Horowitz, Michael; Rades, Thomas; Wishart, Judith; Feinle-Bisset, Christine

    2007-06-01

    Animal studies suggest that the effects of fatty acids on gastric emptying and pancreatic secretion are both concentration and load dependent, while their suppressive effect on energy intake is only load dependent. We postulated that, in humans, the modulation of antropyloroduodenal pressure waves, plasma cholecystokinin (CCK) and peptide YY (PYY) concentrations and energy intake by intraduodenal lauric acid, a fatty acid with 12 carbon atoms ('C12') would be load, but not concentration, dependent. Two groups of 12 healthy males were each studied on three separate occasions in double-blind randomized fashion. Antropyloroduodenal pressure waves, plasma CCK and PYY, and appetite perceptions were measured during intraduodenal infusions of C12 at (1) different loads of (i) 0.2, (ii) 0.3 and (iii) 0.4 kcal min(-1) (all 56 mM) for 90 min, and (2) different concentrations of (i) 40, (ii) 56 and (iii) 72 mM (all 0.4 kcal min(-1)) for 60 min. Energy intake at a buffet meal consumed immediately following each infusion was quantified. Suppression of antral and duodenal pressure waves, stimulation of pyloric pressure waves, stimulation of plasma CCK and PYY, and suppression of energy intake, were related to the load of C12 administered (r>0.65, P<0.05). In contrast, there were no concentration-dependent effects of C12 on any of these parameters. In conclusion, in humans, the effects of intraduodenal C12 on antropyloroduodenal motility, plasma CCK and PYY and energy intake appear to be related to load, but not concentration, at least at the loads and concentrations evaluated.

  10. Function and regulation of cholecystokinin octapeptide, β-endorphin and gastrin in anorexic infantile rats treated with ErBao Granules

    Institute of Scientific and Technical Information of China (English)

    Yong Ping Du; Yue Ping Zhang; Shou Chuan Wang; Jian Shi; Shao Hua Wu

    2001-01-01

    AIM To study the role of cholecystokinin octapeptide ( CCK-8), β-endorphin ( β-EP), and gastrin in an anorexic infantile rat model and no subsequent regulation of nose peptides by the Yunpi complex prescription ErBao Granule. METHODS We fed infantile rats with special prepared forage. A liquid extract of ErBao Granule was administered to the rats daily for 3weeks, CCK-8, β-EP, and gastrin concentrations in hypothalamus, gastric antrum, and plasma of the rats were measured by radioimmunoassay,and were compared with controls. RESULTS Treatment of rats with ErBao Granule inhibited CCK-8 secretion and increased β-EP and gastrin secretion. CCK-8 concentration in hypothalamus and plasma of model control group increased significantly and correlated negatively with food intake of models.respectively. β-EP concentration in gastric antrum and plasma of model control group decreased significantly and showed a positive correlation with food intake of models,respectively. Hypothalamus concentration of β-EP was similar in models and controls. Gastrin concentration in gastric antrum of models was lower than in the blank control group, and correlated positively to food intake of models.Finally, CCK-8 concentrations in plasma of rats showed a positive correlation with plasma β-EP(r- 0.68, P<0.05).CONCLUSION The increased plasma and hypothalamus concentration of CCK-8, decreased gastric antrum and plasma level of β-EP. and decreased gastric antrum concentration of gastrin are associated significantly with the anorexia of infantile anorexic rat models produced by special forage. ErBao Granule can reverse these changes, which may be the major mechanisms of ErBao Granule simulating feeding.

  11. Effects of psychological stress on small intestinal motility and expression of cholecystokinin and vasoactive intestinal polypeptide in plasma and small intestine in mice

    Institute of Scientific and Technical Information of China (English)

    Shu-Guang Cao; Wan-Chun Wu; Zhen Han; Meng-Ya Wang

    2005-01-01

    AIM: To investigate the effects of psychological stress on small intestinal motility and expression of cholecystokinin(CCK) and vasoactive intestinal polypeptide (VIP) in plasma and small intestine, and to explore the relationship between small intestinal motor disorders and gastrointestinal hormones under psychological stress.METHODS: Thirty-six mice were randomly divided into psychological stress group and control group. A mouse model with psychological stress was established by housing the mice with a hungry cat in separate layers of a two-layer cage. A semi-solid colored marker (carbon-ink) was used for monitoring small intestinal transit. CCK and VIP levels in plasma and small intestine in mice were measured by radioimmunoassay (RIA).RFSULTS: Small intestinal transit was inhibited (52.18±19.15%vs 70.19±17.79%, P<0.01) in mice after psychological stress, compared to the controls. Small intestinal CCK levels in psychological stress mice were significantly lower than those in the control group (0.75±0.53 μg/g vs 1.98±1.17 μg/g,P<0.01), whereas plasma CCK concentrations were not different between the groups. VIP levels in small intestine were significantly higher in psychological stress mice than those in the control group (8.45±1.09 μg/g vs 7.03±2.36 μg/g,P<0.01), while there was no significant difference in plasma VTP levels between the two groups.CONCLUSION: Psychological stress inhibits the small intestinal transit, probably by down-regulating CCK and up-regulating VIP expression in small intestine.

  12. Protein hydrolysate-induced cholecystokinin secretion from enteroendocrine cells is indirectly mediated by the intestinal oligopeptide transporter PepT1.

    Science.gov (United States)

    Liou, Alice P; Chavez, Diana I; Espero, Elvis; Hao, Shuzhen; Wank, Stephen A; Raybould, Helen E

    2011-05-01

    Dietary protein is a major stimulant for cholecystokinin (CCK) secretion by the intestinal I cell, however, the mechanism by which protein is detected is unknown. Indirect functional evidence suggests that PepT1 may play a role in CCK-mediated changes in gastric motor function. However, it is unclear whether this oligopeptide transporter directly or indirectly activates the I cell. Using both the CCK-expressing enteroendocrine STC-1 cell and acutely isolated native I cells from CCK-enhanced green fluorescent protein (eGFP) mice, we aimed to determine whether PepT1 directly activates the enteroendocrine cell to elicit CCK secretion in response to oligopeptides. Both STC-1 cells and isolated CCK-eGFP cells expressed PepT1 transcripts. STC-1 cells were activated, as measured by ERK(1/2) phosphorylation, by both peptone and the PepT1 substrate Cefaclor; however, the PepT1 inhibitor 4-aminomethyl benzoic acid (AMBA) had no effect on STC-1 cell activity. The PepT1-transportable substrate glycyl-sarcosine dose-dependently decreased gastric motility in anesthetized rats but had no affect on activation of STC-1 cells or on CCK secretion by CCK-eGFP cells. CCK secretion was significantly increased in response to peptone but not to Cefaclor, cephalexin, or Phe-Ala in CCK-eGFP cells. Taken together, the data suggest that PepT1 does not directly mediate CCK secretion in response to PepT1 specific substrates. PepT1, instead, may have an indirect role in protein sensing in the intestine.

  13. Celiac and the cranial mesenteric arteries supply gastrointestinal sites that regulate meal size and intermeal interval length via cholecystokinin-58 in male rats.

    Science.gov (United States)

    Sayegh, Ayman I; Washington, Martha C; Johnson, Ruth E; Johnson-Rouse, Tanisha; Freeman, Corren; Harrison, Anna; Lucas, Jennifer; Shelby, Mandy; Fisher, Brittley; Willis, William; Reeve, Joseph J

    2015-01-01

    The site(s) of action that control meal size and intermeal interval (IMI) length by cholecystokinin-58 (CCK-58), the only detectable endocrine form of CCK in the rat, are not known. To test the hypothesis that the gastrointestinal tract may contain such sites, we infused low doses of CCK-58 (0.01, 0.05, 0.15 and 0.25nmol/kg) into the celiac artery (CA, supplying stomach and upper duodenum), the cranial mesenteric artery (CMA, supplying small and most of the large intestines), the femoral artery (FA, control) and the portal vein (PV, draining the gastrointestinal tract) prior to the onset of the dark cycle in freely fed male rats. We measured the first meal size (chow), second meal size, IMI and satiety ratio (SR, IMI/meal size). We found that (1) all doses of CCK-58 given in the CA and the highest dose given in the CMA reduced the first meal size, (2) all doses of CCK-58 given in the CA reduced the second meal size, (3) a CCK-58 dose of 0.15nmol/kg given in the CA and 0.15 and 0.25nmol/kg given in the CMA prolonged the IMI, (4) CCK-58 (0.05, 0.15, 0.25nmol/kg) given in the CA and 0.25nmol/kg given in the CMA increased the SR, and (5) CCK-58 given in the FA and PV had no effect on the meal size or intermeal interval. These results support our hypothesis that the gastrointestinal tract contains sites of action that regulate meal size and IMI length via CCK-58. The stomach and upper duodenum may contain sites regulating meal size, whereas the small intestine and part of the large intestine may contain sites regulating the IMI.

  14. Studies of cholecystokinin-stimulated biliary secretions reveal a high molecular weight copper-binding substance in normal subjects that is absent in patients with Wilson's disease.

    Science.gov (United States)

    Iyengar, V; Brewer, G J; Dick, R D; Chung, O Y

    1988-03-01

    Copper is unique among cations in that its balance is regulated by the liver. The liver regulates copper balance by excretion of copper (we call it regulatory copper) in the bile destined for loss in the stool. However, most copper secreted into the gastrointestinal tract, for example, that in saliva and gastric juice, is reabsorbed. The biochemical mechanism by which the normal liver "packages" regulatory copper to prevent its reabsorption is not understood. Whatever the mechanism, it appears to have failed in Wilson's disease, because patients with Wilson's disease do not excrete adequate amounts of regulatory copper in their bile to prevent copper accumulation. In the present work, we have studied cholecystokinin-stimulated biliary secretions obtained by intestinal intubation of five normal subjects and five patients with Wilson's disease. Studies of these secretions reveal: (1) that normal but not Wilson's disease biliary samples had a copper-containing peak in the void volume from Sephadex G-75 columns; (2) that the amount of copper in this peak extrapolated to 24 hours of secretion was appropriate to maintain normal copper balance; (3) that the amount of copper in this peak increased with dietary copper supplementation of normal subjects; (4) that normal but not Wilson's disease biliary samples cross-reacted with each of two ceruloplasmin antibodies; and (5) that the high molecular weight Sephadex G-75 fraction from normal but not from Wilson's disease biliary samples cross-reacted with ceruloplasmin antibody. We postulate that the high molecular weight copper-containing substance observed with Sephadex chromatography in normal biliary samples but absent in Wilson's disease samples is the copper-packaging mechanism for copper balance regulation.(ABSTRACT TRUNCATED AT 250 WORDS)

  15. Straightening: existence, uniqueness and stability.

    Science.gov (United States)

    Destrade, M; Ogden, R W; Sgura, I; Vergori, L

    2014-04-08

    One of the least studied universal deformations of incompressible nonlinear elasticity, namely the straightening of a sector of a circular cylinder into a rectangular block, is revisited here and, in particular, issues of existence and stability are addressed. Particular attention is paid to the system of forces required to sustain the large static deformation, including by the application of end couples. The influence of geometric parameters and constitutive models on the appearance of wrinkles on the compressed face of the block is also studied. Different numerical methods for solving the incremental stability problem are compared and it is found that the impedance matrix method, based on the resolution of a matrix Riccati differential equation, is the more precise.

  16. Straightening: existence, uniqueness and stability

    Science.gov (United States)

    Destrade, M.; Ogden, R. W.; Sgura, I.; Vergori, L.

    2014-01-01

    One of the least studied universal deformations of incompressible nonlinear elasticity, namely the straightening of a sector of a circular cylinder into a rectangular block, is revisited here and, in particular, issues of existence and stability are addressed. Particular attention is paid to the system of forces required to sustain the large static deformation, including by the application of end couples. The influence of geometric parameters and constitutive models on the appearance of wrinkles on the compressed face of the block is also studied. Different numerical methods for solving the incremental stability problem are compared and it is found that the impedance matrix method, based on the resolution of a matrix Riccati differential equation, is the more precise. PMID:24711723

  17. Local Existence of Spinor Potentials

    CERN Document Server

    Andersson, F

    1999-01-01

    We present a new, simple proof of existence for the Lanczos spinor potential in 3+1 dimensions that introduces a potential $T_{ABCD}= T_{(ABC)D}$ of the Lanczos potential together with several generalizations to other index configurations and metric signatures. The potential $T_{ABCD}$ can also be used to express, in a concise way, the gauge freedom left in the Lanczos potential after the differential gauge has been specified. We consider Einstein spacetimes and prove that in those spacetimes any symmetric (3,1)-spinor possesses a symmetric potential $H_{ABA'B'}$. Potentials of this type have earlier occurred in some special cases investigated e.g., by Torres del Castillo, Bergqvist and ourselves.

  18. Does the polystomatic gland exist?

    Science.gov (United States)

    Imai, M; Shibata, T; Moriguchi, K; Kinbara, M

    1989-03-01

    According to the P.N.A., the N.A.J. and some scholars, the sublingual gland has the ductus sublingualis major and ductus sublinguales minores. This means that the gland is a polystomatic gland. We intended to determine whether the so-called polystomatic gland exists or not. 1. According to the P.N.A., the N.A.J. and some scholars, the gl. sublingualis has the ductus sublingualis major and ductus sublinguales minores. This means the gland is a polystomatic gland. However, the formation of one gland with plural excretory ducts is embryologically impossible, in other words, the polystomatic gland does not exist. 2. Many scholars described that the gl. sublingualis was composed of the gl. sublingualis major and g11. sublinguales minores. However, they are completely different kinds of glands. Accordingly, we suggest the terms for these glands: the g1. sublingualis and its ductus sublingualis ("major" is useless), the g11. sublinguales minores and their ductus sublinguales minores. 3. The N.A.V.J. and some scholars use the term g1. sublingualis polystomatica or parvicanalaris. However, this is a group of a number of independent glands each of which has its own excretory duct. Such a gland should not be regarded as a single gland. We suggest that the term g11. sublinguales minores and their excretory ducts should be replaced with the term the ductus sublinguales minores. 4. The g1. lingualis anterior, g1. retromolaris and g1. lacrimalis are not single glands but a group of several independent glands each of which has its own excretory duct. Accordingly, they should be termed the g11. linguales anteriores, g11. retromolares and g11. lacrimales such as the g11. labiales, g11. buccales and g11. palatinae.

  19. NCBI nr-aa BLAST: CBRC-CJAC-01-1653 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-CJAC-01-1653 sp|Q63931|CCKAR_CAVPO Cholecystokinin type A receptor (CCK-A receptor) (CCK-AR) (Chole...cystokinin-1 receptor) (CCK1-R) gb|AAB29504.1| cholecystokinin A receptor; CCK-A receptor [Cavia] Q63931 0.0 92% ...

  20. Somatostatin receptors

    DEFF Research Database (Denmark)

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

    2003-01-01

    therefore been acknowledged to be a third endogenous ligand at SRIF receptors. This review goes through mechanisms of signal transduction, pharmacology, and anatomical distribution of SRIF receptors. Structurally, SRIF receptors belong to the superfamily of G protein-coupled (GPC) receptors, sharing....... The generation of knock-out (KO) mice, intended as a means to define the contributions made by individual receptor subtypes, necessarily marks but an approximation. Furthermore, we must now take into account the stunning complexity of receptor co-operation indicated by the observation of receptor homo......-peptides, receptor agonists and antagonists. Relatively long half lives, as compared to those of the endogenous ligands, have been paramount from the outset. Motivated by theoretical puzzles or the shortcomings of present-day diagnostics and therapy, investigators have also aimed to produce subtype...

  1. Existe sujeito em Michel Maffesoli?

    Directory of Open Access Journals (Sweden)

    Marli Appel da Silva

    2010-06-01

    Full Text Available Este ensaio discute a concepção de sujeito na abordagem teórica de Michel Maffesoli. As ideias desse autor estão em voga em alguns meios acadêmicos no Brasil e são difundidas por algumas mídias de grande circulação nacional. Entretanto, ao longo de suas obras, os pressupostos que definem quem é o sujeito maffesoliano se encontram pouco clarificados. Portanto, para alcançar o objetivo a que se propõe, este ensaio desenvolve uma análise da epistemologia e da ontologia maffesoliana com a finalidade de compreender as origens dos pressupostos desse autor, ou seja, as teorias e os autores em que Maffesoli se baseou para desenvolver uma visão de sujeito. Com essa compreensão, pretende-se responder à questão: existe sujeito na abordagem teórica de Maffesoli.

  2. Does Metabolically Healthy Obesity Exist?

    Science.gov (United States)

    Muñoz-Garach, Araceli; Cornejo-Pareja, Isabel; Tinahones, Francisco J.

    2016-01-01

    The relationship between obesity and other metabolic diseases have been deeply studied. However, there are clinical inconsistencies, exceptions to the paradigm of “more fat means more metabolic disease”, and the subjects in this condition are referred to as metabolically healthy obese (MHO).They have long-standing obesity and morbid obesity but can be considered healthy despite their high degree of obesity. We describe the variable definitions of MHO, the underlying mechanisms that can explain the existence of this phenotype caused by greater adipose tissue inflammation or the different capacity for adipose tissue expansion and functionality apart from other unknown mechanisms. We analyze whether these subjects improve after an intervention (traditional lifestyle recommendations or bariatric surgery) or if they stay healthy as the years pass. MHO is common among the obese population and constitutes a unique subset of characteristics that reduce metabolic and cardiovascular risk factors despite the presence of excessive fat mass. The protective factors that grant a healthier profile to individuals with MHO are being elucidated. PMID:27258304

  3. Changes in the plasma membrane in metabolic disease: impact of the membrane environment on G protein-coupled receptor structure and function.

    Science.gov (United States)

    Desai, Aditya J; Miller, Laurence J

    2017-07-10

    Drug development targeting GPCRs often utilizes model heterologous cell expression systems, reflecting an implicit assumption that the membrane environment has little functional impact on these receptors or on their responsiveness to drugs. However, much recent data have illustrated that membrane components can have an important functional impact on intrinsic membrane proteins. This review is directed toward gaining a better understanding of the structure of the plasma membrane in health and disease, and how this organelle can influence GPCR structure, function and regulation. It is important to recognize that the membrane provides a potential mode of lateral allosteric regulation of GPCRs and can affect the effectiveness of drugs and their biological responses in various disease states, which can even vary among individuals across the population. The type 1 cholecystokinin receptor is reviewed as an exemplar of a class A GPCR that is affected in this way by changes in the plasma membrane. © 2017 The British Pharmacological Society.

  4. Common Hepatic Branch of Vagus Nerve-Dependent Expression of Immediate Early Genes in the Mouse Brain by Intraportal L-Arginine: Comparison with Cholecystokinin-8

    Directory of Open Access Journals (Sweden)

    Daisuke Yamada

    2017-06-01

    Full Text Available Information from the peripheral organs is thought to be transmitted to the brain by humoral factors and neurons such as afferent vagal or spinal nerves. The common hepatic branch of the vagus (CHBV is one of the main vagus nerve branches, and consists of heterogeneous neuronal fibers that innervate multiple peripheral organs such as the bile duct, portal vein, paraganglia, and gastroduodenal tract. Although, previous studies suggested that the CHBV has a pivotal role in transmitting information on the status of the liver to the brain, the details of its central projections remain unknown. The purpose of the present study was to investigate the brain regions activated by the CHBV. For this purpose, we injected L-arginine or anorexia-associated peptide cholecystokinin-8 (CCK, which are known to increase CHBV electrical activity, into the portal vein of transgenic Arc-dVenus mice expressing the fluorescent protein Venus under control of the activity-regulated cytoskeleton-associated protein (Arc promotor. The brain slices were prepared from these mice and the number of Venus positive cells in the slices was counted. After that, c-Fos expression in these slices was analyzed by immunohistochemistry using the avidin-biotin-peroxidase complex method. Intraportal administration of L-arginine increased the number of Venus positive or c-Fos positive cells in the insular cortex. This action of L-arginine was not observed in CHBV-vagotomized Arc-dVenus mice. In contrast, intraportal administration of CCK did not increase the number of c-Fos positive or Venus positive cells in the insular cortex. Intraportal CCK induced c-Fos expression in the dorsomedial hypothalamus, while intraportal L-arginine did not. This action of CCK was abolished by CHBV vagotomy. Intraportal L-arginine reduced, while intraportal CCK increased, the number of c-Fos positive cells in the nucleus tractus solitarii in a CHBV-dependent manner. The present results suggest that the CHBV

  5. Physiological and morphological diversity of immunocytochemically defined parvalbumin- and cholecystokinin-positive interneurones in CA1 of the adult rat hippocampus.

    Science.gov (United States)

    Pawelzik, Hannelore; Hughes, David I; Thomson, Alex M

    2002-02-18

    To investigate the electrophysiological properties, synaptic connections, and anatomy of individual parvalbumin-immunoreactive (PV-IR) and cholecystokinin-immunoreactive (CCK-IR) interneurones in CA1, dual intracellular recordings using biocytin-filled microelectrodes in slices of adult rat hippocampus were combined with fluorescence labelling of PV- and CCK-containing cells. Of 36 PV-IR cells, 29 were basket cells, with most of their axonal arbours in the stratum pyramidale (SP). Six were bistratified cells with axons ramifying throughout stratum oriens (SO) and stratum radiatum (SR). One was a putative axo-axonic cell with an axonal arbour confined to half of the SP and a narrow adjacent region of the SO. Of 27 CCK-IR neurones, 13 were basket cells, with most of their axonal arbours in the SP, and included basket cells with somata in the SP (6), SO (3), and SR (2) and at the border between the stratum lacunosum-moleculare (SLM) and the SR (2). In addition, several dendrite-targeting cell classes expressed CCK-IR: 4 of 9 bistratified cells with axons ramifying in the SO and SR; all five Schaffer-associated cells whose axons ramified extensively in the SR; both cells classified as quadrilaminar because their axons ramified in the SO, SP, SR, and SLM; one SO-SO cell whose dendritic and axonal arbours were contained within the SO; and one perforant path-associated cell with axonal and dendritic arbours within the distal SR and SLM. The majority (31 of 36) of PV-IR neurones recorded were fast-spiking, and most fast-spiking cells tested (25 of 29 basket, 1 axo-axonic, and 5 of 6 bistratified cells) were PV-IR. However, 1 of 6 regular-spiking basket, 1 of 4 regular-spiking bistratified, and 3 of 5 burst-firing basket cells were also PV-IR. In contrast, the majority (17 of 27) of the CCK-IR neurones recorded were regular-spiking, 3 were burst-firing, and 7 were fast-spiking. These data confirm that the majority of PV-IR and CCK-IR axon terminals innervate proximal

  6. Why does allergic contact dermatitis exist?

    Science.gov (United States)

    McFadden, J P; Puangpet, P; Basketter, D A; Dearman, R J; Kimber, I

    2013-04-01

    The skin immune system's propensity to produce allergic contact dermatitis (ACD) to harmless chemicals, while otherwise being an efficient defence system, represents a dermatological paradox. We postulate that a major role in signalling in ACD is played by Toll-like receptor (TLR)2 and TLR4, and arises from their activation by extracellular danger-associated molecular patterns (DAMPs). Ligand activation of TLR4/2 results in the expression of interleukins (ILs) IL-1β, IL-6, IL-12, IL-18 and IL-23, tumour necrosis factor-α and interferon-α. These cytokines promote acquisition of sensitization, and facilitate elicitation of contact allergy via multiple mechanisms, including the recruitment of CD4+ Th1 and Th17 cells. As Th1 cells secrete large amounts of DAMPs, a DAMP immune circuit (positive-feedback loop) is created. This is an important driver of skin sensitization and skin inflammation. Pathogenic extracellular bacteria, but not commensal bacteria, produce pathogen-associated molecular pattern molecules, which stimulate the expression of Th1- and Th17-promoting cytokines via TLR2 and TLR4. This also induces an immune circuit. The ability of the skin immune system to activate host defence mechanisms and to distinguish between pathogenic bacteria and commensals provides an explanation for why skin sensitization and ACD develop, as they are processes that rely on the same biological pathways. These pathways may also shed light on the pathogenesis of chronic pustular inflammatory dermatoses (e.g. acne vulgaris). The existence of safety signals from commensal bacteria, which prevent initiation of these pathways, may provide opportunities for novel therapeutic approaches to the treatment of inflammatory skin diseases.

  7. Role of CCK-A receptor in the regulation of pancreatic bicarbonate secretion in conscious rats: a study in naturally occurring CCK-A receptor gene knockout rats.

    Science.gov (United States)

    Miyasaka, K; Suzuki, S; Kanai, S; Masuda, M; Funakoshi, A

    1999-10-01

    Whether cholecystokinin (CCK) has a direct action on duct cells and the role of CCK-A receptor in bicarbonate secretion were examined by comparing the results obtained from OLETF (CCK-A receptor-deficient rats) and control (LETO) rats. Rats were prepared with cannulae for draining bile and pancreatic juice separately, with two duodenal cannulae and an external jugular vein cannula. The experiments were conducted without anesthesia. The responses of bicarbonate secretion to intravenous infusion of CCK, acetyl-beta-methylcholine (Ach), and 2-deoxy-D-glucose (2DG), and to intraduodenal infusion of HCl and a liquid meal were examined. To examine the synergistic effect between CCK and secretin, the effect of CCK during a background secretin infusion was examined in LETO rats. CCK did not stimulate bicarbonate secretion in either strain, nor in LETO rats with secretin infusion. When gastric acid secretion was prevented by administration of omeprazole, Ach did not increase bicarbonate secretion, but 2DG did in both strains. Intraduodenal infusion of HCI and a liquid meal significantly increased bicarbonate secretion in both strains; however, the responses were much less in OLETF than LETO rats. In conclusion, intravenous injection of CCK did not stimulate bicarbonate secretion, and the lack of CCK-A receptor decreased bicarbonate secretion in response to luminal stimulants.

  8. Presynaptic P2 receptors?

    Science.gov (United States)

    Stone, T W; O'Kane, E M; Nikbakht, M R; Ross, F M

    2000-07-01

    Although the emphasis in ATP research has been on postjunctional receptors, there is also evidence for presynaptic receptors regulating transmitter release in the autonomic nervous system. Recent work has attempted to identify similar mechanisms in the central nervous system. Some of the existing results can be explained by the metabolism of nucleotides to adenosine or adenosine 5'-monophosphate (AMP). However, studies of presynaptic effects using sensitive electrophysiological tests such as paired-pulse interactions indicate that nucleotides can act at presynaptic sites, but that their effects may be mediated by a release of adenosine. Results are also described which indicate that, under some conditions, nucleotides can mediate phenomena such as long-term potentiation, which probably involves a significant presynaptic element. In part these effects may involve a nucleotide-induced release of adenosine and the simultaneous activation of P1 and P2 receptors.

  9. 八肽胆囊收缩素对TNF-α诱导的大鼠滑膜细胞株RSC-364 IL-6的作用及其可能的分子机制%Effects of cholecystokinin octapeptide on TNF- α- induced IL- 6 expression and its possible molecular mechanismin rat synovial cell strain RSC-364

    Institute of Scientific and Technical Information of China (English)

    赵占胜; 金玉怀; 丛斌; 李淑瑾; 徐锦荣; 姚玉霞; 凌亦凌

    2007-01-01

    AIM: To investigate the effect of sulfated cholecystokinin octapeptide (CCK -8 ) on TNF -α induced IL - 6 mRNA expression, NF - κB activation in the rat fibroblast - like synovial cell strain RSC - 364 and its possible receptor mechanisms. METHODS: RSC -364 cells were stimulated with TNF - α( 10 μg/L) in the presence or absence of sCCK- 8( 10-8 - 10-6 mol/L) or/and CCK receptor antagonist proglumide(2 mg/L). IL -6 and CCK receptor A/B (CCK- AR/CCK/BR) mRNA expression were assayed by reverse transcription polymerase chain reaction (RT- PCR) at 3 h after stimulation, and nuclear factor - κB (NF - κB) binding activity was analyzed by electrophoretic mobility shift assay (EMSA) at lh after stimulation. At 30 min of stimulation the IκB protein level in cytoplasma was measured by Western blotting. RESULTS: Both CCK - AR and CCK - BR were constitutively expressed on RSC - 364. sCCK - 8, at concentrations from 10-8 mol/L to 10 -6 mol/L, significantly increased IL - 6 mRNA expression, CCK - AR and CCK - BR mRNA expression, NF - κB binding activity and IκB protein degradation. The effects of sCCK - 8 on NF - κB activity and IκB degradation level were attenuated by CCK receptor antagonist proglumide. CONCLUSION: sCCK - 8 upregulats TNF - α- induced IL - 6 mRNA expression by NF - κB pathway through its receptor on rat synoviocytes, suggesting its possible regulatory role in the pathogenesis of rheumatoid arthritis.%目的:观察硫酸化八肽胆囊收缩素(sCCK-8)对TNF-α诱导大鼠滑膜细胞株RSC-364IL-6mRNA表达及核因子NF-κB的影响及其可能的受体机制.方法:大鼠滑膜细胞株RSC-364经TNF-α(10μg/L)、sCCK-8(10-8-10-6 mol/L)、CCK受体拮抗剂丙谷胺(2 mg/L)及溶剂单独或联合孵育3 h,用RT-PCR检测细胞IL-6、CCK-AR及CCK-BR mRNA的表达,孵育1 h,用电泳迁移率检测NF-κB活性,孵育30 min,用Western blotting检测胞浆IκB蛋白表达.结果:RSC-364细胞固有表达CCK-A/B受体,sCCK-8(10-8-10-6 mol/L)使IL-6

  10. 10 CFR 4.127 - Existing facilities.

    Science.gov (United States)

    2010-01-01

    ... 10 Energy 1 2010-01-01 2010-01-01 false Existing facilities. 4.127 Section 4.127 Energy NUCLEAR... 1973, as Amended Discriminatory Practices § 4.127 Existing facilities. (a) Accessibility. A recipient... make each of its existing facilities or every part of an existing facility accessible to and usable by...

  11. 28 CFR 41.57 - Existing facilities.

    Science.gov (United States)

    2010-07-01

    ... 28 Judicial Administration 1 2010-07-01 2010-07-01 false Existing facilities. 41.57 Section 41.57... Practices Program Accessibility § 41.57 Existing facilities. (a) A recipient shall operate each program or... existing facilities or every part of an existing facility accessible to and usable by handicapped...

  12. CCK(1) receptor is essential for normal meal patterning in mice fed high fat diet.

    Science.gov (United States)

    Donovan, Michael J; Paulino, Gabriel; Raybould, Helen E

    2007-12-05

    Cholecystokinin (CCK), released by lipid in the intestine, initiates satiety by acting at cholecystokinin type 1 receptors (CCK(1)Rs) located on vagal afferent nerve terminals located in the wall of the gastrointestinal tract. In the present study, we determined the role of the CCK(1)R in the short term effects of a high fat diet on daily food intake and meal patterns using mice in which the CCK(1)R gene is deleted. CCK(1)R(-/-) and CCK(1)R(+/+) mice were fed isocaloric high fat (HF) or low fat (LF) diets ad libitum for 18 h each day and meal size, meal frequency, intermeal interval, and meal duration were determined. Daily food intake was unaltered by diet in the CCK(1)R(-/-) compared to CCK(1)R(+/+) mice. However, meal size was larger in the CCK(1)R(-/-) mice compared to CCK(1)R(+/+) mice when fed a HF diet, with a concomitant decrease in meal frequency. Meal duration was increased in mice fed HF diet regardless of phenotype. In addition, CCK(1)R(-/-) mice fed a HF diet had a 75% decrease in the time to 1st meal compared to CCK(1)R(+/+) mice following a 6 h fast. These data suggest that lack of the CCK(1)R results in diminished satiation, causing altered meal patterns including larger, less frequent meals when fed a high fat diet. These results suggest that the CCK(1)R is involved in regulating caloric intake on a meal to meal basis, but that other factors are responsible for regulation of daily food intake.

  13. A chronic high fat diet alters the homologous and heterologous control of appetite regulating peptide receptor expression.

    Science.gov (United States)

    Kentish, Stephen J; Wittert, Gary A; Blackshaw, L Ashley; Page, Amanda J

    2013-08-01

    Leptin, ghrelin and neuropeptide W (NPW) modulate vagal afferent activity, which may underlie their appetite regulatory actions. High fat diet (HFD)-induced obesity induces changes in the plasma levels of these peptides and alters the expression of receptors on vagal afferents. We investigated homologous and heterologous receptor regulation by leptin, ghrelin and NPW. Mice were fed (12 weeks) a standard laboratory diet (SLD) or HFD. Nodose ganglia were cultured overnight in the presence or absence of each peptide. Leptin (LepR), ghrelin (GHS-R), NPW (GPR7) and cholecystokinin type-1 (CCK1R) receptor mRNA, and the plasma leptin, ghrelin and NPW levels were measured. SLD: leptin reduced LepR, GPR7, increased GHS-R and CCK1R mRNA; ghrelin increased LepR, GPR7, CCK1R, and decreased GHS-R. HFD: leptin decreased GHS-R and GPR7, ghrelin increased GHS-R and GPR7. NPW decreased all receptors except GPR7 which increased with HFD. Plasma leptin was higher and NPW lower in HFD. Thus, HFD-induced obesity disrupts inter-regulation of appetite regulatory receptors in vagal afferents.

  14. Role of CCK1 and Y2 receptors in activation of hindbrain neurons induced by intragastric administration of bitter taste receptor ligands.

    Science.gov (United States)

    Hao, Shuzhen; Sternini, Catia; Raybould, Helen E

    2008-01-01

    G-protein-coupled receptors signaling bitter taste (T2Rs) in the oral gustatory system and the alpha-subunit of the taste-specific G-protein gustducin are expressed in the gastrointestinal (GI) tract. alpha-Subunit of the taste-specific G-protein gustducin colocalizes with markers of enteroendocrine cells in human and mouse GI mucosa, including peptide YY. Activation of T2Rs increases cholecystokinin (CCK) release from the enteroendocrine cell line, STC-1. The aim of this study was to determine whether T2R agonists in the GI tract activate neurons in the nucleus of the solitary tract (NTS) and whether this activation is mediated by CCK and peptide YY acting at CCK(1) and Y(2) receptors. Immunocytochemistry for the protooncogene c-Fos protein, a marker for neuronal activation, was used to determine activation of neurons in the midregion of the NTS, the region where vagal afferents from the GI tract terminate. Intragastric administration of the T2R agonist denatonium benzoate (DB), or phenylthiocarbamide (PTC), or a combination of T2R agonists significantly increased the number of Fos-positive neurons in the mid-NTS; subdiaphragmatic vagotomy abolished the NTS response to the mixture of T2R agonists. Deletion of CCK(1) receptor gene or blockade of CCK(1) receptors with devazepide abolishes the activation of NTS neurons in response to DB, but had no effect on the response to PTC. Administration of the Y(2) receptor antagonist BIIE0246 blocks the activation of NTS neurons to DB, but not PTC. These findings suggest that activation of neurons in the NTS following administration of T2R agonists to the GI tract involves CCK(1) and Y(2) receptors located on vagal afferent terminals in the gut wall. T2Rs may regulate GI function via release of regulatory peptides and activation of the vagal reflex pathway.

  15. No more pain upon Gq-protein-coupled receptor activation: role of endocannabinoids.

    Science.gov (United States)

    Hu, Sherry Shu-Jung; Ho, Yu-Cheng; Chiou, Lih-Chu

    2014-02-01

    Marijuana has been used to relieve pain for centuries. The analgesic mechanism of its constituents, the cannabinoids, was only revealed after the discovery of cannabinoid receptors (CB1 and CB2) two decades ago. The subsequent identification of the endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG), and their biosynthetic and degradation enzymes discloses the therapeutic potential of compounds targeting the endocannabinoid system for pain control. Inhibitors of the anandamide and 2-AG degradation enzymes, fatty acid amide hydrolase and monoacylglycerol lipase, respectively, may be superior to direct cannabinoid receptor ligands as endocannabinoids are synthesized on demand and rapidly degraded, focusing action at generating sites. Recently, a promising strategy for pain relief was revealed in the periaqueductal gray (PAG). It is initiated by Gq-protein-coupled receptor (Gq PCR) activation of the phospholipase C-diacylglycerol lipase enzymatic cascade, generating 2-AG that produces inhibition of GABAergic transmission (disinhibition) in the PAG, thereby leading to analgesia. Here, we introduce the antinociceptive properties of exogenous cannabinoids and endocannabinoids, involving their biosynthesis and degradation processes, particularly in the PAG. We also review recent studies disclosing the Gq PCR-phospholipase C-diacylglycerol lipase-2-AG retrograde disinhibition mechanism in the PAG, induced by activating several Gq PCRs, including metabotropic glutamatergic (type 5 metabotropic glutamate receptor), muscarinic acetylcholine (M1/M3), and orexin 1 receptors. Disinhibition mediated by type 5 metabotropic glutamate receptor can be initiated by glutamate transporter inhibitors or indirectly by substance P, neurotensin, cholecystokinin and capsaicin. Finally, the putative role of 2-AG generated after activating the above neurotransmitter receptors in stress-induced analgesia is discussed.

  16. Plasma cholecystokinin in obese patients before and after jejunoileal bypass with 3:1 or 1:3 jejunoileal ratio--no role in the increased risk of gallstone formation

    DEFF Research Database (Denmark)

    Sørensen, T I; Toftdahl, D B; Højgaard, L

    1994-01-01

    bypass surgery with either a 1:3 jejunoileal ratio (n = 14) or a 3:1 ratio (n = 15), and in unoperated obese patients (n = 7). Plasma CCK levels were determined during fasting and during 150 min following ingestion of a liquid test meal. RESULTS: There were no significant changes over time following......BACKGROUND AND AIM: Jejunoileal bypass surgery for obesity increases the risk of gallstone formation, and, contrary to expectations, the incidence is greater in patients with a long as compared to a short ileum left in continuity. Impaired gallbladder motility due to reduced cholecystokinin (CCK......) stimulation could be an explanation. The aim of this study was to investigate the CCK levels in such patients. SETTING: The randomized trial of bypass surgery named The Danish Obesity Project. DESIGN AND METHODS: We compared plasma levels of CCK in obese patients at three, nine or 15 months after jejunoileal...

  17. Neuropeptide Y (NPY), cocaine- and amphetamine-regulated transcript (CART) and cholecystokinin (CCK) in winter skate (Raja ocellata): cDNA cloning, tissue distribution and mRNA expression responses to fasting.

    Science.gov (United States)

    MacDonald, Erin; Volkoff, Hélène

    2009-04-01

    cDNAs encoding for neuropeptide Y (NPY), cocaine- and amphetamine-regulated transcript (CART) and cholecystokinin (CCK) were cloned in an elasmobranch fish, the winter skate. mRNA tissue distribution was examined for the three peptides as well as the effects of two weeks of fasting on their expression. Skate NPY, CART and CCK sequences display similarities with sequences for teleost fish but in general the degree of identity is relatively low (50%). All three peptides are present in brain and in several peripheral tissues, including gut and gonads. Within the brain, the three peptides are expressed in the hypothalamus, telencephalon, optic tectum and cerebellum. Two weeks of fasting induced an increase in telencephalon NPY and an increase in CCK in the gut but had no effects on hypothalamic NPY, CART and CCK, or on telencephalon CART. Our results provide basis for further investigation into the regulation of feeding in winter skate.

  18. Mu opioid receptors are in discrete hippocampal interneuron subpopulations.

    Science.gov (United States)

    Drake, Carrie T; Milner, Teresa A

    2002-01-01

    In the rat hippocampal formation, application of mu opioid receptor (MOR) agonists disinhibits principal cells, promoting excitation-dependent processes such as epileptogenesis and long-term potentiation. However, the precise location of MORs in particular inhibitory circuits, has not been determined, and the roles of MORs in endogenous functioning are unclear. To address these issues, the distribution of MOR-like immunoreactivity (-li) was examined in several populations of inhibitory hippocampal neurons in the CA1 region using light and electron microscopy. We found that MOR-li was present in many parvalbumin-containing basket cells, but absent from cholecystokinin-labeled basket cells. MOR-li was also commonly in interneurons containing somatostatin-li or neuropeptide Y-li that resembled the "oriens-lacunosum-moleculare" (O-LM) interneurons innervating pyramidal cell distal dendrites. Finally, MOR-li was in some vasoactive intestinal peptide- or calretinin-containing profiles resembling interneurons that primarily innervate other interneurons. These findings indicate that MOR-containing neurons form a neurochemically and functionally heterogeneous subset of hippocampal GABAergic neurons. MORs are most frequently on interneurons that are specialized to inhibit pyramidal cells, and are on a limited number of interneurons that target other interneurons. Moreover, the distribution of MORs to different neuronal types in several laminae, some relatively far from endogenous opioids, suggests normal functional roles that are different from the actions seen with exogenous agonists such as morphine.

  19. Central nesfatin-1 reduces dark-phase food intake and gastric emptying in rats: differential role of corticotropin-releasing factor2 receptor.

    Science.gov (United States)

    Stengel, Andreas; Goebel, Miriam; Wang, Lixin; Rivier, Jean; Kobelt, Peter; Mönnikes, Hubert; Lambrecht, Nils W G; Taché, Yvette

    2009-11-01

    Nesfatin-1, derived from nucleobindin2, is expressed in the hypothalamus and reported in one study to reduce food intake (FI) in rats. To characterize the central anorexigenic action of nesfatin-1 and whether gastric emptying (GE) is altered, we injected nesfatin-1 into the lateral brain ventricle (intracerebroventricular, icv) or fourth ventricle (4v) in chronically cannulated rats or into the cisterna magna (intracisternal, ic) under short anesthesia and compared with ip injection. Nesfatin-1 (0.05 microg/rat, icv) decreased 2-3 h and 3-6 h dark-phase FI by 87 and 45%, respectively, whereas ip administration (2 microg/rat) had no effect. The corticotropin-releasing factor (CRF)(1)/CRF(2) antagonist astressin-B or the CRF(2) antagonist astressin(2)-B abolished icv nesfatin-1's anorexigenic action, whereas an astressin(2)-B analog, devoid of CRF-receptor binding affinity, did not. Nesfatin-1 icv induced a dose-dependent reduction of GE by 26 and 43% that was not modified by icv astressin(2)-B. Nesfatin-1 into the 4v (0.05 microg/rat) or ic (0.5 microg/rat) decreased cumulative dark-phase FI by 29 and 60% at 1 h and by 41 and 37% between 3 and 5 h, respectively. This effect was neither altered by ic astressin(2)-B nor associated with changes in GE. Cholecystokinin (ip) induced Fos expression in 43% of nesfatin-1 neurons in the paraventricular hypothalamic nucleus and 24% of those in the nucleus tractus solitarius. These data indicate that nesfatin-1 acts centrally to reduce dark phase FI through CRF(2)-receptor-dependent pathways after forebrain injection and CRF(2)-receptor-independent pathways after hindbrain injection. Activation of nesfatin-1 neurons by cholecystokinin at sites regulating food intake may suggest a role in gut peptide satiation effect.

  20. CCK1 and CCK2 Receptors Are Expressed on Pancreatic Stellate Cells and Induce Collagen Production

    Science.gov (United States)

    Berna, Marc J.; Seiz, Oliver; Nast, Jan Friso; Benten, Daniel; Bläker, Michael; Koch, Johannes; Lohse, Ansgar W.; Pace, Andrea

    2010-01-01

    The gastrointestinal hormone cholecystokinin (CCK) can induce acute pancreatitis in rodents through its action on acinar cells. Treatment with CCK, in combination with other agents, represents the most commonly used model to induce experimental chronic pancreatitis. Pancreatic stellate cells (PSC) are responsible for pancreatic fibrosis and therefore play a predominant role in the genesis of chronic pancreatitis. However, it is not known whether PSC express CCK receptors. Using real time PCR techniques, we demonstrate that CCK1 and CCK2 receptors are expressed on rat PSC. Interestingly both CCK and gastrin significantly induced type I collagen synthesis. Moreover, both inhibit proliferation. These effects are comparable with TGF-β-stimulated PSC. Furthermore, the natural agonists CCK and gastrin induce activation of pro-fibrogenic pathways Akt, ERK, and Src. Using specific CCK1 and CCK2 receptor (CCK2R) inhibitors, we found that Akt activation is mainly mediated by CCK2R. Akt activation by CCK and gastrin could be inhibited by the PI3K inhibitor wortmannin. Activation of ERK and the downstream target Elk-1 could be inhibited by the MEK inhibitor U0126. These data suggest that CCK and gastrin have direct activating effects on PSC, are able to induce collagen synthesis in these cells, and therefore appear to be important regulators of pancreatic fibrogenesis. Furthermore, similar to TGF-β, both CCK and gastrin inhibit proliferation in PSC. PMID:20843811

  1. Gut bitter taste receptor signalling induces ABCB1 through a mechanism involving CCK.

    Science.gov (United States)

    Jeon, Tae-Il; Seo, Young-Kyo; Osborne, Timothy F

    2011-08-15

    T2Rs (bitter taste-sensing type 2 receptors) are expressed in the oral cavity to prevent ingestion of dietary toxins through taste avoidance. They are also expressed in other cell types, including gut enteroendocrine cells, where their physiological role is enigmatic. Previously, we proposed that T2R-dependent CCK (cholecystokinin) secretion from enteroendocrine cells limits absorption of dietary toxins, but an active mechanism was lacking. In the present study we show that T2R signalling activates ABCB1 (ATP-binding cassette B1) in intestinal cells through a CCK signalling mechanism. PTC (phenylthiocarbamide), an agonist for the T2R38 bitter receptor, increased ABCB1 expression in both intestinal cells and mouse intestine. PTC induction of ABCB1 was decreased by either T2R38 siRNA (small interfering RNA) or treatment with YM022, a gastrin receptor antagonist. Thus gut ABCB1 is regulated through signalling by CCK/gastrin released in response to PTC stimulation of T2R38 on enteroendocrine cells. We also show that PTC increases the efflux activity of ABCB1, suggesting that T2R signalling limits the absorption of bitter tasting/toxic substances through modulation of gut efflux membrane transporters.

  2. Distribution of melatonin receptor in human fetal brain

    Institute of Scientific and Technical Information of China (English)

    WANG Guo-quan; SHAO Fu-yuan; ZHAO Ying; LIU Zhi-min

    2001-01-01

    Objective: To study the distribution of 2 kinds of melatonin receptor subtypes (mtl and MT2) in human fetal brain. Methods: The fetal brain tissues were sliced and the distribution ofmelatonin receptors in human fetal brain were detected using immunohistochemistry and in situ hybridization. Results: Melatonin receptor mtl existed in the cerebellun and hypothalamus, melatonin receptor MT2 exists in hypothalamus, occipital and medulla. Conclusion: Two kinds of melatonin receptors, mtl and MT2 exist in the membrane and cytosol of brain cells, indicating that human fetal brain is a target organ of melatonin.

  3. NCBI nr-aa BLAST: CBRC-FRUB-02-0193 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-FRUB-02-0193 ref|NP_001079277.1| cholecystokinin A receptor [Xenopus laevis] sp|P70031|CCKAR_XENLA Chol...ecystokinin receptor (CCK-XLR) gb|AAB09052.1| cholecystokinin receptor NP_001079277.1 1e-137 61% ...

  4. 10 CFR 611.206 - Existing facilities.

    Science.gov (United States)

    2010-01-01

    ... 10 Energy 4 2010-01-01 2010-01-01 false Existing facilities. 611.206 Section 611.206 Energy... PROGRAM Facility/Funding Awards § 611.206 Existing facilities. The Secretary shall, in making awards to those manufacturers that have existing facilities, give priority to those facilities that are oldest or...

  5. 45 CFR 1170.32 - Existing facilities.

    Science.gov (United States)

    2010-10-01

    ... 45 Public Welfare 3 2010-10-01 2010-10-01 false Existing facilities. 1170.32 Section 1170.32... ASSISTED PROGRAMS OR ACTIVITIES Accessibility § 1170.32 Existing facilities. (a) Accessibility. A recipient... require a recipient to make each of its existing facilities or every part of a facility accessible to and...

  6. 45 CFR 1151.22 - Existing facilities.

    Science.gov (United States)

    2010-10-01

    ... 45 Public Welfare 3 2010-10-01 2010-10-01 false Existing facilities. 1151.22 Section 1151.22... Prohibited Accessibility § 1151.22 Existing facilities. (a) A recipient shall operate each program or... make each of its existing facilities or every part of a facility accessible to and usable by...

  7. 14 CFR 1251.301 - Existing facilities.

    Science.gov (United States)

    2010-01-01

    ... 14 Aeronautics and Space 5 2010-01-01 2010-01-01 false Existing facilities. 1251.301 Section 1251... HANDICAP Accessibility § 1251.301 Existing facilities. (a) Accessibility. A recipient shall operate each... existing facilities or every part of a facility accessible to and usable by handicapped persons. (b...

  8. 45 CFR 605.22 - Existing facilities.

    Science.gov (United States)

    2010-10-01

    ... 45 Public Welfare 3 2010-10-01 2010-10-01 false Existing facilities. 605.22 Section 605.22 Public... Accessibility § 605.22 Existing facilities. (a) Accessibility. A recipient shall operate each program or... existing facilities or every part of a facility accessible to and usable by qualified handicapped persons...

  9. 34 CFR 104.22 - Existing facilities.

    Science.gov (United States)

    2010-07-01

    ... 34 Education 1 2010-07-01 2010-07-01 false Existing facilities. 104.22 Section 104.22 Education... Accessibility § 104.22 Existing facilities. (a) Accessibility. A recipient shall operate its program or activity.... This paragraph does not require a recipient to make each of its existing facilities or every part of a...

  10. 28 CFR 42.521 - Existing facilities.

    Science.gov (United States)

    2010-07-01

    ... 28 Judicial Administration 1 2010-07-01 2010-07-01 false Existing facilities. 42.521 Section 42...-Implementation of Section 504 of the Rehabilitation Act of 1973 Accessibility § 42.521 Existing facilities. (a... section does not require a recipient to make each of its existing facilities or every part of a...

  11. 45 CFR 1232.14 - Existing facilities.

    Science.gov (United States)

    2010-10-01

    ... 45 Public Welfare 4 2010-10-01 2010-10-01 false Existing facilities. 1232.14 Section 1232.14... ASSISTANCE Accessibility § 1232.14 Existing facilities. (a) A recipient shall operate each program or... existing facilities or every part of a facility accessible to and usable by handicapped persons. (b)...

  12. 28 CFR 35.150 - Existing facilities.

    Science.gov (United States)

    2010-07-01

    ... 28 Judicial Administration 1 2010-07-01 2010-07-01 false Existing facilities. 35.150 Section 35... STATE AND LOCAL GOVERNMENT SERVICES Program Accessibility § 35.150 Existing facilities. (a) General. A... paragraph does not— (1) Necessarily require a public entity to make each of its existing...

  13. Research on Inequalities Exists in the Workplace

    Institute of Scientific and Technical Information of China (English)

    布乃鹏; 樊晶晶; 刘淑华

    2013-01-01

    The is ue of inequalities exists in the workplace has been widely debated in our community recently. And then this essay wil argue inequalities exist in the workplace, in terms of ethnic, gender, and disability. This es ay would of er four perspectives about the view inequalities exist in the workplace and discuss the response from the state, employers and unions.

  14. Lipoxin Receptors

    Directory of Open Access Journals (Sweden)

    Mario Romano

    2007-01-01

    Full Text Available Lipoxins (LXs represent a class of arachidonic acid (AA metabolites that carry potent immunoregulatory and anti-inflammatory properties, LXA4 and LXB4 being the main components of this series. LXs are generated by cooperation between 5-lipoxygenase (LO and 12- or 15-LO during cell-cell interactions or by single cell types. LX epimers at carbon 15, the 15-epi-LXs, are formed by aspirin-acetylated cyclooxygenase-2 (COX-2 in cooperation with 5-LO. 15-epi-LXA4 is also termed aspirin-triggered LX (ATL. In vivo studies with stable LX and ATL analogs have established that these eicosanoids possess potent anti-inflammatory activities. A LXA4 receptor has been cloned. It belongs to the family of chemotactic receptors and clusters with formyl peptide receptors on chromosome 19. Therefore, it was initially denominated formyl peptide receptor like 1 (FPRL1. This receptor binds with high affinity and stereoselectivity LXA4 and ATL. It also recognizes a variety of peptides, synthetic, endogenously generated, or disease associated, but with lower affinity compared to LXA4. For this reason, this receptor has been renamed ALX. This review summarizes the current knowledge on ALX expression, signaling, and potential pathophysiological role. The involvement of additional recognition sites in LX bioactions is also discussed.

  15. Existence conditions for unknown input functional observers

    Science.gov (United States)

    Fernando, T.; MacDougall, S.; Sreeram, V.; Trinh, H.

    2013-01-01

    This article presents necessary and sufficient conditions for the existence and design of an unknown input Functional observer. The existence of the observer can be verified by computing a nullspace of a known matrix and testing some matrix rank conditions. The existence of the observer does not require the satisfaction of the observer matching condition (i.e. Equation (16) in Hou and Muller 1992, 'Design of Observers for Linear Systems with Unknown Inputs', IEEE Transactions on Automatic Control, 37, 871-875), is not limited to estimating scalar functionals and allows for arbitrary pole placement. The proposed observer always exists when a state observer exists for the unknown input system, and furthermore, the proposed observer can exist even in some instances when an unknown input state observer does not exist.

  16. [Olfactory esthesioneuroblastoma: scintigraphic expression of somatostatin receptors].

    Science.gov (United States)

    García Vicente, A; García Del Castillo, E; Soriano Castrejón, A; Alonso Farto, J

    1999-10-01

    Esthesioneuroblastoma is an uncommon tumor originating in the upper nasal cavity and constitutes 3% of all intranasal neoplasms. Few references exist about the expression of somatostatin receptors in these tumors. Our case demonstrates a good correlation between the somatostatin receptor scintigraphy and magnetic resonance imaging.

  17. Asymptotic Existence of Nearly Kirkman Systems

    Institute of Scientific and Technical Information of China (English)

    沈灏; 储文松

    1994-01-01

    It is proved in this paper that,for any given positive integer k≥2,there exists a constant v0=v0(k) such that for v≥v0,the necessary condition v=0 (mod k(k-)) for the existence of a nearly Kirkman system NKS (2,k,v) is also sufficient.Thus we have completely determined the asymptotic existence of NKS.

  18. Do Phantom Cuntz-Krieger Algebras Exist?

    DEFF Research Database (Denmark)

    Arklint, Sara E.

    2013-01-01

    If phantom Cuntz-Krieger algebras do not exist, then purely infinite Cuntz-Krieger algebras can be characterized by outer properties. In this survey paper, a summary of the known results on non-existence of phantom Cuntz-Krieger algebras is given......If phantom Cuntz-Krieger algebras do not exist, then purely infinite Cuntz-Krieger algebras can be characterized by outer properties. In this survey paper, a summary of the known results on non-existence of phantom Cuntz-Krieger algebras is given...

  19. Opioid Receptors.

    Science.gov (United States)

    Stein, Christoph

    2016-01-01

    Opioids are the oldest and most potent drugs for the treatment of severe pain. Their clinical application is undisputed in acute (e.g., postoperative) and cancer pain, but their long-term use in chronic pain has met increasing scrutiny. This article reviews mechanisms underlying opioid analgesia and other opioid actions. It discusses the structure, function, and plasticity of opioid receptors; the central and peripheral sites of analgesic actions and side effects; endogenous and exogenous opioid receptor ligands; and conventional and novel opioid compounds. Challenging clinical situations, such as the tension between chronic pain and addiction, are also illustrated.

  20. God exists with probability 1/(H+1)

    CERN Document Server

    Hoey, Jesse

    2012-01-01

    This note will address the issue of the existence of God from a game theoretic perspective. We will show that, under certain assumptions, man cannot simultaneously be (i) rational and (ii) believe that an infinitely powerful God exists. Game theory and decision theory have long been used to address this thorny question.

  1. Existence Regions of Shock Wave Triple Configurations

    Science.gov (United States)

    Bulat, Pavel V.; Chernyshev, Mikhail V.

    2016-01-01

    The aim of the research is to create the classification for shock wave triple configurations and their existence regions of various types: type 1, type 2, type 3. Analytical solutions for limit Mach numbers and passing shock intensity that define existence region of every type of triple configuration have been acquired. The ratios that conjugate…

  2. On the existence of consistent price systems

    DEFF Research Database (Denmark)

    Bayraktar, Erhan; Pakkanen, Mikko S.; Sayit, Hasanjan

    2014-01-01

    We formulate a sufficient condition for the existence of a consistent price system (CPS), which is weaker than the conditional full support condition (CFS). We use the new condition to show the existence of CPSs for certain processes that fail to have the CFS property. In particular this condition...

  3. Non-existence of KAM Torus

    Institute of Scientific and Technical Information of China (English)

    Chong Qing CHENG

    2011-01-01

    Given an integrable Hamiltonian ho with n-degrees of freedom and a Diophantine frequency w, then, arbitrarily close to ho in the Cr topology with r < 2n, there exists an analytical Hamiltonian h∈ with no KAM torus of rotation vector w. In contrast with it, KAM tori exist if perturbations are small in Cr topology with r > 2n.

  4. Structural reliability of existing city bridges

    NARCIS (Netherlands)

    Hellebrandt, L.; Steenbergen, R.; Vrouwenvelder, T.; Blom, K.

    2015-01-01

    Full probabilistic reliability analysis may be valuable for assessing existing structures. Measures for increasing the safety level are quite costly for existing structures and may be unnecessary when such a decision is grounded on a conservative analysis for determining the structural reliability.

  5. 10 CFR 1040.72 - Existing facilities.

    Science.gov (United States)

    2010-01-01

    ... 10 Energy 4 2010-01-01 2010-01-01 false Existing facilities. 1040.72 Section 1040.72 Energy... § 1040.72 Existing facilities. (a) Accessibility. A recipient shall operate any program or activity to... facilities or every part of a facility accessible to and useable by handicapped persons. (b) Methods. A...

  6. On determining if a specular point exists

    DEFF Research Database (Denmark)

    Rusch, W; Sørensen, O

    1979-01-01

    A technique is presented whereby the existence of a specular point on a convex surface of revolution can be determined without actually finding it. Only the evaluation of two simple algebraic expressions is involved. Should a specular point be found not to exist, a search procedure has been thereby...

  7. Some existence and sufficient conditions of optimality

    Science.gov (United States)

    Assefi, T.

    1976-01-01

    The role of the existence and sufficiency conditions in the field of optimal control was briefly described. The existence theorems are discussed for general nonlinear systems. However, the sufficiency conditions pertain to "nearly" linear systems with integral convex costs. Moreover, a brief discussion of linear systems with multiple-cost functions is presented.

  8. 43 CFR 17.217 - Existing facilities.

    Science.gov (United States)

    2010-10-01

    ... 43 Public Lands: Interior 1 2010-10-01 2010-10-01 false Existing facilities. 17.217 Section 17.217... facilities. (a) Accessibility. A recipient shall operate each program or activity so that when each part is... not require a recipient to make each of its existing facilities or every part of a facility...

  9. Existence test for asynchronous interval iterations

    DEFF Research Database (Denmark)

    Madsen, Kaj; Caprani, O.; Stauning, Ole

    1997-01-01

    In the search for regions that contain fixed points ofa real function of several variables, tests based on interval calculationscan be used to establish existence ornon-existence of fixed points in regions that are examined in the course ofthe search. The search can e.g. be performed...... as a synchronous (sequential) interval iteration:In each iteration step all components of the iterate are calculatedbased on the previous iterate. In this case it is straight forward to base simple interval existence and non-existencetests on the calculations done in each step of the iteration. The search can also...... be performed as an asynchronous (parallel) iteration: Only a few components are changed in each stepand this calculation is in general based on components from differentprevious iterates. For the asynchronous iteration it turns out thatsimple tests of existence and non-existence can be based...

  10. Wykrzyknik - istnienie - zmiana (Exclamation - Existence - Change

    Directory of Open Access Journals (Sweden)

    Maciej Karpiński

    2011-06-01

    Full Text Available It, what exists, so to say, demands for the addressee – the thing exists in the face of (for something (or somebody. In other words, the existence is the relation. The competitive conception of the existence outside the relation (existence isolated leads to the contradiction. The existential proposition ‘Some A exists’, understoodliterally, is the pleonasm. It tends to treat the existential proposition as the conventional figure, expressing the simple act of an A affirmation (the exclamation ‘A!’. The existence’s relation should not be narrowed down only to the relation of perception(esse est percipi. It is needed to be understood widely, as every relation, in which something influences on whatever (that is, some change occurs. This influence (change can take place both inside or outside the consciousness. The existing thing, the influence exerted by it, and the change, occurred as the result of this influence, are identical. Thanks to it, we can eliminate difficulties connected withfinding ‘the point of contact’ between modules of the existence’s relation (that is, ‘the place’ where existing thing and its addressee are connected. The existence, as the relation of influence-change, is modal and gradual (as regards both intensity and extensiveness: the thing, in different aspects, can exist more or less. Theoretically, discussed relation can be symmetrical or antisymmetrical. The concept of error should be redefined. The error concerning the existence (resp. the nonexistence of specified thing, must not mean the incompatibility between this thing and the perception (widely: between this thing and the change causedby this thing in its addressee. The existence is the unity of the thing-perception (resp. the thing-influence-change. That is why the incompatibility can occur only between the state of thing-perception (resp. the thing-influence-change and the related state of duty. The conception of the existence as the relation

  11. Regulation of nutrition-associated receptors in blood monocytes of normal weight and obese humans.

    Science.gov (United States)

    Pivovarova, Olga; Hornemann, Silke; Weimer, Sandra; Lu, Ye; Murahovschi, Veronica; Zhuk, Sergei; Seltmann, Anne-Cathrin; Malashicheva, Anna; Kostareva, Anna; Kruse, Michael; Busjahn, Andreas; Rudovich, Natalia; Pfeiffer, Andreas F H

    2015-03-01

    Obesity, type 2 diabetes and associated metabolic diseases are characterized by low-grade systemic inflammation which involves interplay of nutrition and monocyte/macrophage functions. We suggested that some factors such as nutrient components, neuropeptides involved in the control of gastrointestinal functions, and gastrointestinal hormones might influence immune cell functions and in this way contribute to the disease pathogenesis. The aim of this study was to investigate the mRNA expression of twelve nutrition-associated receptors in peripheral blood mononuclear cells (PBMC), isolated monocytes and monocyte-derived macrophages and their regulation under the switching from the high-carbohydrate low-fat diet to the low-carbohydrate high-fat (LC/HFD) isocaloric diet in healthy humans. The mRNA expression of receptors for short chain fatty acids (GPR41, GPR43), bile acids (TGR5), incretins (GIPR, GLP1R), cholecystokinin (CCKAR), neuropeptides VIP and PACAP (VIPR1, VIPR2), and neurotensin (NTSR1) was detected in PBMC and monocytes, while GPR41, GPR43, GIPR, TGR5, and VIPR1 were found in macrophages. Correlations of the receptor expression in monocytes with a range of metabolic and inflammatory markers were found. In non-obese subjects, the dietary switch to LC/HFD induced the increase of GPR43 and VIPR1 expression in monocytes. No significant differences of receptor expression between normal weight and moderately obese subjects were found. Our study characterized for the first time the expression pattern of nutrition-associated receptors in human blood monocytes and its dietary-induced changes linking metabolic responses to nutrition with immune functions in health and metabolic diseases. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Existence and non-existence results for the SU(3) singular Toda system on compact surfaces

    OpenAIRE

    Battaglia, Luca; Malchiodi, Andrea

    2015-01-01

    We consider the SU(3) Toda system on a compact surface. We give both existence and non-existence results under some conditions on the parameters. Existence results are obtained using variational methods, which involve a geometric inequality of new type; non-existence results are obtained using blow-up analysis and localized Pohozaev identities.

  13. Neto Auxiliary Subunits Regulate Interneuron Somatodendritic and Presynaptic Kainate Receptors to Control Network Inhibition

    Directory of Open Access Journals (Sweden)

    Megan S. Wyeth

    2017-08-01

    Full Text Available Although Netos are considered auxiliary subunits critical for kainate receptor (KAR function, direct evidence for their regulation of native KARs is limited. Because Neto KAR regulation is GluK subunit/Neto isoform specific, such regulation must be determined in cell-type-specific contexts. We demonstrate Neto1/2 expression in somatostatin (SOM-, cholecystokinin/cannabinoid receptor 1 (CCK/CB1-, and parvalbumin (PV-containing interneurons. KAR-mediated excitation of these interneurons is contingent upon Neto1 because kainate yields comparable effects in Neto2 knockouts and wild-types but fails to excite interneurons or recruit inhibition in Neto1 knockouts. In contrast, presynaptic KARs in CCK/CB1 interneurons are dually regulated by both Neto1 and Neto2. Neto association promotes tonic presynaptic KAR activation, dampening CCK/CB1 interneuron output, and loss of this brake in Neto mutants profoundly increases CCK/CB1 interneuron-mediated inhibition. Our results confirm that Neto1 regulates endogenous somatodendritic KARs in diverse interneurons and demonstrate Neto regulation of presynaptic KARs in mature inhibitory presynaptic terminals.

  14. Glucagon-like peptide-1 receptor agonists increase pancreatic mass by induction of protein synthesis.

    Science.gov (United States)

    Koehler, Jacqueline A; Baggio, Laurie L; Cao, Xiemin; Abdulla, Tahmid; Campbell, Jonathan E; Secher, Thomas; Jelsing, Jacob; Larsen, Brett; Drucker, Daniel J

    2015-03-01

    Glucagon-like peptide-1 (GLP-1) controls glucose homeostasis by regulating secretion of insulin and glucagon through a single GLP-1 receptor (GLP-1R). GLP-1R agonists also increase pancreatic weight in some preclinical studies through poorly understood mechanisms. Here we demonstrate that the increase in pancreatic weight following activation of GLP-1R signaling in mice reflects an increase in acinar cell mass, without changes in ductal compartments or β-cell mass. GLP-1R agonists did not increase pancreatic DNA content or the number of Ki67(+) cells in the exocrine compartment; however, pancreatic protein content was increased in mice treated with exendin-4 or liraglutide. The increased pancreatic mass and protein content was independent of cholecystokinin receptors, associated with a rapid increase in S6 phosphorylation, and mediated through the GLP-1R. Rapamycin abrogated the GLP-1R-dependent increase in pancreatic mass but had no effect on the robust induction of Reg3α and Reg3β gene expression. Mass spectrometry analysis identified GLP-1R-dependent upregulation of Reg family members, as well as proteins important for translation and export, including Fam129a, eIF4a1, Wars, and Dmbt1. Hence, pharmacological GLP-1R activation induces protein synthesis, leading to increased pancreatic mass, independent of changes in DNA content or cell proliferation in mice.

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

    Directory of Open Access Journals (Sweden)

    Fior-Chadi D.R.

    1998-01-01

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

  16. Existence theorems for ordinary differential equations

    CERN Document Server

    Murray, Francis J

    2007-01-01

    Theorems stating the existence of an object-such as the solution to a problem or equation-are known as existence theorems. This text examines fundamental and general existence theorems, along with the Picard iterants, and applies them to properties of solutions and linear differential equations.The authors assume a basic knowledge of real function theory, and for certain specialized results, of elementary functions of a complex variable. They do not consider the elementary methods for solving certain special differential equations, nor advanced specialized topics; within these restrictions, th

  17. Physical Relativism as an Interpretation of Existence

    CERN Document Server

    Heinrich, Stuart

    2013-01-01

    Despite the success of modern physics in formulating mathematical theories that can predict the outcome of quantum-scale experiments, the physical interpretations of these theories remain controversial. In this manuscript, we propose a new interpretation of existence that we call physical relativism. Under physical relativism, the difference between mathematical existence and physical existence is clarified, and Wheeler's `it from bit' viewpoint can be objectively evaluated. In addition, physical relativism provides a simple answer to the question of why the universe exists at all, and permits us to derive the maximally biophilic principle, a generalization of the anthropic principle that ascribes high prior likelihood to the observation of a universe with simple physical laws supporting the overall concepts of time, space and the emergent evolution of life.

  18. US Forest Service LANDFIRE Existing Vegetation

    Data.gov (United States)

    US Forest Service, Department of Agriculture — LANDFIRE Existing Vegetation is mapped using predictive landscape models based on extensive field-referenced data, satellite imagery and biophysical gradient layers...

  19. LANDFIRE (90m) Existing Vegetation Type

    Data.gov (United States)

    U.S. Geological Survey, Department of the Interior — This map depicts the distribution of existing vegetation types contained in the LANDFIRE dataset. All 30-meter EVT grids were resampled to 90-meter grids and merged...

  20. Pre-Existing Condition Insurance Plan Data

    Data.gov (United States)

    U.S. Department of Health & Human Services — The Affordable Care Act created the new Pre-Existing Condition Insurance Plan (PCIP) program to make health insurance available to Americans denied coverage by...

  1. Do labour supply and demand curves exist?

    OpenAIRE

    Fleetwood, S.

    2014-01-01

    The objective of this paper is to show that circumstantial and empirical evidence for the existence of labour supply and demand curves is at best inconclusive and at worst casts doubt on their existence. Because virtually all orthodox models of labour markets, simple and complex, are built upon the foundation stones of labour supply and demand curves, these models lack empirically supported foundations. Orthodox labour economists must, therefore, either provide stronger evidence or stop using...

  2. Constraint for the Existence of Ellipsoidal Vesicles

    Institute of Scientific and Technical Information of China (English)

    XIE Yu-Zhang

    2000-01-01

    Under the spontaneous curvature model of lipid bilayers, the constraints for the existence of equilibrium axisym metric oblate and prolate ellipsoidal vesicles are obtained from the general shape equation. They degenerate either to the constraint for the existence of a spherical vesicle or to that of a circular cylindrical vesicle given by Ou-Yang and Helfrich [Phys. Rev. Lett. 59 (1987) 2486; 60(1988)120; Phys. Rev. A 39 (1989) 5280].

  3. Functional interpretation and the existence property

    DEFF Research Database (Denmark)

    Jørgensen, Klaus Frovin

    2004-01-01

    It is shown that functional interpretation can be used to show the existence property of intuitionistic number theory. On the basis of truth variants a comparison is then made between realisability and functional interpretation showing a structural difference between the two.......It is shown that functional interpretation can be used to show the existence property of intuitionistic number theory. On the basis of truth variants a comparison is then made between realisability and functional interpretation showing a structural difference between the two....

  4. CZT imaging detectors for ProtoEXIST

    CERN Document Server

    Hong, J; Chammas, N; Copete, A; Baker, R G; Barthelmy, S D; Gehrels, N; Cook, W R; Burnham, J A; Harrison, F A; Collins, J; Craig, W W

    2006-01-01

    We describe the detector development for a balloon-borne wide-field hard X-ray (20 - 600 keV) telescope, ProtoEXIST. ProtoEXIST is a pathfinder for both technology and science of the proposed implementation of the Black Hole Finder Probe, Energetic X-ray Imaging Survey telescope (EXIST). The principal technology challenge is the development of large area, close-tiled modules of imaging CZT detectors (1000 cm2 for ProtoEXIST1). We review the updates of the detector design and package concept for ProtoEXIST1 and report the current development status of the CZT detectors, using calibration results of our basic detector unit - 2 x 2 x 0.5 cm CZT crystals with 2.5 mm pixels (8 x 8 array). The current prototype (Rev1) of our detector crystal unit (DCU) shows ~4.5 keV electronics noise (FWHM), and the radiation measurements show the energy resolution (FWHM) of the units is 4.7 keV (7.9%) at 59.5 keV, 5.6 keV (4.6%) at 122 keV, and 7.6 keV (2.1%) at 356 keV. The new (Rev2) DCU with revised design is expected to impro...

  5. Objetos intencionais e existência objetiva

    Directory of Open Access Journals (Sweden)

    Jairo José da Silva

    1991-12-01

    Full Text Available Neste artigo quero apontar para a possibilidade de uma ontologia da matemática que, mesmo mantendo alguns pontos em comum com o platonismo e com o construtivismo, desliga-se destes em outros pontos essenciais. Por objeto matemático entendo o foco referencial do discurso matemático, ou seja, aquilo sobre o qual a matemática fala. Entendo que a existência destes objetos é meramente intencional, presuntiva, mas, simultaneamente, objetiva, no sentido de ser uma existência comunalizada, compartilhada por todos aqueles engajados no fazer matemático. A existência objetiva das entidades matemáticas não está, entretanto, garantida de uma vez por todas, mas apenas enquanto o discurso matemático for consistente. Este é o espírito do critério de existência objetiva enunciado que, acredito, deve sustentar uma ontologia matemática sem o pressuposto da existência independente de um domínio de objetos matemáticos, sem o empobrecimento que lhe impõem as diferentes versões construtivistas e sem a aniquilação que lhe infringe o formalismo sem objetos.

  6. Cytokine-Leukotriene Receptor Interactions

    Directory of Open Access Journals (Sweden)

    Marek Rola-Pleszczynski

    2007-01-01

    Full Text Available Biochemical and pharmacological studies have identified the structure of leukotrienes, the pathways that lead to their synthesis, and the signaling events they trigger when they interact with their cognate receptors. A privileged interaction exists between these lipid mediators and another group of molecules essential for inflammation and immune modulation, namely, cytokines. Whereas leukotrienes can trigger the synthesis and release of selected cytokines in distinct cell populations, many cytokines can affect cellular responsiveness to leukotrienes by modulating leukotriene receptor expression. As we progressively begin to unravel these complex interactions, new areas of cell-cell communication and eventual therapeutic interventions will emerge.

  7. Role of CCK/gastrin receptors in gastrointestinal/metabolic diseases and results of human studies using gastrin/CCK receptor agonists/antagonists in these diseases

    Science.gov (United States)

    Berna, Marc J.; Jensen, Robert T.

    2009-01-01

    In this paper, the estabished and possible roles of CCK1 and CCK2 receptors in gastrointestinal (GI) and metabolic diseases are reviewed and available results from human agonist/antagonist studies are discussed. While there is evidence for the involvement of CCK1R in numerous diseases including pancreatic disorders, motility disorders, tumor growth, regulation of satiety and a number of CCK-deficient states, the role of CCK1R in these conditions is not clearly defined. There are encouraging data from several clinical studies of CCK1R antagonists in some of these conditions, but their role as therapeutic agents remains unclear. The role of CCK2R in physiological (atrophic gastritis, pernicious anemia) and pathological (Zollinger-Ellison syndrome) hypergastrinemic states, its effects on the gastric mucosa (ECL cell hyperplasia, carcinoids, parietal cell mass) and its role in acid-peptic disorders are clearly defined. Furthermore, recent studies point to a possible role for CCK2R in a number of GI malignancies. Current data from human studies of CCK2R antagonists are presented and their potential role in the treatment of these conditions reviewed. Furthermore, the role of CCK2 receptors as targets for medical imaging is discussed. Even though cholecystokinin (CCK) and gastrin were among the first gastrointestinal hormones discovered [1,2], both their physiological roles as well as their roles in clinically relevant gastrointestinal diseases remain unclear and even controversial in many cases [3–6]. The structural characterization of CCK and gastrin [7,8], pharmacological identification [9–13] and cloning [14,15] of CCK and gastrin receptors (CCK1R, CCK2R), characterization of receptor location, peptide and receptor genes, development of receptor antagonists and receptor/agonist knockout animals [16–21] have led to important advancements in our understanding of the physiological and pathophysiological role of CCK and gastrin signaling [3]. Most of these topics

  8. Existing bridge evaluation using deficiency point method

    Directory of Open Access Journals (Sweden)

    Vičan Josef

    2016-01-01

    Full Text Available In the transforming EU countries, transportation infrastructure has a prominent position in advancing industry and society. Recent developments show, that attention should be moved from the design of new structures towards the repair and reconstruction of existing ones to ensure and increase their satisfactory structural reliability and durability. The problem is very urgent because many construction projects, especially transport infrastructure, in most European countries are more than 50-60 years old and require rehabilitations based on objective evaluations. Therefore, the paper presents methodology of existing bridge evaluation based on reliability concept using Deficiency Point Method. The methodology was prepared from the viewpoint to determine the priority order for existing bridge rehabilitation.

  9. On the existence of shortest directed networks

    CERN Document Server

    Swanepoel, Konrad J

    2008-01-01

    A directed network connecting a set A to a set B is a digraph containing an a-b path for each a in A and b in B. Vertices in the directed network not in A or B are called Steiner points. We show that in a finitely compact metric space in which geodesics exist, any two finite sets A and B are connected by a shortest directed network. We also bound the number of Steiner points by a function of the sizes of A and B. Previously, such an existence result was known only for the Euclidean plane [M. Alfaro, Pacific J. Math. 167 (1995) 201-214]. The main difficulty is that, unlike the undirected case (Steiner minimal trees), the underlying graphs need not be acyclic. Existence in the undirected case was first shown by E. J. Cockayne [Canad. Math. Bull. 10 (1967) 431-450].

  10. Ghrelin, neuropeptide Y (NPY) and cholecystokinin (CCK) in blunt snout bream (Megalobrama amblycephala): cDNA cloning, tissue distribution and mRNA expression changes responding to fasting and refeeding.

    Science.gov (United States)

    Ji, Wei; Ping, Hai-Chao; Wei, Kai-Jian; Zhang, Gui-Rong; Shi, Ze-Chao; Yang, Rui-Bin; Zou, Gui-Wei; Wang, Wei-Min

    2015-11-01

    Blunt snout bream (Megalobrama amblycephala Yih, 1955) is an endemic freshwater fish in China for which the endocrine mechanism of regulation of feeding has never been examined. Ghrelin, neuropeptide Y (NPY) and cholecystokinin (CCK) play important roles in the regulation of fish feeding. In this study, full-length cDNAs of ghrelin, NPY and CCK were cloned and analyzed from blunt snout bream. Both the ghrelin and NPY genes of blunt snout bream had the same amino acid sequences as grass carp, and CCK also shared considerable similarity with that of grass carp. The three genes were expressed in a wide range of adult tissues, with the highest expression levels of ghrelin in the hindgut, NPY in the hypothalamus and CCK in the pituitary, respectively. Starvation challenge experiments showed that the expression levels of ghrelin and NPY mRNA increased in brain and intestine after starvation, and the expression levels of CCK decreased after starvation. Refeeding could bring the expression levels of the three genes back to the control levels. These results indicated that the feeding behavior of blunt snout bream was regulated by the potential correlative actions of ghrelin, NPY and CCK, which contributed to the defense against starvation. This study will further our understanding of the function of ghrelin, NPY and CCK and the molecular mechanism of feeding regulation in teleosts. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Targeting a G-protein-coupled receptor overexpressed in endocrine tumors by magnetic nanoparticles to induce cell death.

    Science.gov (United States)

    Sanchez, Claire; El Hajj Diab, Darine; Connord, Vincent; Clerc, Pascal; Meunier, Etienne; Pipy, Bernard; Payré, Bruno; Tan, Reasmey P; Gougeon, Michel; Carrey, Julian; Gigoux, Véronique; Fourmy, Daniel

    2014-02-25

    Nanotherapy using targeted magnetic nanoparticles grafted with peptidic ligands of receptors overexpressed in cancers is a promising therapeutic strategy. However, nanoconjugation of peptides can dramatically affect their properties with respect to receptor recognition, mechanism of internalization, intracellular trafficking, and fate. Furthermore, investigations are needed to better understand the mechanism whereby application of an alternating magnetic field to cells containing targeted nanoparticles induces cell death. Here, we designed a nanoplatform (termed MG-IONP-DY647) composed of an iron oxide nanocrystal decorated with a ligand of a G-protein coupled receptor, the cholecystokinin-2 receptor (CCK2R) that is overexpressed in several malignant cancers. MG-IONP-DY647 did not stimulate inflammasome of Raw 264.7 macrophages. They recognized cells expressing CCK2R with a high specificity, subsequently internalized via a mechanism involving recruitment of β-arrestins, clathrin-coated pits, and dynamin and were directed to lysosomes. Binding and internalization of MG-IONP-DY647 were dependent on the density of the ligand at the nanoparticle surface and were slowed down relative to free ligand. Trafficking of CCK2R internalized with the nanoparticles was slightly modified relative to CCK2R internalized in response to free ligand. Application of an alternating magnetic field to cells containing MG-IONP-DY647 induced apoptosis and cell death through a lysosomal death pathway, demonstrating that cell death is triggered even though nanoparticles of low thermal power are internalized in minute amounts by the cells. Together with pioneer findings using iron oxide nanoparticles targeting tumoral cells expressing epidermal growth factor receptor, these data represent a solid basis for future studies aiming at establishing the proof-of-concept of nanotherapy of cancers using ligand-grafted magnetic nanoparticles specifically internalized via cell surface receptors.

  12. Existence and Uniqueness in Shape from Shading

    Institute of Scientific and Technical Information of China (English)

    邓雁萍; 李价谷

    1997-01-01

    For the image of a smooth surface object fully contained within the field of view and illuminated in and arbitrary direction,this paper discusses the existence and uniqueness o the conditions for solving a shape-from-shading problem under the conditions that the Fourier series expansion of the image intensity contains only zero and first order terms in a polar coordinate system.Three theorems are established,one for the existence and two for the uniqueness of z-axis symmetric shape from shading.

  13. Existence of a persistent background of turbulence

    Science.gov (United States)

    Vanzandt, T. E.

    1983-01-01

    A plausible scenario for the existence of a persistent back-ground of turbulence in the free atmosphere is described. The MST radar technique is the only existing technique that can be used to describe the morphology of occurrence of turbulence as a function of altitude, wind speed, shear, weather conditions, geographical location, etc. This technique was used also to assess the degree of universality of shape and amplitude of the buoyancy wave spectrum and the relation between the buoyancy wave spectrum and turbulence.

  14. EXISTENCE OF OPTIMAL STRONG PARTIALLY BALANCED DESIGNS

    Institute of Scientific and Technical Information of China (English)

    Du Beiliang

    2007-01-01

    A strong partially balanced design SPBD(v, b, k; λ,0) whose b is the maximum number of blocks in all SPBD(v, b, k; λ, 0), as an optimal strong partially balanced design, briefly OSPBD(v, k, λ) is studied. In investigation of authentication codes it has been found that the strong partially balanced design can be used to construct authentication codes. This note investigates the existence of optimal strong partially balanced design OSPBD(v, k, 1) for k = 3and 4, and shows that there exists an OSPBD(v, k, 1) for any v ≥ k.

  15. Does the Kuleshov Effect really Exist?

    DEFF Research Database (Denmark)

    Barratt, Daniel; Cabak Rédei, Anna

    2013-01-01

    with a doll, a dead woman in a coffin, and a bowl of soup; the viewers of the three sequences were reported to have perceived Mozhukin’s face as expressing happiness, sadness, and hunger/thoughtfulness respectively. It is not clear, however, whether or not the socalled “Kuleshov effect” really exists...

  16. Proof that chronic lyme disease exists.

    Science.gov (United States)

    Cameron, Daniel J

    2010-01-01

    The evidence continues to mount that Chronic Lyme Disease (CLD) exists and must be addressed by the medical community if solutions are to be found. Four National Institutes of Health (NIH) trials validated the existence and severity of CLD. Despite the evidence, there are physicians who continue to deny the existence and severity of CLD, which can hinder efforts to find a solution. Recognizing CLD could facilitate efforts to avoid diagnostic delays of two years and durations of illness of 4.7 to 9 years described in the NIH trials. The risk to society of emerging antibiotic-resistant organisms should be weighed against the societal risks associated with failing to treat an emerging population saddled with CLD. The mixed long-term outcome in children could also be examined. Once we accept the evidence that CLD exists, the medical community should be able to find solutions. Medical professionals should be encouraged to examine whether: (1) innovative treatments for early LD might prevent CLD, (2) early diagnosis of CLD might result in better treatment outcomes, and (3) more effective treatment regimens can be developed for CLD patients who have had prolonged illness and an associated poor quality of life.

  17. Proof That Chronic Lyme Disease Exists

    Directory of Open Access Journals (Sweden)

    Daniel J. Cameron

    2010-01-01

    Full Text Available The evidence continues to mount that Chronic Lyme Disease (CLD exists and must be addressed by the medical community if solutions are to be found. Four National Institutes of Health (NIH trials validated the existence and severity of CLD. Despite the evidence, there are physicians who continue to deny the existence and severity of CLD, which can hinder efforts to find a solution. Recognizing CLD could facilitate efforts to avoid diagnostic delays of two years and durations of illness of 4.7 to 9 years described in the NIH trials. The risk to society of emerging antibiotic-resistant organisms should be weighed against the societal risks associated with failing to treat an emerging population saddled with CLD. The mixed long-term outcome in children could also be examined. Once we accept the evidence that CLD exists, the medical community should be able to find solutions. Medical professionals should be encouraged to examine whether: (1 innovative treatments for early LD might prevent CLD, (2 early diagnosis of CLD might result in better treatment outcomes, and (3 more effective treatment regimens can be developed for CLD patients who have had prolonged illness and an associated poor quality of life.

  18. EXISTENCE TIME FOR THE SEMILINEAR SCHROEDINGER EQUATION

    Institute of Scientific and Technical Information of China (English)

    WeiMingjun

    2003-01-01

    Based on the methods introduced by Klainerman and Ponce.and Cohn.a lower bounded estimate of the existence time for a kind of semilinear Schroedinger equation is obtained in this paper.The implemantation of this method depends on the Lp-Lq estimate and the energy estimate.

  19. THE EXISTENCE THEOREM OF OPTIMAL GROWTH MODEL

    Institute of Scientific and Technical Information of China (English)

    Gong Liutang; Peng Xianze

    2005-01-01

    This paper proves a general existence theorem of optimal growth theory. This theorem is neither restricted to the case of a constant technology progress, nor stated in terms of mathematical conditions which have no direct economic interpretation and moreover, are difficult to apply.

  20. Modeling Truth Existence in Truth Discovery.

    Science.gov (United States)

    Zhi, Shi; Zhao, Bo; Tong, Wenzhu; Gao, Jing; Yu, Dian; Ji, Heng; Han, Jiawei

    2015-08-01

    When integrating information from multiple sources, it is common to encounter conflicting answers to the same question. Truth discovery is to infer the most accurate and complete integrated answers from conflicting sources. In some cases, there exist questions for which the true answers are excluded from the candidate answers provided by all sources. Without any prior knowledge, these questions, named no-truth questions, are difficult to be distinguished from the questions that have true answers, named has-truth questions. In particular, these no-truth questions degrade the precision of the answer integration system. We address such a challenge by introducing source quality, which is made up of three fine-grained measures: silent rate, false spoken rate and true spoken rate. By incorporating these three measures, we propose a probabilistic graphical model, which simultaneously infers truth as well as source quality without any a priori training involving ground truth answers. Moreover, since inferring this graphical model requires parameter tuning of the prior of truth, we propose an initialization scheme based upon a quantity named truth existence score, which synthesizes two indicators, namely, participation rate and consistency rate. Compared with existing methods, our method can effectively filter out no-truth questions, which results in more accurate source quality estimation. Consequently, our method provides more accurate and complete answers to both has-truth and no-truth questions. Experiments on three real-world datasets illustrate the notable advantage of our method over existing state-of-the-art truth discovery methods.

  1. Repurposing Existing Material for Performance Support.

    Science.gov (United States)

    Harvey, Francis A.; Nelson, Adam

    1995-01-01

    Presents an overview of performance support systems (PSS), describes their role in promoting productivity in agile organizations, and discusses issues related to developing effective performance support using existing orientation, training, or procedural manuals. Topics include strategic principles of agility, and adding value when incorporating…

  2. 36 CFR 9.33 - Existing operations.

    Science.gov (United States)

    2010-07-01

    ... MINERALS MANAGEMENT Non-Federal Oil and Gas Rights § 9.33 Existing operations. (a) Any person conducting... (within thirty (30) days of January 8, 1979), notifies the Superintendent in writing of the nature and... reasons for the suspension and of his right to appeal the suspension under § 9.48. ...

  3. Foucault, Counselling and the Aesthetics of Existence

    Science.gov (United States)

    Peters, Michael A.

    2005-01-01

    Michel Foucault was drawn late in life to study the "arts of the self" in Greco-Roman culture as a basis, following Nietzsche, for what he called an "aesthetics of existence." By this, he meant a set of creative and experimental processes and techniques by which an individual turns him- or herself into a work of art. For Nietzsche, it was above…

  4. Foucault, Counselling and the Aesthetics of Existence

    Science.gov (United States)

    Peters, Michael A.

    2005-01-01

    Michel Foucault was drawn late in life to study the "arts of the self" in Greco-Roman culture as a basis, following Nietzsche, for what he called an "aesthetics of existence." By this, he meant a set of creative and experimental processes and techniques by which an individual turns him- or herself into a work of art. For Nietzsche, it was above…

  5. Psychology's struggle for existence: Second edition, 1913.

    Science.gov (United States)

    Wundt, Wilhelm; Lamiell, James T

    2013-08-01

    Presents an English translation of Wilhelm Wundt's Psychology's struggle for existence: Second edition, 1913, by James T. Lamiell in August, 2012. In his essay, Wundt advised against the impending divorce of psychology from philosophy. (PsycINFO Database Record (c) 2013 APA, all rights reserved).

  6. Vocation as the Quest for Authentic Existence.

    Science.gov (United States)

    Homan, Kenneth B.

    1986-01-01

    Examines the concept of vocation and demonstrates that vocation is the organizing, existential principle of the concept of work. Presents a critical examination of Green's (1968) delineation of job and work and asserts that vocation as the quest for authentic existence is the unifying concept that gives grounding to Green's notion of work. (NB)

  7. Reliability Analysis of Existing Vertical Wall Breakwaters

    DEFF Research Database (Denmark)

    Burcharth, H. F.; Sørensen, John Dalsgaard

    1998-01-01

    Vertical wall breakwaters are used under quite different conditions where failure of the breakwater or a part of it will have very different consequences. Further a number of existing vertical wall breakwaters have been subjected to significant wave loads which have caused partial failures...

  8. Potential roles for calcium-sensing receptor (CaSR) and transient receptor potential ankyrin-1 (TRPA1) in murine anorectic response to deoxynivalenol (vomitoxin).

    Science.gov (United States)

    Wu, Wenda; Zhou, Hui-Ren; Pestka, James J

    2017-01-01

    Food contamination by the trichothecene mycotoxin deoxynivalenol (DON, vomitoxin) has the potential to adversely affect animal and human health by suppressing food intake and impairing growth. In mice, the DON-induced anorectic response results from aberrant satiety hormone secretion by enteroendocrine cells (EECs) of the gastrointestinal tract. Recent in vitro studies in the murine STC-1 EEC model have linked DON-induced satiety hormone secretion to activation of calcium-sensing receptor (CaSR), a G-coupled protein receptor, and transient receptor potential ankyrin-1 (TRPA1), a TRP channel. However, it is unknown whether similar mechanisms mediate DON's anorectic effects in vivo. Here, we tested the hypothesis that DON-induced food refusal and satiety hormone release in the mouse are linked to activation of CaSR and TRPA1. Oral treatment with selective agonists for CaSR (R-568) or TRPA1 (allyl isothiocyanate (AITC)) suppressed food intake in mice, and the agonist's effects were suppressed by pretreatment with corresponding antagonists NPS-2143 or ruthenium red (RR), respectively. Importantly, NPS-2143 or RR inhibited both DON-induced food refusal and plasma elevations of the satiety hormones cholecystokinin (CCK) and peptide YY3-36 (PYY3-36); cotreatment with both antagonists additively suppressed both anorectic and hormone responses to DON. Taken together, these in vivo data along with prior in vitro findings support the contention that activation of CaSR and TRPA1 contributes to DON-induced food refusal by mediating satiety hormone exocytosis from EEC.

  9. Overview of Existing Wind Energy Ordinances

    Energy Technology Data Exchange (ETDEWEB)

    Oteri, F.

    2008-12-01

    Due to increased energy demand in the United States, rural communities with limited or no experience with wind energy now have the opportunity to become involved in this industry. Communities with good wind resources may be approached by entities with plans to develop the resource. Although these opportunities can create new revenue in the form of construction jobs and land lease payments, they also create a new responsibility on the part of local governments to ensure that ordinances will be established to aid the development of safe facilities that will be embraced by the community. The purpose of this report is to educate and engage state and local governments, as well as policymakers, about existing large wind energy ordinances. These groups will have a collection of examples to utilize when they attempt to draft a new large wind energy ordinance in a town or county without existing ordinances.

  10. Existence of Multiagent Equilibria with Limited Agents

    CERN Document Server

    Bowling, M; 10.1613/jair.1332

    2011-01-01

    Multiagent learning is a necessary yet challenging problem as multiagent systems become more prevalent and environments become more dynamic. Much of the groundbreaking work in this area draws on notable results from game theory, in particular, the concept of Nash equilibria. Learners that directly learn an equilibrium obviously rely on their existence. Learners that instead seek to play optimally with respect to the other players also depend upon equilibria since equilibria are fixed points for learning. From another perspective, agents with limitations are real and common. These may be undesired physical limitations as well as self-imposed rational limitations, such as abstraction and approximation techniques, used to make learning tractable. This article explores the interactions of these two important concepts: equilibria and limitations in learning. We introduce the question of whether equilibria continue to exist when agents have limitations. We look at the general effects limitations can have on agent b...

  11. Gambling on the existence of other universes

    CERN Document Server

    Sangalli, Arturo

    2016-01-01

    Speculations and theories about the existence of other worlds have a long history. In recent times, the arguments have shifted away from their typical philosophical and theological character to supposedly become more objective thanks to their scientific underpinnings. A prime example of this is the current parallel universes or multiverse theory, which has the support of a number of famous cosmologists. In this article, we contend that the claim for the existence of those parallel universes, as presented in Max Tegmark's book "Our Mathematical Universe", rests crucially on some questionable probability arguments involving infinity. As a result, a doubt is cast over the multiverse hypothesis: Is it more credible than the counterarguments based on philosophical and metaphysical considerations?

  12. LOVE’S SYMPHONY: MULTIPLICITY OF EXISTENCE

    Directory of Open Access Journals (Sweden)

    CHRISTINE McNEILL-MATTESON

    2016-05-01

    Full Text Available Love, although universal in thought, is explicitly complex and articulately multi-defined in almost every idea and expression. Love written is timeless from the molecules we possess within us, to the cosmos we study and explore. We can only exist and continue to exist in harmony with creation. Harmony reaches far beyond galaxies and universes, flowing backinto the most separate of the smallest molecules. Within all common denominators of harmony there is love: the very catalyst of harmony itself. This paper will look at harmony from a poetic point of view and examine how it is expressed always in the context of the mystery of sentience and conscience from human biology to the divine cosmos

  13. On the existence of MSA coordinates

    CERN Document Server

    Hernández-Pastora, J L

    2009-01-01

    The static solutions of the axially symmetric vacuum Einstein equations with a finite number of Relativistic Multipole Moments are described by means of a function that can be written in the same analytic form as the Newtonian gravitational multipole potential. A family of so-called MSA (Multipole-Symmetry Adapted) coordinates are introduced and calculated at any multipole order to perform the transformation of the Weyl solutions. In analogy with a previous result obtained in Newtonian gravity, the existence of a symmetry of a certain system of differential equations leading to the determination of that kind of multipole solutions in General Relativity is explored. The relationship between the existence of this kind of coordinate and the symmetries mentioned is proved for some cases, and the characterization of the MSA system of coordinates by means of this relationship is discussed.

  14. Co-existence of agricultural production systems.

    Science.gov (United States)

    Jank, Bernhard; Rath, Johannes; Gaugitsch, Helmut

    2006-05-01

    Strategies and best practices for the co-existence of GM and non-GM crops need to be developed and implemented with the participation of farmers and other stakeholders. According to the principle of 'subsidiarity', decisions should be made by the lowest authority possible. When applying this concept to the case of GM crops, the affected society should determine their use and management in a regional decision-making process. Public participation is better accomplished at a lower level, and democratic deficits in decision-making on GMOs are better resolved, enabling farmers to manage or avoid GM crops. Ultimately, voluntary GMO-free zones might be a tool for sustainable co-existence and GM-free production and GMO-free zones might create a specific image for marketing regional products and services, such as tourism.

  15. Implementation of ventilation in existing schools

    DEFF Research Database (Denmark)

    Hviid, Christian Anker; Petersen, Steffen

    Present paper analyses the best-practice solutions for classrooms’ ventilation that fit the objective of quick and inexpensive implementation. The paper decomposes the relations between ventilation and building into manageable elements and analyzes them. The analyses are performed qualitatively......; they evaluate both scientific and practical implementation The analyses lead to a list of criteria associated with the implementation of ventilation in existing schools. Generic retrofitting scenarios which prioritize energy savings, indoor climate and building/facade integration are assembled and illustrated...

  16. Angiotensin-(1-7) Is an Endogenous Ligand for the G Protein-Coupled Receptor Mas

    National Research Council Canada - National Science Library

    Robson A. S. Santos; Ana C. Simoes e Silva; Christine Maric; Denise M. R. Silva; Raquel Pillar Machado; Insa de Buhr; Silvia Heringer-Walther; Sergio Veloso B. Pinheiro; Myriam Teresa Lopes; Michael Bader; Elizabeth P. Mendes; Virgina Soares Lemos; Maria Jose Campagnole-Santos; Heinz-Peter Schultheiss; Robert Speth; Thomas Walther

    2003-01-01

    ...) antagonist indicated the existence of a distinct Ang-(1-7) receptor. We demonstrate that genetic deletion of the G protein-coupled receptor encoded by the Mas protooncogene abolishes the binding of Ang-(1-7) to mouse kidneys...

  17. 'Void existence' as against 'annihilation existence': Differentiating two qualities in primitive mental states.

    Science.gov (United States)

    Valdarsky, Irit Hameiri

    2015-10-01

    This paper attempts to distil out a particular quality of psychic (non)existence, which I call here 'void existence', from the quality predominantly explored in the psychoanalytic discourse on primitive mental states, which I call 'annihilation existence'. Achieving this phenomenological differentiation may make it easier to identify and work through extreme states in the analytic situation, when the patient is under the dominance of 'void existence'. I suggest that it is, as it were, a one-dimensional existence, in an infinite contour-less void, lacking any substantial internal object, lacking any substantial sense of psychic and/or somatic occurrences, and lacking any live representation of this very state of being. Hence, it lacks distress and anxiety, as well as calmness and peace. One might say that it is the inorganic within the organic; a quality of non-alive-ness within life. 'Annihilation existence' is existence in a two- or three-dimensional hollowed world, with flat and/or partial representations of self and object, which attracts acute distress and annihilation anxiety. It is a sort of existence on the brink of non-life, on the brink of the void; where a sense of catastrophic danger is brought on by the never-ending potentiality of the annihilation's realization. Both these psychic qualities can be encapsulated within neurotic and personality disorders, and the dominance of each can serve as defence against the dominance of the other. The theoretical discussion is supported by excerpts from an analysis.

  18. Sustainability in the existing building stock

    DEFF Research Database (Denmark)

    Elle, Morten; Nielsen, Susanne Balslev; Hoffmann, Birgitte

    2005-01-01

    management is a concept relevant to others than large companies. Managing the flows of energy and other resources is a part of facilities management, and an increased professionalism could lead to the reduction of the use of energy and water and the generation of waste and wastewater. This is, however...... sustainable building. In other words: the question is if it sensible to talk about a ‘sustainable building’ without taking the activities in the building into account? In many contexts, maintenance of the existing building stock is not a hot political topic. Facilities management can, however, be a vehicle...

  19. Existing cometary data and future needs

    Science.gov (United States)

    Rahe, J.

    1981-10-01

    To assist scientists studying comets and their interaction with the interplanetary medium, compilations of existing cometary observations and data plans for additional publication are reported. The works cited include updates and/or supplements to: (1) the Catalogue of Cometary Orbits, (2) Physical Characteristics of Comets, (3) the Atlas of Representative Cometary Spectra, (4) the Atlas Cometas-Viento Solar, (5) the Isophotometrischer Atlas der Kometen, and (6) the Atlas of Cometary Forms. An Atlas of Cometary Spectra and an Atlas of Comet Halley 1910 (II) photographs and spectra are in preparation.

  20. Energy Savings Measure Packages: Existing Homes

    Energy Technology Data Exchange (ETDEWEB)

    Casey, S.; Booten, C.

    2011-11-01

    This document presents the most cost effective Energy Savings Measure Packages (ESMP) for existing mixed-fuel and all electric homes to achieve 15% and 30% savings for each BetterBuildings grantee location across the US. These packages are optimized for minimum cost to homeowners for given source energy savings given the local climate and prevalent building characteristics (i.e. foundation types). Maximum cost savings are typically found between 30% and 50% energy savings over the reference home. The dollar value of the maximum annual savings varies significantly by location but typically amounts to $300 - $700/year.

  1. Leibniz on the existence of atoms

    Directory of Open Access Journals (Sweden)

    Ricardo Mena

    Full Text Available ABSTRACT In this paper I present and evaluate Leibniz’s two main arguments against the existence of atoms. In this context atoms are extended particles that are absolutely hard, homogeneous, indivisible, and indestructible by natural means. As we shall see, Leibniz’s arguments are flawed in a very instructive way. The first argument is in tension with the claim that God created the best possible world. The second argument overgeneralizes in an undesirable way. However, as I shall discuss in the last section of the paper, even if the arguments are somehow defective, at least the first one contributes valuable insights to contemporary metaphysics.

  2. Does the Kuleshov Effect really Exist?

    DEFF Research Database (Denmark)

    Barratt, Daniel; Cabak Rédei, Anna

    2013-01-01

    movements were recorded throughout the experiment using a remote eye-tracker (SMI iView X RED). A preliminary analysis of the results suggests that some sort of Kuleshov effect does in fact exist. For the different emotional conditions, the participants tended to choose the appropriate emotion more......, sadness, and hunger/neutral conditions with equivalent stimuli. For each film sequence, the participant was asked: to rate the valence of the depicted person’s emotion; to rate how aroused the person appeared to be; and to identify the type of emotion that the person was feeling. The participant’s eye...

  3. Energy Savings Measure Packages. Existing Homes

    Energy Technology Data Exchange (ETDEWEB)

    Casey, Sean [National Renewable Energy Lab. (NREL), Golden, CO (United States); Booten, Chuck [National Renewable Energy Lab. (NREL), Golden, CO (United States)

    2011-11-01

    This document presents the most cost effective Energy Savings Measure Packages (ESMP) for existing mixed-fuel and all electric homes to achieve 15% and 30% savings for each BetterBuildings grantee location across the United States. These packages are optimized for minimum cost to homeowners for source energy savings given the local climate and prevalent building characteristics (i.e. foundation types). Maximum cost savings are typically found between 30% and 50% energy savings over the reference home; this typically amounts to $300 - $700/year.

  4. Molecular pharmacology of human NMDA receptors

    DEFF Research Database (Denmark)

    Hedegaard, Maiken; Hansen, Kasper Bø; Andersen, Karen Toftegaard

    2012-01-01

    current knowledge of the relationship between NMDA receptor structure and function. We summarize studies on the biophysical properties of human NMDA receptors and compare these properties to those of rat orthologs. Finally, we provide a comprehensive pharmacological characterization that allows side......-by-side comparison of agonists, un-competitive antagonists, GluN2B-selective non-competitive antagonists, and GluN2C/D-selective modulators at recombinant human and rat NMDA receptors. The evaluation of biophysical properties and pharmacological probes acting at different sites on the receptor suggest...... that the binding sites and conformational changes leading to channel gating in response to agonist binding are highly conserved between human and rat NMDA receptors. In summary, the results of this study suggest that no major detectable differences exist in the pharmacological and functional properties of human...

  5. The androgen receptor and estrogen receptor

    NARCIS (Netherlands)

    Oosterkamp, H.M.; Bernards, R.A.

    2002-01-01

    The androgen receptor (AR) and the estrogen receptors (ER) are members of the nuclear receptor (NR) family. These NRs are distinguished from the other transcription factors by their ability to control gene expression upon ligand binding (steroids, retinoids, thyroid hormone, vitamin D, fatty acids,

  6. Ghrelin counteracts insulin-induced activation of vagal afferent neurons via growth hormone secretagogue receptor.

    Science.gov (United States)

    Iwasaki, Yusaku; Dezaki, Katsuya; Kumari, Parmila; Kakei, Masafumi; Yada, Toshihiko

    2015-08-01

    Vagal afferent nerves sense meal-related gastrointestinal and pancreatic hormones and convey their information to the brain, thereby regulating brain functions including feeding. We have recently demonstrated that postprandial insulin directly acts on the vagal afferent neurons. Plasma concentrations of orexigenic ghrelin and anorexigenic insulin show reciprocal dynamics before and after meals. The present study examined interactive effects of ghrelin and insulin on vagal afferent nerves. Cytosolic Ca(2+) concentration ([Ca(2+)]i) in isolated nodose ganglion (NG) neurons was measured to monitor their activity. Insulin at 10(-7)M increased [Ca(2+)]i in NG neurons, and the insulin-induced [Ca(2+)]i increase was inhibited by treatment with ghrelin at 10(-8)M. This inhibitory effect of ghrelin was attenuated by [D-Lys(3)]-GHRP-6, an antagonist of growth hormone-secretagogue receptor (GHSR). Des-acyl ghrelin had little effect on insulin-induced [Ca(2+)]i increases in NG neurons. Ghrelin did not affect [Ca(2+)]i increases in response to cholecystokinin (CCK), a hormone that inhibits feeding via vagal afferent neurons, indicating that ghrelin selectively counteracts the insulin action. These results demonstrate that ghrelin via GHSR suppresses insulin-induced activation of NG neurons. The action of ghrelin to counteract insulin effects on NG might serve to efficiently inform the brain of the systemic change between fasting-associated ghrelin-dominant and fed-associated insulin-dominant states for the homeostatic central regulation of feeding and metabolism.

  7. CCK1-Receptor Stimulation Protects Against Gut Mediator-Induced Lung Damage During Endotoxemia

    Directory of Open Access Journals (Sweden)

    Friederike Eisner

    2013-12-01

    Full Text Available Background/Aims: Cholecystokinin 1-receptor (CCK1-R activation by long chain fatty acid (LCFA absorption stimulates vago-vagal reflex pathways in the brain stem. The present study determines whether this reflex also activates the cholinergic anti-inflammatory pathway, a pathway known to modulate cytokine release during endotoxemia. Methods:Mesenteric lymph was obtained from wild type (WT and CCK1-R knockout (CCK1-R-/- mice intraperitoneally challenged with Lipopolysaccharid (LPS (endotoxemic lymph, EL and intestinally infused with vehicle or LCFA-enriched solution. The lymph was analyzed for TNFα, IL-6 and IL-10 concentration and administered to healthy recipient mice via jugular infusion. Alveolar wall thickness, myeloperoxidase (MPO and TUNEL positive cells were determined in lung tissue of recipient mice. Results: LCFA infusion in WT mice reduced TNFα concentration in EL by 49% compared to vehicle infusion, but had no effect in CCK1-R-/- mice. EL significantly increased the alveolar wall thickness, the number of MPO-positive and TUNEL-positive cells compared to control lymph administration. LCFA infusion in WT, but not in CCK1R-/- mice, significantly reduced these pathological effects of EL. Conclusion: During endotoxemia enteral LCFA absorption reduces TNFα release into mesenteric lymph and attenuates histomorphologic parameters of lung dysfunction. Failure to elicit this effect in CCK1R-/- mice demonstrates that anti-inflammatory properties of LCFAs are mediated through CCK1-Rs.

  8. EXIST Mission Design Concept and Technology Program

    CERN Document Server

    Grindlay, J E; Gehrels, N; Harrison, F A; Hong, J

    2002-01-01

    The Energetic X-ray Imaging Survey Telescope (EXIST) is a proposed very large area coded aperture telescope array, incorporating 8m^2 of pixellated Cd-Zn-Te (CZT) detectors, to conduct a full-sky imaging and temporal hard x-ray (10-600 keV) survey each 95min orbit. With a sensitivity (5sigma, 1yr) of ~0.05mCrab (10-150 keV), it will extend the ROSAT soft x-ray (0.5-2.5keV) and proposed ROSITA medium x-ray (2-10 keV) surveys into the hard x-ray band and enable identification and study of sources ~10-20X fainter than with the ~15-100keV survey planned for the upcoming Swift mission. At ~100-600 keV, the ~1mCrab sensitivity is 300X that achieved in the only previous (HEAO-A4, non-imaging) all-sky survey. EXIST will address a broad range of key science objectives: from obscured AGN and surveys for black holes on all scales, which constrain the accretion history of the universe, to the highest sensitivity and resolution studies of gamma-ray bursts it will conduct as the Next Generation Gamma-Ray Burst mission. We ...

  9. Hard X-ray Timing with EXIST

    CERN Document Server

    Grindlay, J E

    2004-01-01

    The Energetic X-ray Timing Survey Telescope (EXIST) mission concept is under study as the Black Hole Finder Probe (BHFP), one of the three Einstein Probe missions in the Beyond Einstein Program in the current NASA Strategic Plan. EXIST would conduct an all-sky imaging hard X-ray ($\\sim$10-600 keV) survey with unprecedented sensitivity: about 5 $\\times 10^{-13}$ cgs over any factor of 2 bandwidth, or comparable to that achieved at soft X-rays in the ROSAT survey. The proposed angular resolution of 5arcmin, temporal resolution of 10microsec, energy resolution of 1-4 keV over the broad band, and duty cycle of 0.2-0.5 for continuous coverage of any source provide an unprecedented phase space for timing and spectral studies of black holes --from stellar to supermassive, as well as neutron stars and accreting white dwarfs. The large sky coverage allows intrinsically rare events to be studied. One particularly exciting example is the possible detection of tidal disruption of stars near quiescent AGN. Super flares fr...

  10. Overview of EXIST mission science and implementation

    CERN Document Server

    Grindlay, J; Bloom, J; Coppi, P; Soderberg, A; Hong, J; Allen, B; Barthelmy, S; Tagliaferri, G; Moseley, H; Kutyrev, A; Fabbiano, G; Fishman, G; Ramsey, B; Della Ceca, R; Natalucci, L; Ubertini, P

    2010-01-01

    The Energetic X-ray Imaging Survey Telescope (EXIST) is designed to i) use the birth of stellar mass black holes, as revealed by cosmic Gamma-Ray Bursts (GRBs), as probes of the very first stars and galaxies to exist in the Universe. Both their extreme luminosity (~104 times larger than the most luminous quasars) and their hard X-ray detectability over the full sky with wide-field imaging make them ideal "back-lights" to measure cosmic structure with X-ray, optical and near-IR (nIR) spectra over many sight lines to high redshift. The full-sky imaging detection and rapid followup narrow-field imaging and spectroscopy allow two additional primary science objectives: ii) novel surveys of supermassive black holes (SMBHs) accreting as very luminous but rare quasars, which can trace the birth and growth of the first SMBHs as well as quiescent SMBHs (non-accreting) which reveal their presence by X-ray flares from the tidal disruption of passing field stars; and iii) a multiwavelength Time Domain Astrophysics (TDA) s...

  11. Existence of frozen-in coordinate systems

    Science.gov (United States)

    Chertkov, A. D.

    1995-01-01

    The 'frozen-in' coordinate systems were first introduced in the works on 'reconnection' and 'magnetic barrier' theories (see review by M.l.Pudovkin and V.S.Semenov, Space Sci. Rev. 41,1 1985). The idea was to utilize the mathematical apparatus developed for 'general relativity' theory to simplify obtaining solutions to the ideal MHD equations set. Magnetic field (B), plasma velocity (v), and their vector product were used as coordinate vectors. But there exist no stationary solutions of ideal MHD set that satisfies the required boundary conditions at infinity (A.D.Chertkov, Solar Wind Seven Conf.,Pergamon Press,1992,165) having non-zero vector product of v and B where v and B originate from the same sphere. The existence of a solution is the hidden mine of the mentioned theories. The solution is constructed in the coordinate system, which is unknown and indeterminate before obtaining this solution. A substitution of the final solution must be done directly into the initial MHD set in order to check the method. One can demonstrate that 'solutions' of Petschek's problem, obtained by 'frozen-in' coordinate systems, does not satisfy just the 'frozen-in' equation, i.e. induction equation. It stems from the fact that Petschek's 're-connection' model, treated as a boundary problem, is over determined. This problem was incorrectly formulated.

  12. Surveying the Extreme Sky with EXIST

    CERN Document Server

    Grindlay, Jonathan E

    2010-01-01

    The recent hard X-ray surveys performed by INTEGRAL and Swift have started to reveal the demographics of compact sources including Super-Massive Black Holes hosted in AGNs and have proven invaluable in tracking explosive events as the death of massive stars revealed by Gamma-Ray Bursts up to cosmological distances. Whereas the observations have contributed significantly to our understanding of the sources populations in the Local Universe, it has also become evident that revealing the processes that drive the birth and evolution of the first massive stars and galaxies would have required a further big step in both sensitivity and capability to study transient phenomena since their very beginning and covering different wavebands simultaneously. Therefore, after its decennial history as a proposed hard X-ray survey mission, EXIST has now turned into a new, more advanced concept with three instruments on board covering the IR/optical and X-ray/soft gamma-ray bands. The EXIST new design (Grindlay 2009a) is theref...

  13. Existence families, functional calculi and evolution equations

    CERN Document Server

    deLaubenfels, Ralph

    1994-01-01

    This book presents an operator-theoretic approach to ill-posed evolution equations. It presents the basic theory, and the more surprising examples, of generalizations of strongly continuous semigroups known as 'existent families' and 'regularized semigroups'. These families of operators may be used either to produce all initial data for which a solution in the original space exists, or to construct a maximal subspace on which the problem is well-posed. Regularized semigroups are also used to construct functional, or operational, calculi for unbounded operators. The book takes an intuitive and constructive approach by emphasizing the interaction between functional calculus constructions and evolution equations. One thinks of a semigroup generated by A as etA and thinks of a regularized semigroup generated by A as etA g(A), producing solutions of the abstract Cauchy problem for initial data in the image of g(A). Material that is scattered throughout numerous papers is brought together and presented in a fresh, ...

  14. Changes in gene expression of pancreatitis-associated protein and pancreatic secretory trypsin inhibitors in experimental pancreatitis produced by pancreatic duct occlusion in rats: comparison with gene expression of cholecystokinin and secretin.

    Science.gov (United States)

    Funakoshi, A; Miyasaka, K; Jimi, A; Nakamura, E; Teraoka, H

    1995-08-01

    Pancreatic duct occlusion is known to produce a sustained increase in the plasma cholecystokinin (CCK) concentration and to affect the tissue content of CCK in the rat. The tissue content of CCK is correlated with regenerative changes in the pancreas after pancreatic duct occlusion. In the present study, we examined the changes in mRNA levels of pancreatic secretory trypsin inhibitors (PSTIs), pancreatitis-associated protein (PAP), and amylase in the pancreas in comparison with changes in CCK and secretin mRNA levels in the intestine and the histological changes produced by pancreatic duct ligation. Rats with an internal bile fistula and with obstruction of pancreatic flow were prepared and were sacrificed 1, 3, 7, 10, 14, and 28 days later. Then mRNA levels of CCK, secretin, PSTIs, PAP, and amylase were determined by slot-blot analysis. The CCK mRNA level gradually increased to a peak on day 10, was slightly lower on day 14, and returned to the control level on day 28. The level of secretin mRNA did not change. The mRNA levels of PSTIs increased significantly on day 3 after occlusion. PAP mRNA was detectable on days 1 and 3, being maximal on day 1. The mRNA level of amylase was markedly decreased on days 1 and 3, then remained lower than the control level. Histological examination showed acute inflammatory changes in the pancreas on days 1 and 3 and regenerative changes from day 7. These results suggest that a change in gene expression of PAP reflects acute inflammatory changes in the pancreas most sensitively.

  15. Role of capsaicin-sensitive peripheral sensory neurons in anorexic responses to intravenous infusions of cholecystokinin, peptide YY-(3-36), and glucagon-like peptide-1 in rats.

    Science.gov (United States)

    Reidelberger, Roger; Haver, Alvin; Anders, Krista; Apenteng, Bettye

    2014-10-15

    Cholecystokinin (CCK)-induced suppression of feeding is mediated by vagal sensory neurons that are destroyed by the neurotoxin capsaicin (CAP). Here we determined whether CAP-sensitive neurons mediate anorexic responses to intravenous infusions of gut hormones peptide YY-(3-36) [PYY-(3-36)] and glucagon-like peptide-1 (GLP-1). Rats received three intraperitoneal injections of CAP or vehicle (VEH) in 24 h. After recovery, non-food-deprived rats received at dark onset a 3-h intravenous infusion of CCK-8 (5, 17 pmol·kg⁻¹·min⁻¹), PYY-(3-36) (5, 17, 50 pmol·kg⁻¹·min⁻¹), or GLP-1 (17, 50 pmol·kg⁻¹·min⁻¹). CCK-8 was much less effective in reducing food intake in CAP vs. VEH rats. CCK-8 at 5 and 17 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 39 and 71% in VEH rats and 7 and 18% in CAP rats. In contrast, PYY-(3-36) and GLP-1 were similarly effective in reducing food intake in VEH and CAP rats. PYY-(3-36) at 5, 17, and 50 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 15, 33, and 70% in VEH rats and 13, 30, and 33% in CAP rats. GLP-1 at 17 and 50 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 48 and 60% in VEH rats and 30 and 52% in CAP rats. These results suggest that anorexic responses to PYY-(3-36) and GLP-1 are not primarily mediated by the CAP-sensitive peripheral sensory neurons (presumably vagal) that mediate CCK-8-induced anorexia.

  16. Fluorescent visualisation of the hypothalamic oxytocin neurones activated by cholecystokinin-8 in rats expressing c-fos-enhanced green fluorescent protein and oxytocin-monomeric red fluorescent protein 1 fusion transgenes.

    Science.gov (United States)

    Katoh, A; Shoguchi, K; Matsuoka, H; Yoshimura, M; Ohkubo, J-I; Matsuura, T; Maruyama, T; Ishikura, T; Aritomi, T; Fujihara, H; Hashimoto, H; Suzuki, H; Murphy, D; Ueta, Y

    2014-05-01

    The up-regulation of c-fos gene expression is widely used as a marker of neuronal activation elicited by various stimuli. Anatomically precise observation of c-fos gene products can be achieved at the RNA level by in situ hybridisation or at the protein level by immunocytochemistry. Both of these methods are time and labour intensive. We have developed a novel transgenic rat system that enables the trivial visualisation of c-fos expression using an enhanced green fluorescent protein (eGFP) tag. These rats express a transgene consisting of c-fos gene regulatory sequences that drive the expression of a c-fos-eGFP fusion protein. In c-fos-eGFP transgenic rats, robust nuclear eGFP fluorescence was observed in osmosensitive brain regions 90 min after i.p. administration of hypertonic saline. Nuclear eGFP fluorescence was also observed in the supraoptic nucleus (SON) and paraventricular nucleus (PVN) 90 min after i.p. administration of cholecystokinin (CCK)-8, which selectively activates oxytocin (OXT)-secreting neurones in the hypothalamus. In double transgenic rats that express c-fos-eGFP and an OXT-monomeric red fluorescent protein 1 (mRFP1) fusion gene, almost all mRFP1-positive neurones in the SON and PVN expressed nuclear eGFP fluorescence 90 min after i.p. administration of CCK-8. It is possible that not only a plane image, but also three-dimensional reconstruction image may identify cytoplasmic vesicles in an activated neurone at the same time.

  17. Evidence for the existence of nociceptors in rat thoracolumbar fascia.

    Science.gov (United States)

    Mense, Siegfried; Hoheisel, Ulrich

    2016-07-01

    Recently, the existence of nociceptive fibers in fascia tissue has attracted much interest. Fascia can be a source of pain in several disorders such as fasciitis and non-specific low back pain. However, little is known about the properties of fascia nociceptors and possible changes of the fascia innervation by nociceptors under pathological circumstances. In this histologic study, the density of presumably nociceptive fibers and free nerve endings was determined in the three layers of the rat TLF: inner layer (IL, covering the multifidus muscle), middle layer (ML) and outer layer (OL). As markers for nociceptive fibers, antibodies to the neuropeptides CGRP and SP as well as to the transient receptor potential vanilloid 1 (TRPV1) were used. As a pathological state, inflammation of the TLF was induced with injection of complete Freund's adjuvant. The density of CGRP- and SP-positive fibers was significantly increased in the inner and outer layer of the inflamed fascia. In the thick middle layer, no inflammation-induced change occurred. In additional experiments, a neurogenic inflammation was induced in the fascia by electrical stimulation of dorsal roots. In these experiments, plasma extravasation was visible in the TLF, which is clear functional evidence for the existence of fascia nociceptors. The presence of nociceptors in the TLF and the increased density of presumably nociceptive fibers under chronic painful circumstances may explain the pain from a pathologically altered fascia. The fascia nociceptors probably contribute also to the pain in non-specific low back pain. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. On the existence of stationary Ricci solitons

    CERN Document Server

    Figueras, Pau

    2016-01-01

    Previously the DeTurck 'trick' has been used to render the stationary Einstein's equation a well posed elliptic system that may be solved numerically by geometric flow or directly. Whilst in the static case for pure gravity with zero or negative cosmological constant there is a simple proof that solving the modified "harmonic" Einstein's equation leads to a solution of the original Einstein system - i.e. not a Ricci soliton - in the stationary case this argument no longer works. Here we provide a new argument that extends the static result to the case of stationary spacetimes that possess a "$t$-$\\phi$" reflection symmetry. Defining a "soliton charge" from the asymptotic behaviour of the solution, we show that this quantity is always non-positive. Provided asymptotic conditions are chosen such that this charge vanishes, then stationary solitons cannot exist.

  19. Existence of six-$\\alpha$ linear structure

    CERN Document Server

    Iwata, Yoritaka; Itagaki, Naoyuki; Maruhn, Joachim A; Otsuka, Takaharu

    2014-01-01

    The stable existence of a six-$\\alpha$ linear structure in highly excited states of $^{24}$Mg is studied based on a systematic Cranked Hartree-Fock calculation with various Skyrme-type interactions. Its stability is examined by allowing the transition of the cluster structure to the shell-model like structure. Especially, the six-$\\alpha$ linear state is exposed to two major instabilities: the bending motion, which is the main path for the transition to low-lying states, and the spin-orbit interaction, which is the driving force to break the $\\alpha$ clusters and enhance the independent motion of the nucleons. The linear structure with large angular momentum is obtained as a meta-stable stationary state.

  20. Welfare Economics: A Story of Existence

    Directory of Open Access Journals (Sweden)

    Khalid Iqbal

    2017-06-01

    Full Text Available The purpose of this study is to explore that, despite severe challenges, welfare economics still exists. This descriptive study is conducted through some specific time line developments in this field. Economists are divided over the veracity and survival of the welfare economics. Welfare economics emphasizes on the optimum resource and goods allocation with the objective of better living standard, materialistic gains, social welfare and ethical decisions. It origins back to the political economics and utilitarianism. Adam Smith, Irving Fisher and Pareto contributed significantly towards it. During 1930 to 1940, American and British approaches were developed. Many economists tried to explore the relationship between level of income and happiness. Amartya Sen gave the comparative approach and Tinbergen pioneered the theory of equity. Contemporarily the futuristic restoration of welfare economics is on trial and hopes are alive. This study may be useful to understand the transitional and survival process of welfare economics.

  1. On the existence of Levi Foliations

    Directory of Open Access Journals (Sweden)

    RENATA N. OSTWALD

    2001-03-01

    Full Text Available Let L be a real 3 dimensional analytic variety. For each regular point p L there exists a unique complex line l p on the space tangent to L at p. When the field of complex line p l p is completely integrable, we say that L is Levi variety. More generally; let L M be a real subvariety in an holomorphic complex variety M. If there exists a real 2 dimensional integrable distribution on L which is invariant by the holomorphic structure J induced by M, we say that L is a Levi variety. We shall prove: Theorem. Let be a Levi foliation and let be the induced holomorphic foliation. Then, admits a Liouvillian first integral. In other words, if is a 3 dimensional analytic foliation such that the induced complex distribution defines an holomorphic foliation ; that is, if is a Levi foliation; then admits a Liouvillian first integral--a function which can be constructed by the composition of rational functions, exponentiation, integration, and algebraic functions (Singer 1992. For example, if f is an holomorphic function and if theta is real a 1-form on ; then the pull-back of theta by f defines a Levi foliation : f*theta = 0 which is tangent to the holomorphic foliation : df = 0. This problem was proposed by D. Cerveau in a meeting (see Fernandez 1997.Seja L Ì uma variedade real de dimensão 3. Para todo ponto regular p Î L existe uma única reta complexa l p no espaço tangente à L em p. Quando o campo de linhas complexas p l p é completamente integrável, dizemos que L é uma variedade de Levi. Mais geralmente, seja L Ì M uma subvariedade real em uma variedade analítica complexa. Se existe uma distribuição real integrável de dimensão 2 em L que é invariante pela estrutura holomorfa J induzida pela variedade complexa M, dizemos que L é uma variedade de Levi. Vamos provar: Teorema. Seja uma folheação de Levi e seja a folheação holomorfa induzida. Então tem integral primeira Liouvilliana. Em outras palavras, se é uma folheação real de

  2. Sustainability in the existing building stock

    DEFF Research Database (Denmark)

    Jensen, Jesper Ole

    2005-01-01

    This paper explores the role of Facilities Management in the relation to sustainable development in the existing building stock. Facilities management is a concept still developing as the management of buildings are becoming more and more professional. Many recognize today that facilities...... management is a concept relevant to others than large companies. Managing the flows of energy and other resources is a part of facilities management, and an increased professionalism could lead to the reduction of the use of energy and water and the generation of waste and wastewater. This is, however......, QRWfacilities management’s most important contribution to sustainable development in the built environment. Space management is an essential tool in facilities management – and it could be considered a powerful tool in sustainable development; remembering that the building not being built is perhaps the most...

  3. Testing Metadata Existence of Web Map Services

    Directory of Open Access Journals (Sweden)

    Jan Růžička

    2011-05-01

    Full Text Available For a general user is quite common to use data sources available on WWW. Almost all GIS software allow to use data sources available via Web Map Service (ISO/OGC standard interface. The opportunity to use different sources and combine them brings a lot of problems that were discussed many times on conferences or journal papers. One of the problem is based on non existence of metadata for published sources. The question was: were the discussions effective? The article is partly based on comparison of situation for metadata between years 2007 and 2010. Second part of the article is focused only on 2010 year situation. The paper is created in a context of research of intelligent map systems, that can be used for an automatic or a semi-automatic map creation or a map evaluation.

  4. The enhancement of existing DES Maplet interface

    Science.gov (United States)

    Abdullah, Nur Lina; Mutalip, Rasidah Abdull; Abdullah, Kamilah

    2014-07-01

    This study pertains to the process of Data Encryption Standard, DES. DES consists of encryption and decryption processes linked with mathematical elements such as algebra and number theory. Preliminary, studies revealed that most of mathematics students face a problem in understanding the complicated process of DES. In modern learning methods, learning environment becomes more interesting with the use of computer and a variety of mathematical software packages. Several mathematical softwares such as Maple, Mathematica, Mathlab and Sage were developed in order to fulfill the specific calculation requirements. Correspondingly, motivated from that, this study incorporated with Maple to enhance the existing DES Maplet interface to be more interactive and user-friendly compared to the original version.

  5. Do Bare Rocks Exist on the Moon?

    Science.gov (United States)

    Allen, Carlton; Bandfield, Joshua; Greenhagen, Benjamin; Hayne, Paul; Leader, Frank; Paige, David

    2017-01-01

    Astronaut surface observations and close-up images at the Apollo and Chang'e 1 landing sites confirm that at least some lunar rocks have no discernable dust cover. However, ALSEP (Apollo Lunar Surface Experiments Package) measurements as well as astronaut and LADEE (Lunar Atmosphere and Dust Environment Explorer) orbital observations and laboratory experiments possibly suggest that a fine fraction of dust is levitated and moves across and above the lunar surface. Over millions of years such dust might be expected to coat all exposed rock surfaces. This study uses thermal modeling, combined with Diviner (a Lunar Reconnaissance Orbiter experiment) orbital lunar eclipse temperature data, to further document the existence of bare rocks on the lunar surface.

  6. Lost interest for existing compounds: New boosts.

    Science.gov (United States)

    Friedhoff, Lawrence T; Dailey, James

    2015-07-01

    Development of new drugs is typically thought of as a bottom-up endeavor where basic science identifies a target, various strategies are used to generate drugs that stimulate or inhibit the target, the drugs are first tested for safety and efficacy in animals and finally efficacy and safety are evaluated in a well defined clinical development process. However, this is not the only way that new drug products are developed. Many new products come from re-initiating development of discontinued drugs, finding new uses for existing drugs, creating a new product by obtaining marketing approval in expanded territories, obtaining approvals for new formulations or a single isomer of a previously approved racemic drug, converting products from prescription to over-the- counter use or converting folk medicines or vitamins to modern pharmaceuticals. Based on this long and successful history of contributions to modern therapeutics, these alternative sources of new products should not be neglected.

  7. Normokalemic periodic paralysis revisited: does it exist?

    Science.gov (United States)

    Chinnery, Patrick F; Walls, Timothy J; Hanna, Michael G; Bates, David; Fawcett, Peter R W

    2002-08-01

    Normokalemic periodic paralysis (normoKPP) is well established in the literature, but there are doubts as to whether it exists as a discrete entity. Retrospective clinical and molecular analysis has confirmed suspicions that most normoKPP families actually have a variant of hyperkalemic periodic paralysis (hyperKPP) due to a mutation of the muscle-specific sodium channel gene (SCN4A). However, the original normoKPP family described by Poskanzer and Kerr (Poskanzer DC, Kerr DNS. A third type of periodic paralysis, with normokalemia and favourable response to sodium chloride. Am J Med 1961;31:328-342) has remained unchallenged. We identified the Met1592Val mutation of SCN4A in an affected descendent of this original normoKPP family. This is the final piece in the puzzle: normoKPP is actually a variant of hyperKPP and is not a distinct disorder.

  8. Compilation of Existing Neutron Screen Technology

    Directory of Open Access Journals (Sweden)

    N. Chrysanthopoulou

    2014-01-01

    Full Text Available The presence of fast neutron spectra in new reactors is expected to induce a strong impact on the contained materials, including structural materials, nuclear fuels, neutron reflecting materials, and tritium breeding materials. Therefore, introduction of these reactors into operation will require extensive testing of their components, which must be performed under neutronic conditions representative of those expected to prevail inside the reactor cores when in operation. Due to limited availability of fast reactors, testing of future reactor materials will mostly take place in water cooled material test reactors (MTRs by tailoring the neutron spectrum via neutron screens. The latter rely on the utilization of materials capable of absorbing neutrons at specific energy. A large but fragmented experience is available on that topic. In this work a comprehensive compilation of the existing neutron screen technology is attempted, focusing on neutron screens developed in order to locally enhance the fast over thermal neutron flux ratio in a reactor core.

  9. [The depression epidemic does not exist].

    Science.gov (United States)

    van der Feltz-Cornelis, Christina M

    2009-01-01

    There has been much discussion in the media about the question of the existence of a depression epidemic. This leads on to the questions of whether the social and economic approaches are adequate, and what the alternatives are. The concept of the disease 'depression' can be defined using a medical model, or from a patient's or a societal perspective. From a medical perspective, indeed a depression epidemic has ensued from the increased prosperity and the associated decompression of the mortality rate. Society responded with preventative measures and policies aimed at improving functioning in the workplace. However, patients with a major depressive disorder (MDD) who are eligible for treatment are often not motivated to take it up, or are undertreated. Research is necessary in order to explore what patients think about the identification and treatment of depression. The confusion regarding the concept of depression found in the media, needs to be cleared.

  10. Sustainability in the existing building stock

    DEFF Research Database (Denmark)

    Elle, Morten; Nielsen, Susanne Balslev; Hoffmann, Birgitte

    2005-01-01

    This paper explores the role of Facilities Management in the relation to sustainable development in the existing building stock. Facilities management is a concept still developing as the management of buildings are becoming more and more professional. Many recognize today that facilities...... management is a concept relevant to others than large companies. Managing the flows of energy and other resources is a part of facilities management, and an increased professionalism could lead to the reduction of the use of energy and water and the generation of waste and wastewater. This is, however......, QRWfacilities management’s most important contribution to sustainable development in the built environment. Space management is an essential tool in facilities management – and it could be considered a powerful tool in sustainable development; remembering that the building not being built is perhaps the most...

  11. The existence of a bug chasing subculture.

    Science.gov (United States)

    Moskowitz, David A; Roloff, Michael E

    2007-01-01

    This study attempted to authenticate the existence of a controversial subculture of gay men, the 'bug chasers', whose main attribute is an active desire to voluntarily contract the human immunodeficiency virus (HIV), and examine the tenacity with which this subculture actually searches for seroconversion. Using a quasi-randomized survey of personal profiles, bug chasers were compared against barebackers, a culture of gay men that practice intentional unprotected anal intercourse. Bug chasers were authenticated as an observable subculture of barebackers where most reported apathy to the serostatus of their partner or an active want of a serodiscordant partner, and a preference towards practicing unprotected anal intercourse. As anticipated, two subgroups with varying tenacities were found within the sample of bug chasers. Apathetic chasers were found only to be in search of partners with sero-ambiguous status. Ardent chasers were found only to be in search of certifiably serodiscordant partners.

  12. On the Existence of Spacetime Structure

    CERN Document Server

    Curiel, E

    2015-01-01

    I examine the debate between substantivalists and relationalists about the ontological character of spacetime and conclude it is not well posed. I argue that the so-called Hole Argument does not bear on the debate, because it provides no clear criterion to distinguish the positions. I propose two such precise criteria and construct separate arguments based on each to yield contrary conclusions, one supportive of something like relationalism and the other of something like substantivalism. The lesson is that one must fix an investigative context in order to make such criteria precise, but different investigative contexts yield inconsistent results. I examine questions of existence about spacetime structures other than the spacetime manifold itself to argue that it is more fruitful to focus on pragmatic issues of physicality, a notion that lends itself to several different explications, all of philosophical interest, none privileged a priori over any of the others. I conclude by suggesting an extension of the l...

  13. Co-existence in multispecies biofilm communities

    DEFF Research Database (Denmark)

    Røder, Henriette Lyng

    each other and in understanding the key mechanisms and interactions involved. In the introduction of this thesis the most important concepts of multi-species interactions and biofilm development are explained. After this the topic changes to the various ways of examining community interactions...... of member species increases. After this, various approaches taken by different studies when investigating multispecies communities are discussed, and different techniques for studying multispecies biofilm are described. In manuscript 2, a diverse group of bacteria was co-isolated from a meat processing...... the community. The increased biofilm biomass produced by the new wrinkled variant of X. retroflexus lead to a more positive or neutral co-existence with P. amylolyticus compared to the wild type X. retroflexus. Manuscript 6 investigated how a multispecies biofilm was affected from grazing by the heterotrophic...

  14. Does filial piety exist under Chinese communism?

    Science.gov (United States)

    Chow, N

    1991-01-01

    China has been known for centuries for its traditions of respecting the old. While this tradition has been weakened in the modern era, it still remains as the most important value underlying the practice of supporting the old in present-day China. This article looks into the meaning of filial piety, or xiao, and examines how it has been observed both in the old and modern times. It argues that though the Chinese communists have found filial piety ideologically repulsive, they have nevertheless tolerated it and even used it as the basis for a welfare network to support the elderly in the villages. However, in order to be truthful to their socialist ideology, they have also provided for urban workers the most sophisticated state-financed retirement benefits. Two different kinds of systems to support the elderly hence exist in China. The tensions resulting from this dichotomous situation are examined.

  15. Does the Kuleshov Effect Really Exist?

    DEFF Research Database (Denmark)

    Barratt, Daniel; Rédei, Anna Cabak; Innes-Ker, Åse

    2016-01-01

    of the target person in terms of valence, arousal, and category. The participants’ eye movements were recorded throughout. The results suggest that some sort of Kuleshov effect does in fact exist. For each emotional condition, the participants tended to choose the appropriate category more frequently than...... to replicate Kuleshov’s original experiment using an improved experimental design. In a behavioral and eye tracking study, 36 participants were each presented with 24 film sequences of neutral faces across six emotional conditions. For each film sequence, the participants were asked to evaluate the emotion...... the alternative options, while the answers to the valence and arousal questions also went in the expected directions. The eye tracking data showed how the participants attended to different regions of the target person’s face (in light of the intermediate context), but did not reveal the expected differences...

  16. The pastor as model for peaceful existence

    Directory of Open Access Journals (Sweden)

    Terence Cooke

    2011-06-01

    Full Text Available Many people are disillusioned in the democratic South Africa. That is because they went out from the assumption that with the dawn of democracy, violence would disappear. Unfortunately this did not happen. As with most things in life it is not an either � or, but a both � and scenario. In fact, violence is part of the democratic system. Real peace between men and powers can only be the peace of God, the peace which alone heals all disorder. The peace of the world is at best peaceful coexistence, not peace.In South Africa we have a negotiated agreement to peaceful coexistence, and sometimes, for example, after the miracle of the 1994 election and the euphoria of the World Cups of 1995, 2007 and 2010, we may even think we have achieved real peace. It is indeed in these times of euphoria that the people of South Africa may be tempted to lower our aim and settle for second best thinking that we have arrived.Model is used not in the sense of the pastor being an example of a peaceful existence to be followed. It is rather used in the sense that a pastor in his or her professional capacity has the knowledge of the meaning of the term �peaceful existence� and also the hermeneutic competency to apply that knowledge in concrete situations. This opens the exiting possibility that pastors can become travel companions on the road to real peace.The different aspects of being a pastor, office bearer, professional and person, each contribute to the pastor being a model for peace. It must be emphasised that the different aspects always work together as a unity and the strength of the pastor as a model for a peaceful existence is in the simultaneous application of these aspects in the context in which the pastor lives.

  17. KEEPERS OF INFORMATION OF ITS EXISTENCE REASONS

    Directory of Open Access Journals (Sweden)

    Y. M. Amirbegov

    2015-01-01

    Full Text Available The main subject of our research is all that is in our minds its concrete expression as objective forms of being, designated by the concept "matter", and on a range of factors of collation: curvature, polarity, tonality, length, height, width, frequency-order – by concept "form". Our goal - to find out why and how unstablemortal world, where “everything flows and everything changes”, stores information about these forms of being our knowledge of them. Researching the subject of our interest by dialectical method of reasoning, we concluded that the information about the forms of being saved by our knowledge because the elements of the molecular structures of our tissue cells - keepers of information of its existence reasons, as well as our tissue cells interspersed in generations, similar repeating the ontogeny of their predecessors, which preserves the structure of our brain tissue and preserving our knowledge. Following the intended purpose, we find that the principle of formation of matter forms in the causal stages of movement is one, whereas the quantitative and qualitative differences between the forms of becoming being are inexhaustible. Forms and patterns of life are mixed, some of which are centralized by unity (nucleus, others - no. Centralized structure (photon, atom, solar system, human tissue cell, man except complex of collation factors differ from decentralized (non-nuclear structures (stone, metal, clay, etc. that interspersed in generations, reproducing his likeness. About why the centralized by unity keepers of information of its existence reasons generated and generate their likeness, and what saves information about the forms of being of our knowledge, and will be discussed in this article.

  18. Energy consumptions in existing buildings; Les consommations d'energie des batiments existants

    Energy Technology Data Exchange (ETDEWEB)

    Nuss, St. [Ecole Nationale Superieure des Arts et Industries de Strasbourg, 78 - Saint-Remy-Les-Chevreuse (France)]|[Costic, 78 - Sainte Remy les Chevreuses (France)

    2002-05-01

    This document presents a sectoral analysis of the energy consumptions in existing French buildings: 1) - residential sector: social buildings, private dwellings; 2) - tertiary sector: office buildings, hotels, commercial buildings, school buildings, hospitals; 3) - industry; 4) - general status. (J.S.)

  19. THE EXISTENCE AND THE NON-EXISTENCE OF GLOBAL SOLUTIONS OF A FREE BOUNDARY PROBLEM

    Institute of Scientific and Technical Information of China (English)

    Yin Rong; Yu Wanghui

    2004-01-01

    We study a free boundary problem of parabolic equations with a pos-itive parameter τ included in the coefficient of the derivative with respect to the timevariable t. This problem arises from some reaction-diffusion system. We prove that, ifτ is large enough, the solution exists for 0 < t < +∞; while, if τ is small enough, thesolution exists only in finite time.

  20. GLP-1 Receptor Agonists

    Science.gov (United States)

    ... in Balance › GLP-1 Receptor Agonists Fact Sheet GLP-1 Receptor Agonists May, 2012 Download PDFs English Espanol Editors Silvio ... are too high or too low. What are GLP-1 receptor agonist medicines? GLP-1 receptor agonist medicines, also called ...

  1. Evidence of paired M2 muscarinic receptors

    Energy Technology Data Exchange (ETDEWEB)

    Potter, L.T.; Ballesteros, L.A.; Bichajian, L.H.; Ferrendelli, C.A.; Fisher, A.; Hanchett, H.E.; Zhang, R. (Univ. of Miami School of Medicine, FL (USA))

    1991-02-01

    Binding assays involving various antagonists, including N-(3H) methylscopolamine, (3H)quinuclidinyl benzilate, AFDX-116, pirenzepine, and propylbenzilylcholine mustard, disclosed only a single population of M2 muscarinic receptors in membranes from the rat brainstem (medulla, pons, and colliculi). However, competition curves between N-(3H)methylscopolamine and various agonists, including oxotremorine, cis-dioxolane, and acetylethylcholine mustard, showed approximately equal numbers of guanine nucleotide-sensitive high affinity (H) sites and guanine nucleotide-insensitive low affinity (L) sites. This 50% H phenomenon persisted in different buffers, at different temperatures, after the number of receptors was halved (and, thus, the remaining receptor to guanine nucleotide-binding protein ratio was doubled), after membrane solubilization with digitonin, and when rabbit cardiac membranes were used instead of rat brainstem membranes. Preferential occupation of H sites with acetylethylcholine mustard, and of L sites with quinuclidinyl benzilate or either mustard, yielded residual free receptor populations showing predominantly L and H sites, respectively. Low concentrations of (3H)-oxotremorine-M labeled only H sites, and the Bmax for these sites was 49% of the Bmax found with (3H)quinuclidinyl benzilate plus guanine nucleotide. These and other results are most consistent with the idea that H and L receptor sites exist on separate but dimeric receptor molecules and with the hypothesis that only the H receptors cycle between high and low affinity, depending upon interactions between this receptor molecule and a guanine nucleotide-binding protein.

  2. The delta opioid receptor tool box.

    Science.gov (United States)

    Vicente-Sanchez, Ana; Segura, Laura; Pradhan, Amynah A

    2016-12-03

    In recent years, the delta opioid receptor has attracted increasing interest as a target for the treatment of chronic pain and emotional disorders. Due to their therapeutic potential, numerous tools have been developed to study the delta opioid receptor from both a molecular and a functional perspective. This review summarizes the most commonly available tools, with an emphasis on their use and limitations. Here, we describe (1) the cell-based assays used to study the delta opioid receptor. (2) The features of several delta opioid receptor ligands, including peptide and non-peptide drugs. (3) The existing approaches to detect delta opioid receptors in fixed tissue, and debates that surround these techniques. (4) Behavioral assays used to study the in vivo effects of delta opioid receptor agonists; including locomotor stimulation and convulsions that are induced by some ligands, but not others. (5) The characterization of genetically modified mice used specifically to study the delta opioid receptor. Overall, this review aims to provide a guideline for the use of these tools with the final goal of increasing our understanding of delta opioid receptor physiology.

  3. ECOLOGICAL CONDITIONS OF EXISTENCE OF MYCOBACTERIA POPULATIONS

    Directory of Open Access Journals (Sweden)

    R. A. Nuratinov

    2014-01-01

    Full Text Available Abstract. Aim. Adaptation possibilities of mycobacteria in the conditions of existence in the external environment and habitats of animals and man are studied. Adaptation mechanisms, which have pathogenic mycobacteria, allow them to survive long and circulate in the environment, which leads to special sanitary and epidemiological value of pathogens of tuberculosis. Location. Russia, Dagestan.Results. Mycobacterium tuberculosis has a high resistance to influence of cold, heat, chemical and physical factors, moisture and light. They carry high and low temperatures, while more than a year pathogenic properties, and even more in the dark and without sunlight. It should be noted that the stability of pathogenic species of mycobacteria in the external environment is relatively lower than that of saprophytes, capable of quickly adapting to the external environment. Raonin’s groups have more widespread in environment, in water, soil, air, plants, and habitats of animals, products of plant and animal origin and their often isolated from clinical samples.Main conclusions. Environmental conditions define the intensity of habitats of any species of mycobacteria in certain landscapes and their circulation in macroorganism. The impact of the various elements of the environment both in the macro- and microorganisms is a response that was the basis for the development of the doctrine about “limiting factors”. This concept applies not only to the necessary for mycobacteria chemical elements, but also to all the other environmental factors (temperature, humidity, aeration conditions etc. Minimum and maximum intensity factors determine the limits of endurance species. Beyond these limits, due to sharply expressed extreme conditions and is portable microorganism existence of species is not possible. The most favorable for the species optimum intensity of environmental factors, usually occupied a middle position. This provision is significantly

  4. ProtoEXIST: advanced prototype CZT coded aperture telescopes for EXIST

    Science.gov (United States)

    Allen, Branden; Hong, Jaesub; Grindlay, Josh; Barthelmy, Scott D.; Baker, Robert G.; Gehrels, Neil A.; Garson, Trey; Krawczynski, Henric S.; Cook, Walter R.; Harrison, Fiona A.; Apple, Jeffrey A.; Ramsey, Brian D.

    2010-07-01

    ProtoEXIST1 is a pathfinder for the EXIST-HET, a coded aperture hard X-ray telescope with a 4.5 m2 CZT detector plane a 90x70 degree field of view to be flown as the primary instrument on the EXIST mission and is intended to monitor the full sky every 3 h in an effort to locate GRBs and other high energy transients. ProtoEXIST1 consists of a 256 cm2 tiled CZT detector plane containing 4096 pixels composed of an 8x8 array of individual 1.95 cm x 1.95 cm x 0.5 cm CZT detector modules each with a 8 x 8 pixilated anode configured as a coded aperture telescope with a fully coded 10° x 10° field of view employing passive side shielding and an active CsI anti-coincidence rear shield, recently completed its maiden flight out of Ft. Sumner, NM on the 9th of October 2009. During the duration of its 6 hour flight on-board calibration of the detector plane was carried out utilizing a single tagged 198.8 nCi Am-241 source along with the simultaneous measurement of the background spectrum and an observation of Cygnus X-1. Here we recount the events of the flight and report on the detector performance in a near space environment. We also briefly discuss ProtoEXIST2: the next stage of detector development which employs the NuSTAR ASIC enabling finer (32×32) anode pixilation. When completed ProtoEXIST2 will consist of a 256 cm2 tiled array and be flown simultaneously with the ProtoEXIST1 telescope.

  5. Does occupational health nursing exist in India?

    Directory of Open Access Journals (Sweden)

    Rajnarayan R Tiwari

    2014-01-01

    Full Text Available Background: Occupational health services are important to develop healthy and productive work forces, which should be delivered through occupational health team. Occupational health nurse (OHN is an important member of this team and is required to apply nursing principles in conserving the health of workers in occupational settings. Purpose: This article attempts to map the occupational health nursing courses in India and design competencies and curriculum for such a course. Materials and Methods: Information through the Internet, printed journals, and perspectives of the key stakeholders were the principal sources of data. Discussion: In India, there is a need to initiate a course on occupational health nursing to provide occupational health services for the organized and unorganized sector workforce. A certificate course for occupational health nursing for 3-4 months duration offered through contact session mode can be an opportune beginning. However, to cater employed nurses an online course can be another effective alternative. The theoretical part should essentially include modules on occupational diseases, industrial hygiene, and occupational health legislation, whereas the modules on practical aspects can include visits to industries. Taking into account the existing norms of Indian Factories Act for hazardous units of organized sector an estimated 1,34,640 OHNs are required. Conclusion: There is a need-supply gap in the number of occupational health nursing manpower in India, which can be attributed to the absence of any course to train such manpower.

  6. Existence dimension of media-educational space

    Directory of Open Access Journals (Sweden)

    B. V. Bratanich

    2014-03-01

    Full Text Available The world media culture is the everyday existential context of self­identity. Entry into the media culture turns and practice, and by the adequate development of the problem field of human existence. Education as a way to self­determine human ways and purposes of entry into the modern media culture in the field of communication and interaction with other people, mediated by electronic media. In the presence of global media space fundamental information plays a crucial role in socialization, is formed at the intersection of the education system and the electronic media, which gives grounds to determine exactly media­educational community primary medium of socialization in the age of online media. Media­ education environment creates more favorable conditions to educational activities has become a way of self­identity, as it results of creative activity of the subject taken by others as taking it himself, his personality. Its major advantage as space being is to provide the maximum activity of the individual in determining the trajectory of development. A common basis for resolving the risks socialization and being the person in the media education area are the values and goals of self­development, formulated within postmodern education.

  7. Seismic evaluation methods for existing buildings

    Energy Technology Data Exchange (ETDEWEB)

    Hsieh, B.J.

    1995-07-01

    Recent US Department of Energy natural phenomena hazards mitigation directives require the earthquake reassessment of existing hazardous facilities and general use structures. This applies also to structures located in accordance with the Uniform Building Code in Seismic Zone 0 where usually no consideration is given to seismic design, but where DOE specifies seismic hazard levels. An economical approach for performing such a seismic evaluation, which relies heavily on the use of preexistent structural analysis results is outlined below. Specifically, three different methods are used to estimate the seismic capacity of a building, which is a unit of a building complex located on a site considered low risk to earthquakes. For structures originally not seismically designed, which may not have or be able to prove sufficient capacity to meet new arbitrarily high seismic design requirement and which are located on low-seismicity sites, it may be very cost effective to perform detailed site-specific seismic hazard studies in order to establish the true seismic threat. This is particularly beneficial, to sites with many buildings and facilities to be seismically evaluated.

  8. Do cement nanoparticles exist in space ?

    CERN Document Server

    Bilalbegovic, G; Mohacek-Grosev, V

    2014-01-01

    The calcium-silicate-hydrate is used to model properties of cement on Earth. We study cementitious nanoparticles and propose these structures as components of cosmic dust grains. Quantum density functional theory methods are applied for the calculation of infrared spectra of Ca4Si4O14H4, Ca6Si3O13H2, and Ca12Si6O26H4 clusters. We find bands distributed over the near, mid and far-infrared region. A specific calcium-silicate-hydrate spectral feature at 14 microns, together with the bands at 10 and 18 microns which exist for other silicates as well, could be used for a detection of cosmic cement. We compare calculated bands with the 14 microns features in the spectra of HD 45677, HD 44179, and IRC+10420 which were observed by Infrared Space Observatory and classified as remaining. High abundance of oxygen atoms in cementitious nanoparticles could partially explain observed depletion of this element from the interstellar medium into dust grains.

  9. Expert system interaction with existing analysis codes

    Energy Technology Data Exchange (ETDEWEB)

    Ransom, V.H.; Fink, R.K.; Bertch, W.J.; Callow, R.A.

    1986-01-01

    Coupling expert systems with existing engineering analysis codes is a promising area in the field of artificial intelligence. The added intelligence can provide for easier and less costly use of the code and also reduce the potential for code misuse. This paper will discuss the methods available to allow interaction between an expert system and a large analysis code running on a mainframe. Concluding remarks will identify potential areas of expert system application with specific areas that are being considered in a current research program. The difficulty of interaction between an analysis code and an expert system is due to the incompatibility between the FORTRAN environment used for the analysis code and the AI environment used for the expert system. Three methods, excluding file transfer techniques, are discussed to help overcome this incompatibility. The first method is linking the FORTRAN routines to the LISP environment on the same computer. Various LISP dialects available on mainframes and their interlanguage communication capabilities are discussed. The second method involves network interaction between a LISP machine and a mainframe computer. Comparisons between the linking method and networking are noted. The third method involves the use of an expert system tool that is campatible with a FORTRAN environment. Several available tools are discussed. With the interaction methods identified, several potential application areas are considered. Selection of the specific areas that will be developed for the pilot project and applied to a thermal-hydraulic energy analysis code are noted.

  10. Modernization of existing VVER-1000 surveillance programs

    Energy Technology Data Exchange (ETDEWEB)

    Kochkin, V.; Erak, D.; Makhotin, D. [NRC ' Kurchatov Inst.' , 1 Kurchatov Square, Moscow 123182 (Russian Federation)

    2011-07-01

    According to generally accepted world practice, evaluation of the reactor pressure vessel (RPV) material behavior during operation is carried out using tests of surveillance specimens. The main objective of the surveillance program consists in insurance of safe RPV operation during the design lifetime and lifetime-extension period. At present, the approaches of pressure vessels residual life validation based on the test results of their surveillance specimens have been developed and introduced in Russia and are under consideration in other countries where vodo-vodyanoi energetichesky reactors- (VVER-) 1000 are in operation. In this case, it is necessary to ensure leading irradiation of surveillance specimens (as compared to the pressure vessel wall) and to provide uniformly irradiated specimen groups for mechanical testing. Standard surveillance program of VVER-1000 has several significant shortcomings and does not meet these requirements. Taking into account program of lifetime extension of VVER-1000 operating in Russia, it is necessary to carry out upgrading of the VVER-1000 surveillance program. This paper studies the conditions of a surveillance specimen's irradiation and upgrading of existing sets to provide monitoring and prognosis of RPV material properties for extension of the reactor's lifetime up to 60 years or more. (authors)

  11. Sharing information among existing data sources

    Science.gov (United States)

    Ashley, W. R., III

    1999-01-01

    The sharing of information between law enforcement agencies is a premise for the success of all jurisdictions. A wealth of information resides in both the databases and infrastructures of local, state, and regional agencies. However, this information is often not available to the law enforcement professionals who require it. When the information is, available, individual investigators must not only know that it exists, but where it resides, and how to retrieve it. In many cases, these types of cross-jurisdictional communications are limited to personal relationships that result from telephone calls, faxes, and in some cases, e-mail. As criminal elements become more sophisticated and distributed, law enforcement agencies must begin to develop infrastructures and common sharing mechanisms that address a constantly evolving criminal threat. Historically, criminals have taken advantage of the lack of communication between law enforcement agencies. Examples of this are evident in the search for stolen property and monetary dealings. Pawned property, cash transactions, and failure to supply child support are three common cross- jurisdictional crimes that could be better enforced by strengthening the lines of communication. Criminal behavior demonstrates that it is easier to profit from their actions by dealing in separate jurisdictions. For example, stolen property is sold outside of the jurisdiction of its origin. In most cases, simply traveling a short distance to the adjoining county or municipality is sufficient to ensure that apprehension of the criminal or seizure of the stolen property is highly unlikely. In addition to the traditional burglar, fugitives often sell or pawn property to finance their continued evasion from the law. Sharing of information in a rapid manner would increase the ability of law enforcement personnel to track and capture fugitives, as well as criminals. In an example to combat this threat, the State of Florida recently acted on the need to

  12. David Barker: the revolution that anticipates existence

    Directory of Open Access Journals (Sweden)

    Italo Farnetani

    2014-01-01

    Full Text Available David Barker is the man who “anticipated" the existence of babies by focusing attention on the importance of the fetus and what takes place during intrauterine life. Barker was one of the physicians who in the last decades brought about the greatest changes in medicine, changes so important as to represent a veritable revolution in medical thought. According to Barker's studies, the embryo obviously has a genetic complement coming from the mother and father, but from the very first stages of development it begins to undergo the influence of the outside environment, just as occurs for adults whose biological, psychological and pathological aspects are influenced by the environment to a not well-established percentage between genetic complement and epigenetics. Much of our future lives as adults is decided in our mothers' wombs. If Barker's discovery was revolutionary from the cultural standpoint, it was even more so from the strictly medical one. Barker's research method was rigid from the methodological standpoint, but innovative and speculative in its working hypotheses, with a humanistic slant. Barker's idea has another practical corollary: it is evident that the role of obstetricians, perinatologists and neonatologists is more and more relevant in medicine and future prevention. Unquestionably, besides the enormous merits of his clinical research, among the benefits that Barker has contributed there is that of having helped us to see things from new points of view. Not only is the neonate (and even more so the fetus not an adult of reduced proportions, but perhaps the neonate is the "father" of the adult person.

  13. Illness as a condition of our existence in the world: on illness and pathic existence.

    Science.gov (United States)

    Martinsen, Elin Håkonsen; Solbakk, Jan Helge

    2012-06-01

    This paper seeks to find different ways of addressing illness as an experience essential to the understanding of being a human being. As a conceptual point of departure, we suggest the notion of 'pathic existence' as developed by the German physician and philosopher Viktor von Weizsäcker (1886-1957). Through an analysis of his conceptualisation of the pathic and of pathic categories, we demonstrate how this auxiliary typology may be of help in unveiling different modes of ill-being, or Kranksein. Furthermore, we show how illness plays a paradigmatic role in this type of existence. We discuss how von Weizsäcker's claim of illness as "a way of being human" indicates how such a view of the illness existence both differs from and touches upon other streams of thought within the philosophy of medicine and medical ethics. Finally, we highlight some of the normative implications emerging from this perspective of relevance in today's medicine.

  14. A precariedade humana e a existência estilizada Human precariousness and stylized existence

    Directory of Open Access Journals (Sweden)

    Rita Paiva

    2013-04-01

    Full Text Available Este artigo tematiza o desamparo vivenciado pela consciência ante a ausência de bases sólidas para seus anseios de felicidade e para suas representações simbólicas. Com esse propósito, toma como objeto de reflexão um dos ensaios filosóficos de Albert Camus, O mito de Sísifo, equacionando a possibilidade de uma ética que estilize a vida, sem que se minimize a dolorosa precariedade da existência humana. Posteriormente, em diálogo com alguns textos de M. Foucault, a reflexão procura estabelecer os vínculos possíveis entre a ética camusiana e a ética como uma estética da existência, tal como pensada entre os gregos antigos.This article discusses the helplessness experienced by the consciousness vis-à-vis the absence of solid bases for its longings for happiness and for its symbolic representations. For this purpose, the object of reflection of the article is one of Albert Camus' philosophical essays, The Myth of Sisyphus, and we inquire into the possibility of an ethics that stylizes life without minimizing the painful precariousness of human existence. Making reference to certain texts by Foucault, we attempt to establish possible connections between Camus' ethics and an ethics of the aesthetics of existence as found in the thinkers of ancient Greece.

  15. ProtoEXIST: Advanced Prototype CZT Coded Aperture Telescopes for EXIST

    CERN Document Server

    Allen, Branden; Grindlay, Josh; Barthelmy, Scott D; Baker, Robert G; Gehrels, Neil A; Garson, Trey; Krawwczynski, Henric S; Cook, Walter R; Harrison, Fiona A; Apple, Jeffery A; Ramsey, Brian D; 10.1117/12.857940

    2010-01-01

    {\\it ProtoEXIST1} is a pathfinder for the {\\it EXIST-HET}, a coded aperture hard X-ray telescope with a 4.5 m$^2$ CZT detector plane a 90$\\times$70 degree field of view to be flown as the primary instrument on the {\\it EXIST} mission and is intended to monitor the full sky every 3 h in an effort to locate GRBs and other high energy transients. {\\it ProtoEXIST1} consists of a 256 cm$^2$ tiled CZT detector plane containing 4096 pixels composed of an 8$\\times$8 array of individual 1.95 cm $\\times$ 1.95 cm $\\times$ 0.5 cm CZT detector modules each with a 8 $\\times$ 8 pixilated anode configured as a coded aperture telescope with a fully coded $10^\\circ\\times10^\\circ$ field of view employing passive side shielding and an active CsI anti-coincidence rear shield, recently completed its maiden flight out of Ft. Sumner, NM on the 9th of October 2009. During the duration of its 6 hour flight on-board calibration of the detector plane was carried out utilizing a single tagged 198.8 nCi Am-241 source along with the simult...

  16. Solution assembly of cytokine receptor ectodomain complexes

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Zining; Ciardelli, T.L. [Dartmouth Medical School, Hanover, NH (United States). Dept. of Pharmacology and Toxicology; Johnson, K.W. [Chiron Corp., Emeryville, CA (United States)] [and others

    1995-09-01

    For the majority of single transmembrane-spanning cell surface receptors, signal transmission across the lipid bilayer barrier involves several discrete components of molecular recognition. The interaction between ligand and the extracellular segment of its cognate receptor (ectodomain) initiates either homomeric or heteromeric association of receptor subunits. Specific recognition among these subunits may then occur between ectodomain regions, within the membrane by interhelical contact or inside the cell between cytoplasmic domains. Any or all of these interactions may contribute to the stability of the signaling complex. It is the characteristics of ligand binding by the ectodomains of these receptors that controls the heteromeric or homomeric nature and the stoichiometry of the complex. Cytokines and their receptors belong to a growing family of macromolecular systems that exhibit these functional features and share many structural similarities as well. Interleukin-2 is a multifunctional cytokine that represents, perhaps, the most complex example to date of ligand recognition among the hematopoietin receptor family. It is the cooperative binding of IL-2 by all three proteins on the surface of activated T-lymphocytes, however, that ultimately results in crosslinking of the {beta}- and {gamma}-subunits and signaling via association of their cytoplasmic domains. Although the high-affinity IL-2R functions as a heterotrimer, heterodimers of the receptor subunits are also physiologically important. The {alpha}/{beta} heterodimer or {open_quotes}pseudo-high affinity{close_quotes} receptor captures IL-2 as a preformed cell surface complex while the {beta}/{gamma} intermediate affinity site exists, in the absence of the {alpha} subunit, on the majority of natural killer cells. We have begun to study stable complexes of cytokine receptor ectodomains of defined composition and that mimic the ligand binding characteristics of the equivalent cell surface receptor sites.

  17. Comparative biodistribution of 12 {sup 111}In-labelled gastrin/CCK2 receptor-targeting peptides

    Energy Technology Data Exchange (ETDEWEB)

    Laverman, Peter; Joosten, Lieke; Eek, Annemarie; Roosenburg, Susan; Oyen, Wim J.G.; Boerman, Otto C. [Radboud University Nijmegen Medical Centre, Department of Nuclear Medicine, Nijmegen (Netherlands); Peitl, Petra Kolenc [University Medical Centre Ljubljana, Department of Nuclear Medicine, Ljubljana (Slovenia); Maina, Theodosia [National Center for Scientific Research Demokritos, Molecular Radiopharmacy, Institute of Radioisotopes-Radiodiagnostic Products, Athens (Greece); Maecke, Helmut [University Hospital Freiburg, Department of Nuclear Medicine, Freiburg (Germany); Aloj, Luigi [Fondazione ' ' G. Pascale' ' , Department of Nuclear Medicine, Istituto Nazionale Tumouri, Naples (Italy); Guggenberg, Elisabeth von [Innsbruck Medical University, Department of Nuclear Medicine, Innsbruck (Austria); Sosabowski, Jane K. [Queen Mary, University of London, Centre for Molecular Oncology and Imaging, Institute of Cancer, Barts and The London School of Medicine and Dentistry, London (United Kingdom); Jong, Marion de [Erasmus MC, Department of Nuclear Medicine, Rotterdam (Netherlands); Reubi, Jean-Claude [University of Berne, Institute of Pathology, Berne (Switzerland)

    2011-08-15

    Cholecystokinin 2 (CCK-2) receptor overexpression has been demonstrated in various tumours such as medullary thyroid carcinomas and small-cell lung cancers. Due to this high expression, CCK-2 receptors might be suitable targets for radionuclide imaging and/or radionuclide therapy. Several CCK-2 receptor-binding radiopeptides have been developed and some have been tested in patients. Here we aimed to compare the in vivo tumour targeting properties of 12 {sup 111}In-labelled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated gastrin/CCK2 receptor-binding peptides. Two CCK8-based peptides and ten gastrin-based peptide analogues were tested. All peptides were conjugated with DOTA and labelled with {sup 111}In. Biodistribution studies were performed in mice with subcutaneous CCK2/gastrin receptor-expressing tumours and with receptor-negative tumours contralaterally. Biodistribution was studied by counting dissected tissues at 1 and 4 h after injection. Both the CCK analogues displayed relatively low tumour uptake (approximately 2.5%ID/g) as compared to minigastrin analogues. Two linear minigastrin peptides (MG0 and sargastrin) displayed moderate tumour uptake at both 1 and 4 h after injection, but also very high kidney uptake (both higher than 48%ID/g). The linear MG11, lacking the penta-Glu sequence, showed lower tumour uptake and also low kidney uptake. Varying the N-terminal Glu residues in the minigastrin analogues led to improved tumour targeting properties, with PP-F11 displaying the optimal biodistribution. Besides the monomeric linear peptides, a cyclized peptide and a divalent peptide were tested. Based on these studies, optimal peptides for peptide receptor radionuclide targeting of CCK2/gastrin receptor-expressing tumours were the linear minigastrin analogue with six D-Glu residues (PP-F11), the divalent analogue MGD5 and the cyclic peptide cyclo-MG1. These peptides combined high tumour uptake with low kidney retention, and may

  18. The role of NMDA and non-NMDA receptors in the NTS in mediating three distinct sympathoinhibitory reflexes.

    Science.gov (United States)

    Sartor, Daniela M; Verberne, Anthony J M

    2007-12-01

    Cholecystokinin (CCK) elicits a sympathetic vasomotor reflex that is implicated in gastrointestinal circulatory control. We sought to determine (1) the site in the solitary tract nucleus (NTS) responsible for mediating this reflex and (2) the possible involvement of excitatory amino acid (EAA) receptors. In addition, we sought to determine whether the NTS site responsible for mediating the baroreflex (phenylephrine, PE, 10 microg/kg i.v.) and the von Bezold-Jarisch reflex (phenylbiguanide, PBG, 10 microg/kg i.v) overlap with that involved in the CCK-induced reflex (CCK, 4 microg/kg, i.v.), and to compare the relative importance of NMDA and non-NDMA receptors in these reflexes. In separate experiments, the effects of PE, PBG, and CCK on mean arterial blood pressure, heart rate, and splanchnic sympathetic nerve discharge were tested before and after bilateral microinjection into the NTS of the gamma-aminobutyric acid(A) (GABA(A)) agonist muscimol, the EAA antagonist kynurenate, the NMDA receptor antagonist D: (-)-2-amino-5-phosphopentanoic acid (AP-5), the non-NMDA receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX), AP-5 + NBQX, or vehicle. While all treatments (except vehicle) significantly attenuated/abolished/reversed the splanchnic sympathoinhibitory responses to PE, PBG, and CCK, the extent of blockade varied between the different treatment groups. Both NMDA and non-NMDA receptors were essential to the baroreflex and the von Bezold-Jarisch reflex, whereas the CCK reflex was more dependent on non-NMDA receptors. Muscimol, kynurenate, and AP-5 + NBQX significantly attenuated the bradycardic responses to PE and PBG (P NTS responsible for eliciting all three reflexes, NMDA and non-NMDA receptors are recruited differentially for the full expression of these reflexes. The CCK-induced sympathoinhibitory reflex is unique in that it relies predominantly on non-NMDA receptors in the NTS and elicits bradycardic effects that

  19. GABA B receptor subunit expression in glia.

    Science.gov (United States)

    Charles, K J; Deuchars, J; Davies, C H; Pangalos, M N

    2003-09-01

    GABA(B) receptor subunits are widely expressed on neurons throughout the CNS, at both pre- and postsynaptic sites, where they mediate the late, slow component of the inhibitory response to the major inhibitory neurotransmitter GABA. The existence of functional GABA(B) receptors on nonneuronal cells has been reported previously, although the molecular composition of these receptors has not yet been described. Here we demonstrate for the first time, using immunohistochemistry the expression of GABA(B1a), GABA(B1b), and GABA(B2) on nonneuronal cells of the rat CNS. All three principle GABA(B) receptor subunits were expressed on these cells irrespective of whether they had been cultured or found within brain tissue sections. At the ultrastructural level GABA(B) receptor subunits were expressed on astrocytic processes surrounding both symmetrical and assymetrical synapses in the CA1 subregion of the hippocampus. In addition, GABA(B1a), GABA(B1b), and GABA(B2) receptor subunits were expressed on activated microglia in culture but were not found on myelin forming oligodendrocytes in the white matter of rat spinal cord. Together these data demonstrate that the obligate subunits of functional GABA(B) receptors are expressed in astrocytes and microglia in the rat CNS.

  20. Existence and non-existence results for a nonlinear heat equation

    Directory of Open Access Journals (Sweden)

    Canan Celik

    2007-02-01

    Full Text Available In this study, we consider the nonlinear heat equation $$displaylines{ u_{t}(x,t = Delta u(x,t + u(x,t^p quad hbox{in } Omega imes (0,T,cr Bu(x,t = 0 quad hbox{on } partialOmega imes (0,T,cr u(x,0 = u_0(x quad hbox{in } Omega,}$$ with Dirichlet and mixed boundary conditions, where $Omega subset mathbb{R}^n$ is a smooth bounded domain and $p = 1+ 2 /n$ is the critical exponent. For an initial condition $u_0 in L^1$, we prove the non-existence of local solution in $L^1$ for the mixed boundary condition. Our proof is based on comparison principle for Dirichlet and mixed boundary value problems. We also establish the global existence in $L^{1+epsilon}$ to the Dirichlet problem, for any fixed $epsilon > 0$ with $|u_0|_{1+epsilon}$ sufficiently small.